Unexpected evidence for active brown adipose tissue in adult humans (original) (raw)
International journal of endocrinology, 2013
In January 2012, Boström and colleagues identified a new muscle tissue secreted peptide, which they named irisin, to highlight its role as a messenger that comes from skeletal muscle to other parts of the body. Irisin is a cleaved and secreted fragment of FNDC5 (also known as FRCP2 and PeP), a member of fibronectin type III repeat containing gene family. Major interest in this protein arose because of its great therapeutic potential in diabetes and perhaps also therapy for obesity. Here we review the most important aspects of irisin's action and discuss its involvement in energy and metabolic homeostasis and whether the beneficial effects of exercise in these disease states could be mediated by this protein. In addition the effects of irisin at the central nervous system (CNS) are highlighted. It is concluded that although current and upcoming research on irisin is very promising it is still necessary to deepen in several aspects in order to clarify its full potential as a meani...
3,5-Diiodo-L-Thyronine Activates Brown Adipose Tissue Thermogenesis in Hypothyroid Rats
PLOS ONE, 2015
3,5-diiodo-l-thyronine (T2), a thyroid hormone derivative, is capable of increasing energy expenditure, as well as preventing high fat diet-induced overweight and related metabolic dysfunction. Most studies to date on T2 have been carried out on liver and skeletal muscle. Considering the role of brown adipose tissue (BAT) in energy and metabolic homeostasis, we explored whether T2 could activate BAT thermogenesis. Using euthyroid, hypothyroid, and T2-treated hypothyroid rats (all maintained at thermoneutrality) in morphological and functional studies, we found that hypothyroidism suppresses the maximal oxidative capacity of BAT and thermogenesis, as revealed by reduced mitochondrial content and respiration, enlarged cells and lipid droplets, and increased number of unilocular cells within the tissue. In vivo administration of T2 to hypothyroid rats activated BAT thermogenesis and increased the sympathetic innervation and vascularization of tissue. Likewise, T2 increased BAT oxidative capacity in vitro when added to BAT homogenates from hypothyroid rats. In vivo administration of T2 to hypothyroid rats enhanced mitochondrial respiration. Moreover, UCP1 seems to be a molecular determinant underlying the effect of T2 on mitochondrial thermogenesis. In fact, inhibition of mitochondrial respiration by GDP and its reactivation by fatty acids were greater in mitochondria from T2-treated hypothyroid rats than untreated hypothyroid rats. In vivo administration of T2 led to an increase in PGC-1α protein levels in nuclei (transient) and mitochondria (longer lasting), suggesting a coordinate effect of T2 in these organelles that ultimately promotes net activation of mitochondrial biogenesis and BAT thermogenesis. The effect of T2 on PGC-1α is similar to that elicited by triiodothyronine. As a whole, the data reported here indicate T2 is a thyroid hormone derivative able to activate BAT thermogenesis.
PLoS ONE, 2011
Mammal adipose tissues require mitochondrial activity for proper development and differentiation. The components of the mitochondrial respiratory chain/oxidative phosphorylation system (OXPHOS) are encoded by both mitochondrial and nuclear genomes. The maintenance of mitochondrial DNA (mtDNA) is a key element for a functional mitochondrial oxidative activity in mammalian cells. To ascertain the role of mtDNA levels in adipose tissue, we have analyzed the alterations in white (WAT) and brown (BAT) adipose tissues in thymidine kinase 2 (Tk2) H126N knockin mice, a model of TK2 deficiencyinduced mtDNA depletion. We observed respectively severe and moderate mtDNA depletion in TK2-deficient BAT and WAT, showing both tissues moderate hypotrophy and reduced fat accumulation. Electron microscopy revealed altered mitochondrial morphology in brown but not in white adipocytes from TK2-deficient mice. Although significant reduction in mtDNA-encoded transcripts was observed both in WAT and BAT, protein levels from distinct OXPHOS complexes were significantly reduced only in TK2-deficient BAT. Accordingly, the activity of cytochrome c oxidase was significantly lowered only in BAT from TK2-deficient mice. The analysis of transcripts encoding up to fourteen components of specific adipose tissue functions revealed that, in both TK2-deficient WAT and BAT, there was a consistent reduction of thermogenesis related gene expression and a severe reduction in leptin mRNA. Reduced levels of resistin mRNA were found in BAT from TK2-deficient mice. Analysis of serum indicated a dramatic reduction in circulating levels of leptin and resistin. In summary, our present study establishes that mtDNA depletion leads to a moderate impairment in mitochondrial respiratory function, especially in BAT, causes substantial alterations in WAT and BAT development, and has a profound impact in the endocrine properties of adipose tissues.
In Utero Programming of Later Adiposity: The Role of Fetal Growth Restriction
Journal of Pregnancy, 2012
Intrauterine growth restriction (IUGR) is strongly associated with obesity in adult life. The mechanisms contributing to the onset of IUGR-associated adult obesity have been studied in animal models and humans, where changes in fetal adipose tissue development, hormone levels and epigenome have been identified as principal areas of alteration leading to later life obesity. Following an adverse in utero development, IUGR fetuses display increased lipogenic and adipogenic capacity in adipocytes, hypoleptinemia, altered glucocorticoid signalling, and chromatin remodelling, which subsequently all contribute to an increased later life obesity risk. Data suggest that many of these changes result from an enhanced activity of the adipose master transcription factor regulator, peroxisome proliferator-activated receptor-γ (PPARγ) and its coregulators, increased lipogenic fatty acid synthase (FAS) expression and activity, and upregulation of glycolysis in fetal adipose tissue. Increased expression of fetal hypothalamic neuropeptide Y (NPY), altered hypothalamic leptin receptor expression and partitioning, reduced adipose noradrenergic sympathetic innervations, enhanced adipose glucocorticoid action, and modifications in methylation status in the promoter of hepatic and adipose adipogenic and lipogenic genes in the fetus also contribute to obesity following IUGR. Therefore, interventions that inhibit these fetal developmental changes will be beneficial for modulation of adult body fat accumulation.
Human Multipotent Adipose-Derived Stem Cells Differentiate into Functional Brown Adipocytes
Stem Cells, 2009
In contrast to the earlier contention, adult humans have been shown recently to possess active brown adipose tissue with a potential of being of metabolic significance. Up to now, brown fat precursor cells have not been available for human studies. We have shown previously that human multipotent adipose-derived stem (hMADS) cells exhibit a normal karyotype and high self-renewal ability; they are known to differentiate into cells that exhibit the key properties of human white adipocytes, that is, uncoupling protein two expression, insulin-stimulated glucose uptake, lipolysis in response to b-agonists and atrial natriuretic peptide, and release of adiponectin and leptin. Herein, we show that, upon chronic exposure to a specific PPARc but not to a PPARb/d or a PPARa agonist, hMADS cell-derived white adipocytes are able to switch to a brown phenotype by expressing both uncoupling protein one (UCP1) and CIDEA mRNA. This switch is accompanied by an increase in oxygen consumption and uncoupling. The expression of UCP1 protein is associated to stimulation of respiration by b-AR agonists, including b3-AR agonist. Thus, hMADS cells represent an invaluable cell model to screen for drugs stimulating the formation and/or the uncoupling capacity of human brown adipocytes that could help to dissipate excess caloric intake of individuals.
Early Life Nutritional Programming of Obesity: Mother-Child Cohort Studies
Annals of Nutrition and Metabolism, 2013
obese women are uncomplicated and result in offspring of normal weight, leaving the main determinants of later adverse outcomes to be clarified. Conclusions: The workshop provided insights of primary measurements for the characterization of sustainable nutritional intervention strategies in the mother, infant and child for preventing obesity in later life.
Genetic and functional characterization of clonally derived adult human brown adipocytes
Nature medicine, 2015
Brown adipose tissue (BAT) acts in mammals as a natural defense system against hypothermia, and its activation to a state of increased energy expenditure is believed to protect against the development of obesity. Even though the existence of BAT in adult humans has been widely appreciated, its cellular origin and molecular identity remain elusive largely because of high cellular heterogeneity within various adipose tissue depots. To understand the nature of adult human brown adipocytes at single cell resolution, we isolated clonally derived adipocytes from stromal vascular fractions of adult human BAT from two individuals and globally analyzed their molecular signatures. We used RNA sequencing followed by unbiased genome-wide expression analyses and found that a population of uncoupling protein 1 (UCP1)-positive human adipocytes possessed molecular signatures resembling those of a recruitable form of thermogenic adipocytes (that is, beige adipocytes). In addition, we identified mole...
Journal of Biological Chemistry, 2011
Brown adipose tissue has a central role in thermogenesis to maintain body temperature through energy dissipation in small mammals, and has recently been verified to function in adult humans as well. Here we demonstrate that the heart-type fatty acid binding protein, FABP3, is essential for cold tolerance and efficient fatty acid oxidation in mouse brown adipose tissue, despite the abundant expression of adipose-type fatty acid binding protein, FABP4 (also known as aP2). Fabp3 -/mice exhibit extreme cold sensitivity despite induction of uncoupling and oxidative genes, and hydrolysis of brown adipose tissue lipid stores. However, using FABP3 gain-and lossof-function approaches in brown adipocytes, we detected a correlation between FABP3 levels and the utilization of exogenous fatty acids. Thus, Fabp3 -/brown adipocytes fail to oxidize exogenously supplied fatty acids, whereas enhanced Fabp3 expression promotes more efficient oxidation. These results suggest that FABP3 levels are a determinant of fatty acid oxidation efficiency by brown adipose tissue, and that FABP3 represents a potential target for modulation of energy dissipation.
Brown adipose tissue: what have we learned since its recent identification in human adults
Arquivos Brasileiros de Endocrinologia & Metabologia, 2014
Brown adipose tissue, an essential organ for thermoregulation in small and hibernating mammals due to its mitochondrial uncoupling capacity, was until recently considered to be present in humans only in newborns. The identification of brown adipose tissue in adult humans since the development and use of positron emission tomography marked with 18-fluorodeoxyglucose (PET-FDG) has raised a series of doubts and questions about its real importance in our metabolism. In this review, we will discuss what we have learnt since its identification in humans as well as both new and old concepts, some of which have been marginalized for decades, such as diet-induced thermogenesis. Arq Bras Endocrinol Metab. 2014;58(9):889-99
A Genome Scan for Positive Selection in Thoroughbred Horses
PLoS ONE, 2009
Thoroughbred horses have been selected for exceptional racing performance resulting in system-wide structural and functional adaptations contributing to elite athletic phenotypes. Because selection has been recent and intense in a closed population that stems from a small number of founder animals Thoroughbreds represent a unique population within which to identify genomic contributions to exercise-related traits. Employing a population genetics-based hitchhiking mapping approach we performed a genome scan using 394 autosomal and X chromosome microsatellite loci and identified positively selected loci in the extreme tail-ends of the empirical distributions for (1) deviations from expected heterozygosity (Ewens-Watterson test) in Thoroughbred (n = 112) and global differentiation among four geographically diverse horse populations (F ST ). We found positively selected genomic regions in Thoroughbred enriched for phosphoinositide-mediated signalling (3.2-fold enrichment; P,0.01), insulin receptor signalling (5.0-fold enrichment; P,0.01) and lipid transport (2.2fold enrichment; P,0.05) genes. We found a significant overrepresentation of sarcoglycan complex (11.1-fold enrichment; P,0.05) and focal adhesion pathway (1.9-fold enrichment; P,0.01) genes highlighting the role for muscle strength and integrity in the Thoroughbred athletic phenotype. We report for the first time candidate athletic-performance genes within regions targeted by selection in Thoroughbred horses that are principally responsible for fatty acid oxidation, increased insulin sensitivity and muscle strength: ACSS1 (acyl-CoA synthetase short-chain family member 1), ACTA1 (actin, alpha 1, skeletal muscle), ACTN2 (actinin, alpha 2), ADHFE1 (alcohol dehydrogenase, iron containing, 1), MTFR1 (mitochondrial fission regulator 1), PDK4 (pyruvate dehydrogenase kinase, isozyme 4) and TNC (tenascin C). Understanding the genetic basis for exercise adaptation will be crucial for the identification of genes within the complex molecular networks underlying obesity and its consequential pathologies, such as type 2 diabetes. Therefore, we propose Thoroughbred as a novel in vivo large animal model for understanding molecular protection against metabolic disease.
In vivo noninvasive detection of Brown Adipose Tissue through intermolecular zero-quantum MRI
PloS one, 2013
The recent discovery of active Brown Adipose Tissue (BAT) in adult humans has opened new avenues for obesity research and treatment, as reduced BAT activity seem to be implicated in human energy imbalance, diabetes, and hypertension. However, clinical applications are currently limited by the lack of non-invasive tools for measuring mass and function of this tissue in humans. Here we present a new magnetic resonance imaging method based on the normally invisible intermolecular multiple-quantum coherence (1)H MR signal. This method, which doesn't require special hardware modifications, can be used to overcome partial volume effect, the major limitation of MR-based approaches that are currently being investigated for the detection of BAT in humans. With this method we can exploit the characteristic cellular structure of BAT to selectively image it, even when (as in humans) it is intimately mixed with other tissues. We demonstrate and validate this method in mice using PET scans an...
Evidence for two types of brown adipose tissue in humans
Nature Medicine, 2013
2 The previously observed supraclavicular depot of brown adipose tissue (BAT) in adult humans was commonly believed to be the equivalent of the interscapular thermogenic organ of small mammals. This view was very recently disputed by Wu et al., based on the demonstration that this depot is made up by beige or brite brown adipocytes -a newly identified type of brown adipocyte distinct from the classical brown adipocyte that makes up the interscapular thermogenic organ of other mammals. A combination of high resolution imaging techniques, histological and biochemical analyses enabled us to provide evidence for an anatomically distinguishable interscapular BAT depot in human infants that consists of classical brown adipocytes, a cell type so far not proven to exist in humans. Based on these findings, we conclude that infants, as rodents, possess the bona fide interscapular BAT thermogenic organ made up by classical brown adipocytes essential for the survival of small mammals in a cold environment.
Brown fat activation reduces hypercholesterolaemia and protects from atherosclerosis development
Nature communications, 2015
Brown adipose tissue (BAT) combusts high amounts of fatty acids, thereby lowering plasma triglyceride levels and reducing obesity. However, the precise role of BAT in plasma cholesterol metabolism and atherosclerosis development remains unclear. Here we show that BAT activation by β3-adrenergic receptor stimulation protects from atherosclerosis in hyperlipidemic APOE*3-Leiden.CETP mice, a well-established model for human-like lipoprotein metabolism that unlike hyperlipidemic Apoe(-/-) and Ldlr(-/-) mice expresses functional apoE and LDLR. BAT activation increases energy expenditure and decreases plasma triglyceride and cholesterol levels. Mechanistically, we demonstrate that BAT activation enhances the selective uptake of fatty acids from triglyceride-rich lipoproteins into BAT, subsequently accelerating the hepatic clearance of the cholesterol-enriched remnants. These effects depend on a functional hepatic apoE-LDLR clearance pathway as BAT activation in Apoe(-/-) and Ldlr(-/-) mic...
Fat mass- and obesity-associated gene Fto affects the dietary response in mouse white adipose tissue
Scientific reports, 2015
Common variants of human fat mass- and obesity-associated gene Fto have been linked with higher body mass index, but the biological explanation for the link has remained obscure. Recent findings suggest that these variants affect the homeobox protein IRX3. Here we report that FTO has a role in white adipose tissue which modifies its response to high-fat feeding. Wild type and Fto-deficient mice were exposed to standard or high-fat diet for 16 weeks after which metabolism, behavior and white adipose tissue morphology were analyzed together with adipokine levels and relative expression of genes regulating white adipose tissue adipogenesis and Irx3. Our results indicate that Fto deficiency increases the expression of genes related to adipogenesis preventing adipocytes from becoming hypertrophic after high-fat diet. In addition, we report a novel finding of increased Irx3 expression in Fto-deficient mice after high-fat feeding indicating a complex link between FTO, IRX3 and fat metabolism.
PLoS ONE, 2014
The recent discovery of active brown fat in human adults has led to renewed interest in the role of this key metabolic tissue. This is particularly true for neurodegenerative conditions like Huntington disease (HD), an adult-onset heritable disorder with a prominent energy deficit phenotype. Current methods for imaging brown adipose tissue (BAT) are in limited use because they are equipment-wise demanding and often prohibitively expensive. This prompted us to explore how a standard MRI set-up can be modified to visualize BAT in situ by taking advantage of its characteristic fat/water content ratio to differentiate it from surrounding white fat. We present a modified MRI protocol for use on an 11.7 T small animal MRI scanner to visualize and quantify BAT in wild-type and disease model laboratory mice. In this application study using the R6/2 transgenic mouse model of HD we demonstrate a significantly reduced BAT volume in HD mice vs. matched controls (n = 5 per group). This finding provides a plausible structural explanation for the previously described temperature phenotype of HD mice and underscores the significance of peripheral tissue pathology for the HD phenotype. On a more general level, the results demonstrate the feasibility of MR-based BAT imaging in rodents and open the path towards transferring this imaging approach to human patients. Future studies are needed to determine if this method can be used to track disease progression in HD and other disease entities associated with BAT abnormalities, including metabolic conditions such as obesity, cachexia, and diabetes. Citation: Lindenberg KS, Weydt P, Mü ller H-P, Bornstedt A, Ludolph AC, et al. (2014) Two-Point Magnitude MRI for Rapid Mapping of Brown Adipose Tissue and Its Application to the R6/2 Mouse Model of Huntington Disease. PLoS ONE 9(8): e105556.
Retinoic acid has different effects on UCP1 expression in mouse and human adipocytes
BMC Cell Biology, 2013
Background: Increased adipose thermogenesis is being considered as a strategy aimed at preventing or reversing obesity. Thus, regulation of the uncoupling protein 1 (UCP1) gene in human adipocytes is of significant interest. Retinoic acid (RA), the carboxylic acid form of vitamin A, displays agonist activity toward several nuclear hormone receptors, including RA receptors (RARs) and peroxisome proliferator-activated receptor δ (PPARδ). Moreover, RA is a potent positive regulator of UCP1 expression in mouse adipocytes.
PLoS One, 2014
Ephedrine/caffeine combination (EC) has been shown to induce a small-to-moderate weight loss in obese patients. Several mechanisms have been proposed, among which an increased thermogenic capacity of skeletal muscle consequent to the EC-induced up-regulation of uncoupling protein 3 (UCP3) gene expression. We did a parallel group double-blind, placebocontrolled, 4-week trial to investigate this hypothesis. Thirteen morbidly obese women (25-52 years of age, body-mass index 48.064.0 kg/m 2 , range 41.1-57.6) were randomly assigned to EC (200/20 mg, n = 6) or to placebo (n = 7) administered three times a day orally, before undergoing bariatric surgery. All individuals had an energy-deficit diet equal to about 70% of resting metabolic rate (RMR) diet (mean 576961105 kJ/day). The RMR analysed by intention to treat and the UCP3 (long and short isoform) mRNA levels in rectus abdominis were the primary outcomes. Body weight, plasma levels of adrenaline, noradrenaline, triglycerides, free fatty acids, glycerol, TSH, fT4, and fT3 were assessed, as well as fasting glucose, insulin and HOMA index, at baseline and at the end of treatments. Body weight loss was evident in both groups when compared to baseline values (overall 25.263.2%, p,0.0001) without significant differences between the treated groups. EC treatment increased the RMR (+9.266.8%, p = 0.020), differently from placebo which was linked to a reduction of RMR (27.666.5%, p = 0.029). No significant differences were seen in other metabolic parameters. Notably, no changes of either UCP3 short or UCP3 long isoform mRNA levels were evident between EC and placebo group. Our study provides evidence that 4-week EC administration resulted in a pronounced thermogenic effect not related to muscle UCP3 gene expression and weight loss in morbidly obese females under controlled conditions.
Proceedings of the Nutrition Society, 2014
Evidence suggests that at a population level, childhood and adolescent obesity increase the long-term risk of chronic diseases such as type 2 diabetes and CVD. At an individual level, however, the metabolic consequences of obesity in youth vary immensely. Despite comparable BMI, some adolescents develop impaired glucose tolerance while others maintain normal glucose homeostasis. It has been proposed that the variation in the capacity to store lipid in the subcutaneous adipose tissue (SAT) may partially discriminate metabolically healthy from unhealthy obesity. In positive energy balance, a decreased capacity to expand SAT may drive lipid accumulation to visceral adipose tissue, liver and skeletal muscle. This state of lipotoxicity is associated with chronic low-grade inflammation, insulin resistance and dyslipidaemia. The present review examines the differential adipose tissue development and function in children and adolescents who exhibit metabolic dysregulation compared with those who are protected. Additionally, the role of manipulating dietary fat quality to potentially prevent and treat metabolic dysfunction in obesity will be discussed. The findings of the present review highlight the need for further randomised controlled trials to establish the effect of dietary n-3 PUFA on the metabolic phenotype of obese children and adolescents. Furthermore, using a personalised nutrition approach to target interventions to those at risk of, or those with established metabolic dysregulation may optimise the efficacy of modifying dietary fat quality.
The adipose organ: white-brown adipocyte plasticity and metabolic inflammation
Obesity Reviews, 2012
White adipocytes can store energy, whereas brown adipocytes dissipate energy for thermogenesis. These two cell types with opposing functions are contained in multiple fat depots forming the adipose organ. In this review, we outline the plasticity of this organ in physiological (cold exposure, physical exercise and lactation) and pathological conditions (obesity). We also highlight molecules and signalling pathways involved in the browning phenomena of white adipose tissue. This phenotypic change has proved to be effective in the protection against the metabolic disorders associated to obesity and diabetes, not only because brown adipocytes are more 'healthy' than white adipocytes, but also because the simple size reduction of white adipocytes that characterizes the first steps of transdifferentiation can be useful in determining how to avoid triggering death based on critical size and the consequent chronic low-grade inflammation due to macrophage infiltration. Thus, a better understanding of the molecular mechanisms at the basis of white-brown transdifferentiation can be extremely useful to exploit new therapeutic strategies to combat the increasing incidence of metabolic diseases.
Obesity Affects Mitochondrial Citrate Synthase in Human Omental Adipose Tissue
ISRN Obesity, 2013
The activities of some key enzymes in mitochondria from 135 human omental adipose tissue samples of obese and nonobese patients were analyzed for potential association with the patients' state of obesity. The activities of respiratory complexes I and II as well as citrate synthase in isolated mitochondria were measured using spectrophotometric enzyme assays. ATP generation of mitochondria was determined with a bioluminescence assay. Protein levels of citrate synthase were quantified by western blot. The rates of ATP generation and the enzymatic activities of complexes I and II did not display associations with age, gender, obesity, or diabetes. By contrast, the enzymatic activities of citrate synthase and its protein levels were significantly reduced in obesity as compared to controls. In diabetic patients, protein levels but not enzymatic activities of citrate synthase were elevated. Thus, this investigation based on enzymatic assay and determination of protein levels revealed that the development of obesity is associated with a significant impact on citrate synthase in mitochondria of human omental adipose tissue. The state of obesity appears to affect mitochondrial function in human omental adipose tissue by limiting this key enzyme of the tricarboxylic acid cycle rather than by limiting the activities of respiratory chain enzymes.
2014
BACKGROUND: Maternal calorie restriction during pregnancy programs offspring for later overweight and metabolic disturbances. Brown adipose tissue (BAT) is responsible for non-shivering thermogenesis and has recently emerged as a very likely target for human obesity therapy. OBJECTIVE: Here we aimed to assess whether the detrimental effects of undernutrition during gestation could be related to impaired thermogenic capacity in BAT and to investigate the potential mechanisms involved. METHODS: Offspring of control and 20% calorie-restricted rats (days 1-12 of pregnancy) (CR) were studied at the age of 25 days. Protein levels of uncoupling protein 1 (UCP1) and tyrosine hydroxylase (TyrOH); mRNA levels of lipoprotein lipase (LPL), carnitine palmitoyltransferase 1 (CPT1) and deiodinase iodothyronine type II (DIO2) in BAT; and blood parameters including thyroid hormones, were determined. The response to 24-h cold exposure was also studied by measuring body temperature changes over time, and final BAT UCP1 levels. RESULTS: Compared with controls, CR animals displayed in BAT lower UCP1 and TyrOH protein levels and lower LPL and CPT1 mRNA levels; they also showed lower triiodothyronine (T3) plasma levels. CR males, but not females, revealed lower DIO2 mRNA levels than controls. When exposed to cold, CR rats experienced a transient decline in body temperature, but the values were reestablished after 24 h, despite having lower UCP1 levels than controls. CONCLUSIONS: These results suggest that BAT thermogenic capacity is diminished in CR animals, involving impaired BAT sympathetic innervation and thyroid hormone signaling. These alterations make animals more sensitive to cold and may contribute to long-term outcomes of gestational calorie restriction in promoting obesity and related metabolic alterations.
Hypothalamic AMP-activated protein kinase as a mediator of whole body energy balance
Reviews in Endocrine and Metabolic Disorders, 2011
The AMP-activated protein kinase (AMPK) is the downstream constituent of a kinase cascade that acts as a sensor of cellular energy levels. Current data unequivocally indicate that hypothalamic AMPK plays a key role in the control of the whole body energy balance, by integrating peripheral signals, such as hormones and metabolites, with central signals, such as neuropeptides, and eliciting allostatic changes in energy homeostasis. Although the molecular details of these interactions are not fully understood, recent evidence has suggested that the interaction between AMPK with hypothalamic lipid metabolism and other metabolic sensors, such as the uncoupling protein 2 (UCP-2), the mammalian target of rapamycin (mTOR) and the deacetylase sirtuin 1 (SIRT1), may play a main role in the hypothalamic control of feeding and energy expenditure. Here, we summarize the role of hypothalamic AMPK as whole body energy gauge. Understanding this key molecule and especially its functions at central level may provide new therapeutic targets for the treatment of metabolic alterations and obesity.
p62 Links β-adrenergic input to mitochondrial function and thermogenesis
Journal of Clinical Investigation, 2013
The scaffold protein p62 (sequestosome 1; SQSTM1) is an emerging key molecular link among the metabolic, immune, and proliferative processes of the cell. Here, we report that adipocyte-specific, but not CNS-, liver-, muscle-, or myeloid-specific p62-deficient mice are obese and exhibit a decreased metabolic rate caused by impaired nonshivering thermogenesis. Our results show that p62 regulates energy metabolism via control of mitochondrial function in brown adipose tissue (BAT). Accordingly, adipocyte-specific p62 deficiency led to impaired mitochondrial function, causing BAT to become unresponsive to β-adrenergic stimuli. Ablation of p62 leads to decreased activation of p38 targets, affecting signaling molecules that control mitochondrial function, such as ATF2, CREB, PGC1α, DIO2, NRF1, CYTC, COX2, ATP5β, and UCP1. p62 ablation in HIB1B and BAT primary cells demonstrated that p62 controls thermogenesis in a cell-autonomous manner, independently of brown adipocyte development or differentiation. Together, our data identify p62 as a novel regulator of mitochondrial function and brown fat thermogenesis.
The EMBO Journal, 2014
Adrenergic stimulation of brown adipocytes (BA) induces mitochondrial uncoupling, thereby increasing energy expenditure by shifting nutrient oxidation towards thermogenesis. Here we describe that mitochondrial dynamics is a physiological regulator of adrenergically-induced changes in energy expenditure. The sympathetic neurotransmitter Norepinephrine (NE) induced complete and rapid mitochondrial fragmentation in BA, characterized by Drp1 phosphorylation and Opa1 cleavage. Mechanistically, NE-mediated Drp1 phosphorylation was dependent on Protein Kinase-A (PKA) activity, whereas Opa1 cleavage required mitochondrial depolarization mediated by FFAs released as a result of lipolysis. This change in mitochondrial architecture was observed both in primary cultures and brown adipose tissue from cold-exposed mice. Mitochondrial uncoupling induced by NE in brown adipocytes was reduced by inhibition of mitochondrial fission through transient Drp1 DN overexpression. Furthermore, forced mitochondrial fragmentation in BA through Mfn2 knock down increased the capacity of exogenous FFAs to increase energy expenditure. These results suggest that, in addition to its ability to stimulate lipolysis, NE induces energy expenditure in BA by promoting mitochondrial fragmentation. Together these data reveal that adrenergically-induced changes to mitochondrial dynamics are required for BA thermogenic activation and for the control of energy expenditure.
Human mediastinal adipose tissue displays certain characteristics of brown fat
Nutrition & Diabetes, 2013
BACKGROUND: The amount of intra-thoracic fat, of which mediastinal adipose tissue comprises the major depot, is related to various cardiometabolic risk factors. Autopsy and imaging studies indicate that the mediastinal depot in adult humans could contain brown adipose tissue (BAT). To gain a better understanding of this intra-thoracic fat depot, we examined possible BAT characteristics of human mediastinal in comparison with subcutaneous adipose tissue. MATERIALS AND METHODS: Adipose tissue biopsies from thoracic subcutaneous and mediastinal depots were obtained during open-heart surgery from 33 subjects (26 male, 63.7 ± 13.8 years, body mass index 29.3 ± 5.1 kg m À 2 ). Microarray analysis was performed on 10 patients and genes of interest confirmed by quantitative PCR (qPCR) in samples from another group of 23 patients. Adipocyte size was determined and uncoupling protein 1 (UCP1) protein expression investigated with immunohistochemistry.
Brown adipose tissue as an anti-obesity tissue in humans
Obesity Reviews, 2014
During the 11th Stock Conference held in Montreal, Quebec, Canada, worldleading experts came together to present and discuss recent developments made in the field of brown adipose tissue biology. Owing to the vast capacity of brown adipose tissue for burning food energy in the process of thermogenesis, and due to demonstrations of its presence in adult humans, there is tremendous interest in targeting brown adipose tissue as an anti-obesity tissue in humans. However, the future of such therapeutic approaches relies on our understanding of the origin, development, recruitment, activation and regulation of brown adipose tissue in humans. As reviewed here, the 11th Stock Conference was organized around these themes to discuss the recent progress made in each aspect, to identify gaps in our current understanding and to further provide a common groundwork that could support collaborative efforts aimed at a future therapy for obesity, based on brown adipose tissue thermogenesis.
American journal of physiology. Endocrinology and metabolism, 2014
We applied digital gene expression profiling to determine the transcriptome of brown and white adipose tissues (BAT and WAT, respectively) during cold exposure. Male C57BL/6J mice were exposed to cold for 2 or 4 days. A notable induction of genes related to glucose uptake, glycolysis, glycogen metabolism and pentose phosphate pathway was observed in BAT from cold-exposed animals. In addition, glycerol-3-phosphate dehydrogenase 1 (Gpd1) expression was induced in BAT from cold-challenged mice, suggesting increased synthesis of glycerol from glucose. Similarly, expression of lactate dehydrogenases was induced by cold in BAT. Pyruvate dehydrogenase kinase 2 (Pdk2) and Pdk4 were expressed at significantly higher levels in BAT than in WAT, and Pdk2 was induced in BAT by cold. Of notice, only a subset of the changes detected in BAT was observed in WAT. Based on changes in gene expression during cold exposure, we propose a model for the intermediary glucose metabolism in activated BAT: 1) f...
The adipose organ of obesity-prone C57BL/6J mice is composed of mixed white and brown adipocytes
The Journal of Lipid Research, 2012
to occupy distinct anatomical sites in the body. However, previous work, mainly from our lab, supports the notion that WAT and BAT are in fact found together in subcutaneous and visceral fat depots, collectively forming a multidepot organ that we have called the "adipose organ" ( 4, 5 ). This fi nding has opened new perspectives in the physiological relationship between BAT and WAT, including the possibility of their reciprocal transformation (transdifferentiation) ( 6-8 ). Harnessing the mechanism of WAT to BAT transdifferentiation could be useful to develop treatments for obesity and type 2 diabetes, because the absence of BAT or its  adrenergic receptors results in obesity ( 9, 10 ) and transgenic mice overexpressing UCP1 in WAT are obesity resistant ( 11 ). Furthermore, treatment of obese rodents with  3 agonists increases BAT and curbs obesity ( 12, 13 ). Recently, metabolically active BAT has been described in adult humans. Of note, these subjects have a lower body mass index (BMI) and less visceral fat than those without detectable BAT ( 14-20 ). C57BL/6J mice are obesity-and type 2 diabetes-prone ( 21 ). In fact, earlier work has shown that C57BL/6J mice are more predisposed to store fat in response to a high-fat diet and to develop obesity, hyperglycemia, and hyperinsulinemia than their obesity-resistant A/J counterparts ( 22 ). Furthermore, it has been suggested that the obesity and diabetes resistance of A/J mice may be due to a strong increase in brown adipocytes in some "classic" white adipose depots after cold exposure or treatment with a  3 adrenergic agonist ( 23, 24 ). Also, a previous work by our group showed that intermuscular fat in the hind legs of C57BL/6J mice contains fewer brown adipocytes than the intermuscular fat of obesity-resistant Sv129 mice (substrain 129/SVPAS SPF/VAF), suggesting the possibility that a difference in BAT amount could explain the susceptibility to obesity and type 2 diabetes of C57BL/6J Abstract White and brown adipocytes are believed to occupy different sites in the body. We studied the anatomical features and quantitative histology of the fat depots in obesity and type 2 diabetes-prone C57BL/6J mice acclimated to warm or cold temperatures. Most of the fat tissue was contained in depots with discrete anatomical features, and most depots contained both white and brown adipocytes. Quantitative analysis showed that cold acclimation induced an increase in brown adipocytes and an almost equal reduction in white adipocytes; however, there were no signifi cant differences in total adipocyte count or any signs of apoptosis or mitosis, in line with the hypothesis of the direct transformation of white into brown adipocytes. The brown adipocyte increase was accompanied by enhanced density of noradrenergic parenchymal nerve fi bers, with a signifi cant correlation between the density of these fi bers and the number of brown adipocytes. Comparison with data from obesity-resistant Sv129 mice disclosed a signifi cantly different brown adipocyte content in C57BL/6J mice, suggesting that this feature could underpin the propensity of the latter strain to develop obesity. However, the greater C57BL/6J browning capacity can hopefully be harnessed to curb obesity and type 2 diabetes in patients with constitutively low amounts of brown adipose tissue. -Vitali, A., I. Murano, M. C. Zingaretti, A. Frontini, D. Ricquier, and S. Cinti. The adipose organ of obesity-prone C57BL/6J mice is composed of mixed white and brown adipocytes. J. Lipid Res. 2012. 53: 619-629.
ISMRM workshop on fat-water separation: Insights, applications and progress in MRI
Magnetic Resonance in Medicine, 2012
Approximately 130 attendees convened on February 19-22, 2012 for the first ISMRM-sponsored workshop on water-fat imaging. The motivation to host this meeting was driven by the increasing number of research publications on this topic over the past decade. The scientific program included an historical perspective and a discussion of the clinical relevance of water-fat MRI, a technical description of multiecho pulse sequences, a review of data acquisition and reconstruction algorithms, a summary of the confounding factors that influence quantitative fat measurements and the importance of MRI-based biomarkers, a description of applications in the heart, liver, pancreas, abdomen, spine, pelvis, and muscles, an overview of the implications of fat in diabetes and obesity, a discussion on MR spectroscopy, a review of childhood obesity, the efficacy of lifestyle interventional studies, and the role of brown adipose tissue, and an outlook on federal funding
The Journal of Lipid Research, 2014
We used noninvasive magnetic resonance imaging (MRI) and magnetic resonance spectroscopy to compare interscapular brown adipose tissue (iBAT) of wild-type (WT) and uncoupling protein 1 (UCP1)-knockout mice lacking UCP1-mediated nonshivering thermogenesis (NST). Mice were sequentially acclimated to an ambient temperature of 30°C, 18°C, and 5°C. We detected a remodeling of iBAT and a decrease in its lipid content in all mice during cold exposure. Ratios of energy-rich phosphates (ATP/ADP, phosphocreatine/ATP) in iBAT were maintained stable during noradrenergic stimulation of thermogenesis in cold- and warm-adapted mice and no difference between the genotypes was observed. As free fatty acids (FFAs) serve as fuel for thermogenesis and activate UCP1 for uncoupling of oxidative phosphorylation, brown adipose tissue is considered to be a main acceptor and consumer of FFAs. We measured a major loss of FFAs from iBAT during noradrenergic stimulation of thermogenesis. This mobilization of FFAs was observed in iBAT of WT mice as well as in mice lacking UCP1. The high turnover and the release of FFAs from iBAT suggests an enhancement of lipid metabolism, which in itself contributes to the sympathetically activated NST and which is independent from uncoupled respiration mediated by UCP1. Our study demonstrates that MRI, besides its potential for visualizing and quantification of fat tissue, is a valuable tool for monitoring functional in vivo processes like lipid and phosphate metabolism during NST.
Brown adipose tissue activity as a target for the treatment of obesity/insulin resistance
Frontiers in Physiology, 2015
Presence of brown adipose tissue (BAT), characterized by the expression of the thermogenic uncoupling protein 1 (UCP1), has recently been described in adult humans. UCP1 is expressed in classical brown adipocytes, as well as in "beige cells" in white adipose tissue (WAT). The thermogenic activity of BAT is mainly controlled by the sympathetic nervous system. Endocrine factors, such as fibroblast growth factor 21 (FGF21) and bone morphogenic protein factor-9 (BMP-9), predominantly produced in the liver, were shown to lead to activation of BAT thermogenesis, as well as to "browning" of WAT. This was also observed in response to irisin, a hormone secreted by skeletal muscles. Different approaches were used to delineate the impact of UCP1 on insulin sensitivity. When studied under thermoneutral conditions, UCP1 knockout mice exhibited markedly increased metabolic efficiency due to impaired thermogenesis. The impact of UCP1 deletion on insulin sensitivity in these mice was not reported. Conversely, several studies in both rodents and humans have shown that BAT activation (by cold exposure, β3-agonist treatment, transplantation and others) improves glucose tolerance and insulin sensitivity. Interestingly, similar results were obtained by adipose tissue-specific overexpression of PR-domain-containing 16 (PRDM16) or BMP4 in mice. The mediators of such beneficial effects seem to include FGF21, interleukin-6, BMP8B and prostaglandin D2 synthase. Interestingly, some of these molecules can be secreted by BAT itself, indicating the occurrence of autocrine effects. Stimulation of BAT activity and/or recruitment of UCP1-positive cells are therefore relevant targets for the treatment of obesity/type 2 diabetes in humans.
The Journal of Lipid Research, 2009
In these studies, we investigated the role of LMNA in adipose tissue by developing a novel mouse model of lipodystrophy. Transgenic mice were generated that express the LMNA mutation that causes familial partial lipodystrophy of the Dunnigan type (FPLD2). The phenotype observed in FPLD-transgenic mice resembles many of the features of human FPLD2 including lack of fat accumulation, insulin resistance, and enlarged, fatty liver. Similar to the human disease, FPLD2 transgenic mice appear to develop normally, but after several weeks are unable to accumulate fat to the same extent as their wild-type littermates. One poorly understood aspect of lipodystrophies is the mechanism of fat loss. To this end, we have examined the effects of the FPLD2 mutation on fat cell function. Contrary to the current literature, which suggests FPLD2 results in a loss of fat, we found that the key mechanism contributing to the lack of fat accumulation involves not a loss, but an apparent inability of the adipose tissue to renew itself. Specifically, preadipocytes are unable to differentiate into mature and fully functional adipocytes. These findings provide insights not only for the treatment of lipodystrophies, but also for the study of adipogenesis, obesity and insulin resistance.
The tumor suppressors pRB and p53 as regulators of adipocyte differentiation and function
Expert Opinion on Therapeutic Targets, 2009
Background : The retinoblastoma protein (pRB) and p53 are crucial members of regulatory networks controlling the cell cycle and apoptosis, and a hallmark of virtually all cancers is dysregulation of expression or function of pRB or p53. Although they are best known for their role in cancer development, it is now evident that both are implicated in metabolism and cellular development. Objective/methods : To review the role of pRB and p53 in adipocyte differentiation and function emphasizing that pRB and p53, via their effects on adipocyte development and function, play a role in the regulation of energy metabolism and homeostasis. Results/conclusions : pRB is required for adipose conversion and also involved in determining its mitochondrial capacity. p53 inhibits adipogenesis and results suggest that it is involved in maintaining function of adipose tissue.
Thermogenic brown and beige/brite adipogenesis in humans
Annals of Medicine, 2014
Evidence from rodents established an important role of brown adipose tissue (BAT) in energy expenditure. Moreover, to sustain thermogenesis, BAT has been shown to be a powerful sink for draining and oxidation of glucose and triglycerides from blood. The potential of BAT activity in protection against obesity and metabolic syndrome is recognized. Recently, an unexpected presence and activity of BAT has been found in adult humans. Here we review the most recent research in this fi eld and, specifically, how new fi ndings apply to humans. Moreover, we seek to clarify the underlying biological processes occurring beyond the burst of new nomenclature in the fi eld. The cell type responsible for thermogenesis, the brown adipocyte, arises from complex developmental processes. In addition to ' classical ' brown adipocytes, present in developmentally programmed BAT depots, there are brown adipocytes, named ' brite ' (from ' brown-in-white ' ) or ' beige ' , which appear in response to thermogenic stimuli in white fat due to the so-called ' browning ' process. Beige/brite cells appear to be important components of BAT depots in adult humans. In addition to the known control of BAT activity by the sympathetic nervous system, metabolic and hormonal signals originating in muscle or liver (e.g. irisin, FGF21) are recognized as activators of BAT and beige/brite adipocytes.
Identification of inducible brown adipocyte progenitors residing in skeletal muscle and white fat
Proceedings of the National Academy of Sciences, 2011
Brown fat is specialized for energy expenditure and has therefore been proposed to function as a defense against obesity. Despite recent advances in delineating the transcriptional regulation of brown adipocyte differentiation, cellular lineage specification and developmental cues specifying brown-fat cell fate remain poorly understood. In this study, we identify and isolate a subpopulation of adipogenic progenitors (Sca-1 + /CD45 − /Mac1 − ; referred to as Sca-1 + progenitor cells, ScaPCs) residing in murine brown fat, white fat, and skeletal muscle. ScaPCs derived from different tissues possess unique molecular expression signatures and adipogenic capacities. Importantly, although the ScaPCs from interscapular brown adipose tissue (BAT) are constitutively committed brown-fat progenitors, Sca-1 + cells from skeletal muscle and subcutaneous white fat are highly inducible to differentiate into brown-like adipocytes upon stimulation with bone morphogenetic protein 7 (BMP7). Consistent with these findings, human preadipocytes isolated from subcutaneous white fat also exhibit the greatest inducible capacity to become brown adipocytes compared with cells isolated from mesenteric or omental white fat. When muscle-resident ScaPCs are re-engrafted into skeletal muscle of syngeneic mice, BMP7-treated ScaPCs efficiently develop into adipose tissue with brown fat-specific characteristics. Importantly, ScaPCs from obesity-resistant mice exhibit markedly higher thermogenic capacity compared with cells isolated from obesity-prone mice. These data establish the molecular characteristics of tissue-resident adipose progenitors and demonstrate a dynamic interplay between these progenitors and inductive signals that act in concert to specify brown adipocyte development.
PLoS ONE, 2011
There are few diagnostic tools for chronic musculoskeletal pain as structural imaging methods seldom reveal pathological alterations. This is especially true for Whiplash Associated Disorder, for which physical signs of persistent injuries to the neck have yet to be established. Here, we sought to visualize inflammatory processes in the neck region by means Positron Emission Tomography using the tracer 11 C-D-deprenyl, a potential marker for inflammation. Twenty-two patients with enduring pain after a rear impact car accident (Whiplash Associated Disorder grade II) and 14 healthy controls were investigated. Patients displayed significantly elevated tracer uptake in the neck, particularly in regions around the spineous process of the second cervical vertebra. This suggests that whiplash patients have signs of local persistent peripheral tissue inflammation, which may potentially serve as a diagnostic biomarker. The present investigation demonstrates that painful processes in the periphery can be objectively visualized and quantified with PET and that 11 C-D-deprenyl is a promising tracer for these purposes. Citation: Linnman C, Appel L, Fredrikson M, Gordh T, Sö derlund A, et al. (2011) Elevated [11C]-D-Deprenyl Uptake in Chronic Whiplash Associated Disorder Suggests Persistent Musculoskeletal Inflammation. PLoS ONE 6(4): e19182.
Mitochondrial uncoupling proteins and energy metabolism
Frontiers in Physiology, 2015
Understanding the metabolic factors that contribute to energy metabolism (EM) is critical for the development of new treatments for obesity and related diseases. Mitochondrial oxidative phosphorylation is not perfectly coupled to ATP synthesis, and the process of proton-leak plays a crucial role. Proton-leak accounts for a significant part of the resting metabolic rate (RMR) and therefore enhancement of this process represents a potential target for obesity treatment. Since their discovery, uncoupling proteins have stimulated great interest due to their involvement in mitochondrial-inducible proton-leak. Despite the widely accepted uncoupling/thermogenic effect of uncoupling protein one (UCP 1 ), which was the first in this family to be discovered, the reactions catalyzed by its homolog UCP 3 and the physiological role remain under debate. This review provides an overview of the role played by UCP 1 and UCP 3 in mitochondrial uncoupling/functionality as well as EM and suggests that they are a potential therapeutic target for treating obesity and its related diseases such as type II diabetes mellitus.
Brown adipose tissue: Recent insights into development, metabolic function and therapeutic potential
Adipocyte, 2012
Obesity is currently a global pandemic, and is associated with increased mortality and co-morbidities including many metabolic diseases. Obesity is characterized by an increase in adipose mass due to increased energy intake, decreased energy expenditure, or both. While white adipose tissue is specialized for energy storage, brown adipose tissue has a high concentration of mitochondria and uniquely expresses uncoupling protein 1, enabling it to be specialized for energy expenditure and thermogenesis. Although brown fat was once considered only necessary in babies, recent morphological and imaging studies have provided evidence that, contrary to prior belief, this tissue is present and active in adult humans. In recent years, the topic of brown adipose tissue has been reinvigorated with many new studies regarding brown adipose tissue differentiation, function and therapeutic promise. This review summarizes the recent advances, discusses the emerging questions and offers perspective on...
Hypertension Research, 2012
Obesity has a profound adverse impact on health. In this study, we present evidence for high-fat diet (HFD)-induced emergence of brown-like adipocytes in white adipose tissue (WAT) of the spontaneously hypertensive rat (SHR). We studied adult males fed a HFD or normal diet (ND) for 12 weeks. At the end of the 12-week dietary intervention, HFD compared with ND rats showed significantly higher whole-body energy expenditure. HFD vs. ND rats also showed higher expression of genes involved in fatty acid oxidation, mitochondrial biogenesis and brown fat adipogenesis, as well as augmented mitochondrial mass in WAT but not in the liver or skeletal muscle. Consistent with the molecular changes, in HFD but not in ND rats, histological and immunohistochemistry-based analyses of WAT demonstrated the presence of small multilocular cells staining positively for uncoupling protein 1, indicating the emergence of brown-like adipocytes in WAT. Our results suggest that SHR may have the capacity to increase energy expenditure in response to a chronic HFD that may be linked to the emergence of brown-like adipocytes in WAT. Thus, the SHR may be an important genetic model to uncover novel mechanisms of resistance to dietary obesity.
Comprehensive molecular characterization of human adipocytes reveals a transient brown phenotype
Journal of translational medicine, 2015
Functional brown adipose tissue (BAT), involved in energy expenditure, has recently been detected in substantial amounts in adults. Formerly overlooked BAT has now become an attractive anti-obesity target. Molecular characterization of human brown and white adipocytes, using a myriad of techniques including high-throughput RNA sequencing and functional assays, showed that PAZ6 and SW872 cells exhibit classical molecular and phenotypic markers of brown and white adipocytes, respectively. However, the pre-adipocyte cell line SGBS presents a versatile phenotype. A transit expression of classical brown markers such as UCP1 and PPARγ peaked and declined at day 28 post-differentiation initiation. Conversely, white adipocyte markers, including Tcf21, showed reciprocal behavior. Interestingly, leptin levels peaked at day 28 whereas the highest adiponectin mRNA levels were detected at day 14 of differentiation. Phenotypic analysis of the abundance and shape of lipid droplets were consistent ...
Could increased time spent in a thermal comfort zone contribute to population increases in obesity?
Obesity Reviews, 2011
Domestic winter indoor temperatures in the USA, UK and other developed countries appear to be following an upwards trend. This review examines evidence of a causal link between thermal exposures and increases in obesity prevalence, focusing on acute and longer-term biological effects of time spent in thermal comfort compared with mild cold. Reduced exposure to seasonal cold may have a dual effect on energy expenditure, both minimizing the need for physiological thermogenesis and reducing thermogenic capacity. Experimental studies show a graded association between acute mild cold and human energy expenditure over the range of temperatures relevant to indoor heating trends. Meanwhile, recent studies of the role of brown adipose tissue (BAT) in human thermogenesis suggest that increased time spent in conditions of thermal comfort can lead to a loss of BAT and reduced thermogenic capacity. Pathways linking cold exposure and adiposity have not been directly tested in humans. Research in naturalistic and experimental settings is needed to establish effects of changes in thermal exposures on weight, which may raise possibilities for novel public health strategies to address obesity.
Does Adipose Tissue Thermogenesis Play a Role in Metabolic Health?
Journal of Obesity, 2013
The function ascribed to brown adipose tissue in humans has long been confined to thermoregulation in neonates, where this thermogenic capacity was thought lost with maturation. Recently, brown adipose tissue depots have been identified in adult humans. The significant oxidative capacity of brown adipocytes and the ability of their mitochondria to respire independently of ATP production, has led to renewed interest in the role that these adipocytes play in human energy metabolism. In our view, there is a need for robust physiological studies determining the relationship between molecular signatures of brown adipose tissue, adipose tissue mitochondrial function, and whole body energy metabolism, in order to elucidate the significance of thermogenic adipose tissue in humans. Until such information is available, the role of thermogenic adipose tissue in human metabolism and the potential that these adipocytes may prevent or treat obesity and metabolic diseases in humans will remain unknown. In this article, we summarize the recent literature pertaining to brown adipose tissue function with the aims of drawing the readers' attention to the lack of data concerning the role of brown adipocytes in human physiology, and to the potential limitations of current research strategies.
Central control of thermogenesis in mammals
Experimental Physiology, 2008
Thermogenesis, the production of heat energy, is an essential component of the homeostatic repertoire to maintain body temperature in mammals and birds during the challenge of low environmental temperature and plays a key role in elevating body temperature during the febrile response to infection. The primary sources of neurally regulated metabolic heat production are mitochondrial oxidation in brown adipose tissue, increases in heart rate and shivering in skeletal muscle. Thermogenesis is regulated in each of these tissues by parallel networks in the central nervous system, which respond to feedforward afferent signals from cutaneous and core body thermoreceptors and to feedback signals from brain thermosensitive neurons to activate the appropriate sympathetic and somatic efferents. This review summarizes the research leading to a model of the feedforward reflex pathway through which environmental cold stimulates thermogenesis and discusses the influence on this thermoregulatory network of the pyrogenic mediator, prostaglandin E 2 , to increase body temperature. The cold thermal afferent circuit from cutaneous thermal receptors ascends via second-order thermosensory neurons in the dorsal horn of the spinal cord to activate neurons in the lateral parabrachial nucleus, which drive GABAergic interneurons in the preoptic area to inhibit warm-sensitive, inhibitory output neurons of the preoptic area. The resulting disinhibition of thermogenesis-promoting neurons in the dorsomedial hypothalamus and possibly of sympathetic and somatic premotor neurons in the rostral ventromedial medulla, including the raphe pallidus, activates excitatory inputs to spinal sympathetic and somatic motor circuits to drive thermogenesis.
British Journal of Pharmacology, 2010
Background and purpose: Melanin-concentrating hormone (MCH) is an orexigenic neuropeptide expressed in the lateral hypothalamus that is involved in feeding and body weight regulation. Intracerebroventricular infusion of a peptidic MCH1 receptor antagonist ameliorated obesity in murine models. Recently, small molecule MCH1 receptor antagonists have been developed and characterized for the treatment of obesity. However, little is known of the mechanism of the anti-obesity effects of MCH1 receptor antagonists. Experimental approach: To examine the mechanisms of action of the anti-obesity effect of MCH1 receptor antagonists more precisely, we conducted a pair-feeding study in mice with diet-induced obesity (DIO), chronically treated with an orally active and highly selective MCH1 receptor antagonist and examined changes in mRNA expression levels in liver, brown and white adipose tissues. We also assessed the acute effects of the MCH1 receptor antagonist in energy expenditure under thermoneutral conditions. Key results: Treatment with the MCH1 receptor antagonist at 30 mg·kg -1 for 1 month moderately suppressed feeding and significantly reduced body weight by 24%. In contrast, pair-feeding resulted in a smaller weight reduction of 10%. Treatment with the MCH1 receptor antagonist resulted in a higher body temperature compared with the pair-fed group. TaqMan and calorimetry data suggested that the MCH1 receptor antagonist also stimulated thermogenesis.
Scientific reports, 2017
Obesity is associated with severe metabolic diseases such as type 2 diabetes, insulin resistance, cardiovascular disease and some forms of cancer. The pathophysiology of obesity-induced metabolic diseases has been strongly related to white adipose tissue (WAT) dysfunction through several mechanisms such as fibrosis, apoptosis, inflammation, ER and oxidative stress. However, little is known of whether these processes are also present in brown adipose tissue (BAT) during obesity, and the potential consequences on mitochondrial activity. Here we characterized the BAT of obese and hyperglycemic mice treated with a high-fat diet (HFD) for 20 weeks. The hypertrophic BAT from obese mice showed no signs of fibrosis nor apoptosis, but higher levels of inflammation, ER stress, ROS generation and antioxidant enzyme activity than the lean counterparts. The response was attenuated compared with obesity-induced WAT derangements, which suggests that BAT is more resistant to the obesity-induced ins...
Physiological Reports
The DMH is known to regulate brown adipose tissue (BAT) thermogenesis via projections to sympathetic premotor neurons in the raphe pallidus, but there is evidence that the periaqueductal gray (PAG) is also an important relay in the descending pathways regulating thermogenesis. The anatomical projections from the DMH to the PAG subdivisions and their function are largely elusive, and may differ per anterior-posterior level from bregma. We here aimed to investigate the anatomical projections from the DMH to the PAG along the entire anterior-posterior axis of the PAG, and to study the role of these projections in thermogenesis in Wistar rats. Anterograde channel rhodopsin viral tracing showed that the DMH projects especially to the dorsal and lateral PAG. Retrograde rabies viral tracing confirmed this, but also indicated that the PAG receives a diffuse input from the DMH and adjacent hypothalamic subregions. We aimed to study the role of the identified DMH to PAG projections in thermogenesis in conscious rats by specifically activating them using a combination of canine adenovirus-2 (CAV2Cre) and Credependent designer receptor exclusively activated by designer drugs (DREADD) technology. Chemogenetic activation of DMH to PAG projections increased BAT temperature and core body temperature, but we cannot exclude the possibility that at least some thermogenic effects were mediated by adjacent hypothalamic subregions due to difficulties in specifically targeting the DMH and distinct subdivisions of the PAG because of diffuse virus expression. To conclude, our study shows the complexity of the anatomical and functional connection between the hypothalamus and the PAG, and some technical challenges in studying their connection.
Optical visualisation of thermogenesis in stimulated single-cell brown adipocytes
Scientific reports, 2017
The identification of brown adipose deposits in adults has led to significant interest in targeting this metabolically active tissue for treatment of obesity and diabetes. Improved methods for the direct measurement of heat production as the signature function of brown adipocytes (BAs), particularly at the single cell level, would be of substantial benefit to these ongoing efforts. Here, we report the first application of a small molecule-type thermosensitive fluorescent dye, ERthermAC, to monitor thermogenesis in BAs derived from murine brown fat precursors and in human brown fat cells differentiated from human neck brown preadipocytes. ERthermAC accumulated in the endoplasmic reticulum of BAs and displayed a marked change in fluorescence intensity in response to adrenergic stimulation of cells, which corresponded to temperature change. ERthermAC fluorescence intensity profiles were congruent with mitochondrial depolarisation events visualised by the JC-1 probe. Moreover, the avera...
Asymmetric perirenal brown adipose dormancy in adult humans is defined by local sympathetic activity
We here detect dormant brown adipose tissue (BAT) in adult humans, occurring in most of the perirenal fat depot and characterized by a unilocular morphology. This phenotype was contrasted by multilocular BAT accumulating near the adrenal gland. Transcriptomic analysis revealed a gene expression profile of unilocular BAT that was approaching, yet was still distinct from, the expression profile of subcutaneous white adipose tissue (WAT). Candidate gene signatures were recapitulated in a murine model of unilocular brown fat induced by thermoneutrality and high fat diet. We identified SPARC as a candidate adipokine representing a dormant BAT state in the absence of sympathetic activation and CLSTN3 as a novel marker for multilocular BAT. Brown fat precursor cells were present in the entire perirenal fat depot, regardless of state. When differentiated in vitro, these cells responded to acute norepinephrine stimulation by increasing UCP1 gene expression and uncoupled respiration, confirmi...
PLOS ONE, 2015
Brown adipose tissue (BAT) thermogenesis is an emerging target for prevention and treatment of obesity. Mitochondria are the heat generators of BAT. Yet, there is no noninvasive means to image the temporal dynamics of the mitochondrial activity in BAT in vivo. Here, we report a technology for quantitative monitoring of principal kinetic components of BAT adaptive thermogenesis in the living animal, using the PET imaging voltage sensor 18 Ffluorobenzyltriphenylphosphonium (18 F-FBnTP). 18 F-FBnTP targets the mitochondrial membrane potential (ΔΨm)-the voltage analog of heat produced by mitochondria. Dynamic 18 F-FBnTP PET imaging of rat's BAT was acquired just before and during localized skin cooling or systemic pharmacologic stimulation, with and without administration of propranolol. At ambient temperature, 18 F-FBnTP demonstrated rapid uptake and prolonged steadystate retention in BAT. Conversely, cold-induced mitochondrial uncoupling resulted in an immediate washout of 18 F-FBnTP from BAT, which was blocked by propranolol. Specific variables of BAT evoked activity were identified and quantified, including response latency, magnitude and kinetics. Cold stimulation resulted in partial washout of 18 F-FBnTP (39.1% ±14.4% of basal activity). The bulk of 18 F-FBnTP washout response occurred within the first minutes of the cold stimulation, while colonic temperature remained nearly intact. Drop of colonic temperature to shivering zone did not have an additive effect. The ß3-adrenergic agonist CL-316,243 elicited 18 F-FBnTP washout from BAT of kinetics similar to those caused by cold stimulation. Thus, monitoring ΔΨm in vivo using 18 F-FBnTP PET provides insights into the kinetic physiology of BAT. 18 F-FBnTP PET depicts BAT as a highly sensitive and rapidly responsive organ, emitting heat in short burst during the first minutes of stimulation, and preceding change in core temperature. 18 F-FBnTP PET provides a novel set of quantitative metrics highly important for identifying novel therapeutic targets at the mitochondrial level, for developing means to maximize BAT mass and activity, and assessing intervention efficacy.
Sympathetic innervation of the interscapular brown adipose tissue in mouse
Annals of the New York Academy of Sciences
The recent discovery of significant brown fat depots in adult humans has revived discussion of exploiting brown fat thermogenesis in the control of energy balance and body weight. The sympathetic nervous system (SNS) has a key role in the activation of brown fat and functional mapping of its components will be crucial for the development of specific neuromodulation techniques. The mouse is an important species used for molecular genetic modulations, but its small size is not ideal for anatomical dissections, thus brown fat innervation studies are mostly available in larger rodents such as rats and hamsters. Here, we use pseudorabies virus retrograde tracing, whole tissue clearing, and confocal/light sheet microscopy to show the location of pre-and postganglionic neurons selectively innervating the interscapular brown adipose tissue (iBAT) in the mouse. Using iDISCO whole tissue clearing, we identified iBAT projecting postganglionic neurons in the caudal parts of the ipsilateral fused stellate/T1, as well as the T2−T5 sympathetic chain ganglia and preganglionic neurons between levels T2 and T6 of the ipsilateral spinal cord. The methodology enabled high-resolution imaging and 3D rendering of the specific SNS innervation of iBAT and will be helpful to discern peripheral nervous system innervation of other organs and tissues.
P38Α BLOCKS Brown Adipose Tissue Thermogenesis Through P38Δ INHIBITION
PLoS biology, 2018
Adipose tissue has emerged as an important regulator of whole-body metabolism, and its capacity to dissipate energy in the form of heat has acquired a special relevance in recent years as potential treatment for obesity. In this context, the p38MAPK pathway has arisen as a key player in the thermogenic program because it is required for the activation of brown adipose tissue (BAT) thermogenesis and participates also in the transformation of white adipose tissue (WAT) into BAT-like depot called beige/brite tissue. Here, using mice that are deficient in p38α specifically in adipose tissue (p38αFab-KO), we unexpectedly found that lack of p38α protected against high-fat diet (HFD)-induced obesity. We also showed that p38αFab-KO mice presented higher energy expenditure due to increased BAT thermogenesis. Mechanistically, we found that lack of p38α resulted in the activation of the related protein kinase family member p38δ. Our results showed that p38δ is activated in BAT by cold exposure...
Automated segmentation of human cervical-supraclavicular adipose tissue in magnetic resonance images
Scientific Reports
Human brown adipose tissue (BAT), with a major site in the cervical-supraclavicular depot, is a promising anti-obesity target. This work presents an automated method for segmenting cervicalsupraclavicular adipose tissue for enabling time-efficient and objective measurements in large cohort research studies of BAT. Fat fraction (FF) and R 2 * maps were reconstructed from water-fat magnetic resonance imaging (MRI) of 25 subjects. A multi-atlas approach, based on atlases from nine subjects, was chosen as automated segmentation strategy. A semi-automated reference method was used to validate the automated method in the remaining subjects. Automated segmentations were obtained from a pipeline of preprocessing, affine registration, elastic registration and postprocessing. The automated method was validated with respect to segmentation overlap (Dice similarity coefficient, Dice) and estimations of FF, R 2 * and segmented volume. Bias in measurement results was also evaluated. Segmentation overlaps of Dice = 0.93 ± 0.03 (mean ± standard deviation) and correlation coefficients of r > 0.99 (P < 0.0001) in FF, R 2 * and volume estimates, between the methods, were observed. Dice and BMI were positively correlated (r = 0.54, P = 0.03) but no other significant bias was obtained (P ≥ 0.07). The automated method compared well with the reference method and can therefore be suitable for time-efficient and objective measurements in large cohort research studies of BAT. Brown adipose tissue (BAT) is considered as a promising target for treatment of obesity and diabetes 1 due to its high capacity of converting chemical energy into heat 2. Positron emission tomography combined with computed tomography (PET/CT) using [ 18 F]fluorodeoxyglucose (FDG) is currently the most established modality for in vivo imaging of human BAT 3 , of which the main depot is located in the cervical-supraclavicular region 4. As a non-ionizing imaging alternative and complement to PET/CT, magnetic resonance imaging (MRI) has been introduced for studies of human and animal BAT during the metabolically active and inactive states 5-11. One promising MRI technique, multi-echo water-fat MRI, can provide quantitative and simultaneous estimations of fat fraction (FF) and R 2 * 12. The FF and R 2 * metrics might reflect differences between BAT and white adipose tissue (WAT), with respect to water, fat, iron and blood oxygen content, and have been used for characterizing the two types of adipose tissue (AT) 13. An important step in BAT image analysis is segmentation of the BAT depots. In human FDG-PET/CT studies, isolation of metabolically active BAT is guided by the use of combined constraints on FDG standardized uptake value (SUV) and CT Hounsfield units (HU) 3. In studies involving separate examinations with FDG-PET/CT and MRI 14 or simultaneous examinations with integrated FDG-PET/MRI 15 , segmentation of the MR images can be accomplished by using the co-registered PET/CT data or PET data, respectively. In standalone MRI studies, there
Lipids in Health and Disease, 2012
Obesity is reaching epidemic worldwide and is risk factor for cardiovascular disease and type 2 diabetes. Although plasma high density lipoprotein (HDL) and apolipoprotein A-I (apoA-I) are inversely correlated to obesity, whether HDLs have anti-obesity effect remains unclear until a recent study reporting the direct anti-obesity effect of apoA-I and its mimetic peptide. However, the mechanism is not fully understood. Increasing adipose energy expenditure through attainment of brown adipocyte phenotype in white adipose tissue is considered a potential strategy to combat obesity. Specific inhibition of autophagy in adipose tissue is associated with reduced adiposity which is attributed to the attainment of brown adipocyte phenotype in white adipose tissue and the increased energy expenditure. HDL and apoA-I could activate PI3K-Akt-mTORC1 signaling which negatively regulates autophagy. The links between HDL/apoA-I and autophagy brings a new understanding on the anti-obesity effect of HDL and apoA-I.
Environmental Pollutants Effect on Brown Adipose Tissue
Frontiers in Physiology
Brown adipose tissue (BAT) with its thermogenic function due to the presence of the mitochondrial uncoupling protein 1 (UCP1), has been positively associated with improved resistance to obesity and metabolic diseases. During recent years, the potential influence of environmental pollutants on energetic homoeostasis and obesity development has drawn increased attention. The purpose of this review is to discuss how regulation of BAT function could be involved in the environmental pollutant effect on body energy metabolism. We mainly focused in reviewing studies on animal models, which provide a better insight into the cellular mechanisms involved in this effect on body energy metabolism. The current literature supports the hypothesis that some environmental pollutants, acting as endocrine disruptors (EDCs), such as dichlorodiphenyltrichoroethane (DDT) and its metabolite dichlorodiphenylethylene (DDE) as well as some, traffic pollutants, are associated with increased obesity risk, whereas some other chemicals, such as perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), had a reverse association with obesity. Noteworthy, the EDCs associated with obesity and metabolic disorders impaired BAT mass and function. Perinatal exposure to DDT impaired BAT thermogenesis and substrate utilization, increasing susceptibility to metabolic syndrome. Ambient particulate air pollutions induced insulin resistance associated with BAT mitochondrial dysfunction. On the other hand, the environmental pollutants (PFOS/PFOA) elicited a reduction in body weight and adipose mass associated with upregulation of UCP1 and increased oxidative capacity in brownfat mitochondria. Further research is needed to better understand the physiological role of BAT in response to exposure to both obesogenic and anti-obesogenic pollutants and to confirm the same role in humans.
The Unity of Redox and Structural Remodeling of Brown Adipose Tissue in Hypothyroidism
Antioxidants
Brown adipose tissue (BAT) is important for maintaining whole-body metabolic and energy homeostasis. However, the effects of hypothyroidism, one of the most common diseases worldwide, which increases the risk of several metabolic disorders, on BAT redox and metabolic homeostasis remain mostly unknown. We aimed to investigate the dynamics of protein expression, enzyme activity, and localization of antioxidant defense (AD) enzymes in rat interscapular BAT upon induction of hypothyroidism by antithyroid drug methimazole for 7, 15, and 21 days. Our results showed an increased protein expression of CuZn- and Mn-superoxide dismutase, catalase, glutamyl–cysteine ligase, thioredoxin, total glutathione content, and activity of catalase and thioredoxin reductase in hypothyroid rats, compared to euthyroid control. Concomitant with the increase in AD, newly established nuclear, mitochondrial, and peroxisomal localization of AD enzymes was found. Hypothyroidism also potentiated associations betw...
Targeting energy expenditure in muscle as a means of combating obesity
Clinical and Experimental Pharmacology and Physiology, 2010
1. To date, an effective therapeutic agent that induces weight loss in obese subjects remains elusive. In order to establish a successful means to combat obesity, it is imperative that we identify novel targets that regulate energy balance. 2. Exciting new data have created resurgence in interest in the role of thermogenesis in energy balance. Recently, it has been demonstrated that functional brown adipocytes are present in adult humans and that brown adipocytes and myocytes are derived from a similar cell lineage and are thus likely to have similar physiological functions. 3. Recent work in the sheep has demonstrated that diffuse fat beds and skeletal muscle exhibit thermogenic properties. Furthermore, in sheep, central administration of leptin markedly increases postprandial thermogenesis in both fat and muscle tissues. This demonstrates that thermogenic processes in skeletal muscle can be manipulated in a similar way to thermogenesis in brown fat. 4. Given that skeletal muscle comprises a significant portion of bodyweight, approximately 30-40% of total body mass, we predict that energy expended by this tissue is likely to have significant ramifications for the regulation of bodyweight. 5. We propose that manipulation of skeletal muscle thermogenesis may provide a novel avenue for the development of antiobesity therapies.
Adipose and skeletal muscle thermogenesis: studies from large animals
The Journal of endocrinology, 2018
The balance between energy intake and energy expenditure establishes and preserves a 'set-point' body weight. The latter is comprised of three major components including metabolic rate, physical activity and thermogenesis. Thermogenesis is defined as the cellular dissipation of energy via heat production. This process has been extensively characterised in brown adipose tissue (BAT), wherein uncoupling protein 1 (UCP1) creates a proton leak across the inner mitochondrial membrane, diverting protons away from ATP synthesis and resulting in heat dissipation. In beige adipocytes and skeletal muscle, thermogenesis can occur independent of UCP1. Beige adipocytes have been shown to produce heat via UCP1 as well as via both futile creatine and calcium cycling pathways. On the other hand, the UCP1 homologue UCP3 is abundant in skeletal muscle and post-prandial thermogenesis has been associated with UCP3 and the futile calcium cycling. This review will focus on the differential contri...
Medicarpin induces lipolysis via activation of Protein Kinase A in brown adipocytes
BMB Reports
Natural pterocarpan Medicarpin (Med) has been shown to have various beneficial biological roles, including inhibition of osteoclastogenesis, stimulation of bone regeneration and induction of apoptosis. However, the effect of the Med on lipolysis in adipocytes has not been reported. Here, we show the effect of Med on lipolysis in different mouse adipocytes and elucidate the underlying mechanism. We observed that Med treatment promoted release of glycerol in the media. Differentiated mouse brown adipose tissue cells were treated with Med. RNA-Seq analysis was performed to elucidate the effect of med and subsequently was confirmed by qRT-PCR and western blotting analyses. Med treatment increased both protein and gene expression levels of hormone-sensitive lipase (Hsl) and adipose triglyceride lipase (Atgl), which are two critical enzymes necessary for lipolysis. Mechanistic study showed that Med activates Protein Kinase A (PKA) and phosphorylates Hsl at PKA target position at Serine 660. Silencing of PKA gene by short interfering RNA attenuated the Med-induced increase in glycerol release and Hsl phosphorylation. The results unveil that Med boosts lipolysis via a PKA-dependent pathway in adipocytes and may provide a possible avenue of further research of Med mediated reduction of body fat. [
Molecules
Overweight and obesity are among the most prominent health problems in the modern world, mostly because they are either associated with or increase the risk of other diseases such as type 2 diabetes, hypertension, and/or cancer. Most professional organizations define overweight and obesity according to individual body–mass index (BMI, weight in kilograms divided by height squared in meters). Overweight is defined as individuals with BMI from 25 to 29, and obesity as individuals with BMI ≥30. Obesity is the result of genetic, behavioral, environmental, physiological, social, and cultural factors that result in energy imbalance and promote excessive fat deposition. Despite all the knowledge concerning the pathophysiology of obesity, which is considered a disease, none of the existing treatments alone or in combination can normalize blood glucose concentration and prevent debilitating complications from obesity. This review discusses some new perspectives for overweight and obesity tre...
Diffuse Optical Spectroscopy and Imaging to Detect and Quantify Adipose Tissue Browning
Scientific reports, 2017
Adipose (fat) tissue is a complex metabolic organ that is highly active and essential. In contrast to white adipose tissue (WAT), brown adipose tissue (BAT) is deemed metabolically beneficial because of its ability to burn calories through heat production. The conversion of WAT-resident adipocytes to "beige" or "brown-like" adipocytes has recently attracted attention. However, it typically takes a few days to analyze and confirm this browning of WAT through conventional molecular, biochemical, or histological methods. Moreover, accurate quantification of the overall browning process is not possible by any of these methods. In this context, we report the novel application of diffuse reflectance spectroscopy (DRS) and multispectral imaging (MSI) to detect and quantify the browning process in mice. We successfully demonstrated the time-dependent increase in browning of WAT, following its induction through β-adrenergic agonist injections. The results from these optic...
The scaffold protein p62 regulates adaptive thermogenesis through ATF2 nuclear target activation
Nature Communications
During β-adrenergic stimulation of brown adipose tissue (BAT), p38 phosphorylates the activating transcription factor 2 (ATF2) which then translocates to the nucleus to activate the expression of Ucp1 and Pgc-1α. The mechanisms underlying ATF2 target activation are unknown. Here we demonstrate that p62 (Sqstm1) binds to ATF2 to orchestrate activation of the Ucp1 enhancer and Pgc-1α promoter. P62Δ69-251 mice show reduced expression of Ucp1 and Pgc-1α with impaired ATF2 genomic binding. Modulation of Ucp1 and Pgc-1α expression through p62 regulation of ATF2 signaling is demonstrated in vitro and in vivo in p62Δ69-251 mice, global p62−/− and Ucp1-Cre p62flx/flx mice. BAT dysfunction resulting from p62 deficiency is manifest after birth and obesity subsequently develops despite normal food intake, intestinal nutrient absorption and locomotor activity. In summary, our data identify p62 as a master regulator of BAT function in that it controls the Ucp1 pathway through regulation of ATF2 g...
Adipogenesis: A Necessary but Harmful Strategy
International Journal of Molecular Sciences
Obesity is considered to significantly increase the risk of the development of a vast range of metabolic diseases. However, adipogenesis is a complex physiological process, necessary to sequester lipids effectively to avoid lipotoxicity in other tissues, like the liver, heart, muscle, essential for maintaining metabolic homeostasis and has a crucial role as a component of the innate immune system, far beyond than only being an inert mass of energy storage. In pathophysiological conditions, adipogenesis promotes a pro-inflammatory state, angiogenesis and the release of adipokines, which become dangerous to health. It results in a hypoxic state, causing oxidative stress and the synthesis and release of harmful free fatty acids. In this review, we try to explain the mechanisms occurring at the breaking point, at which adipogenesis leads to an uncontrolled lipotoxicity. This review highlights the types of adipose tissue and their functions, their way of storing lipids until a critical p...
Body Mass Index and Colorectal Cancer
Body-mass Index and Health [Working Title]
Colorectal cancer (CRC) is one of the most common cancers in the world. Obesity is an established risk factor for colorectal carcinogenesis. Many epidemiological and experimental studies support this link and tumor-promoting effects of obesity. Body mass index (BMI) is a marker of general obesity. Obesity is also a global health problem and is defined by World Health Organization as BMI > 30 kg/m 2. In this chapter, we give a general review about the mechanisms of obesity on colorectal carcinogenesis and the effects of obesity on clinical outcomes such as disease-free survival (DFS), progression-free survival (PFS) and overall survival (OS), in adjuvant setting and metastatic disease, respectively.
Zbtb16 has a role in brown adipocyte bioenergetics
2012
OBJECTIVE: A better understanding of the processes influencing energy expenditure could provide new therapeutic strategies for reducing obesity. As the metabolic activity of the brown adipose tissue (BAT) and skeletal muscle is an important determinant of overall energy expenditure and adiposity, we investigated the role of genes that could influence cellular bioenergetics in these two tissues. DESIGN: We screened for genes that are induced in both the BAT and skeletal muscle during acute adaptive thermogenesis in the mouse by microarray. We used C57BL/6J mice as well as the primary and immortalized brown adipocytes and C2C12 myocytes to validate the microarray data. Further characterization included gene expression, mitochondrial density, cellular respiration and substrate utilization. We also used a Hybrid Mouse Diversity Panel to assess in vivo effects on obesity and body fat content. RESULTS: We identified the transcription factor Zbtb16 (also known as Plzf and Zfp14) as being induced in both the BAT and skeletal muscle during acute adaptive thermogenesis. Zbtb16 overexpression in brown adipocytes led to the induction of components of the thermogenic program, including genes involved in fatty acid oxidation, glycolysis and mitochondrial function. Enhanced Zbtb16 expression also increased mitochondrial number, as well as the respiratory capacity and uncoupling. These effects were accompanied by decreased triglyceride content and increased carbohydrate utilization in brown adipocytes. Natural variation in Zbtb16 mRNA levels in multiple tissues across a panel of 4100 mouse strains was inversely correlated with body weight and body fat content. CONCLUSION: Our results implicate Zbtb16 as a novel determinant of substrate utilization in brown adipocytes and of adiposity in vivo.
Gaseous Mediators in Temperature Regulation
Comprehensive Physiology, 2011
Deep body temperature (T b) is kept relatively constant despite a wide range of ambient temperature variation. Nevertheless, in particular situations it is beneficial to decrease or to increase T b in a regulated manner. Under hypoxia for instance a regulated drop in T b (anapyrexia) is key to reduce oxygen demand of tissues when oxygen availability is diminished, leading to an increased survival rate in a number of species when experiencing low levels of inspired oxygen. On the other hand, a regulated rise in T b (fever) assists the healing process. These regulated changes in T b are mediated by the brain, where afferent signals converge and the most important regions for the control of T b are found. The brain (particularly some hypothalamic structures located in the preoptic area) modulates efferent activities that cause changes in heat production (modulating brown adipose tissue activity and perfusion, for instance) and heat loss (modulating tail skin vasculature blood flow, for instance). This review highlights key advances about the role of the gaseous neuromodulators nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H 2 S) in thermoregulation, acting both on the brain and the periphery.
Molecular Imaging and Biology, 2011
Purpose: To compare blood glucose levels in patients with or without "detectable" brown adipose tissue (BAT) using 2-deoxy-2-[ 18 F]fluoro-D-glucose positron emission tomography/ computed tomography (FDG PET/CT). Procedures: Nine hundred eight patients had PET/CT scans and were previously identified as having, or not having, FDG uptake in BAT. The original database was retrospectively reviewed for blood glucose level and body mass index (BMI) at the time of imaging. Blood glucose levels were compared between patients with or without FDG uptake in BAT, adjusting for age, sex, and BMI. Results: Fifty-six patients (6.2%) had FDG uptake in BAT. In the univariate analysis, patients without FDG uptake in BAT had a higher risk of glucose ≥100 mg/dL (odds ratio 3.4, 95% CI= 1.6-7.3; P=0.0007). After adjustment for age, sex, BMI, and significant interaction of sex and BMI, patients without BAT tended to have a higher risk of glucose ≥100 mg/dL, although not statistically significant (odds ratio=1.6, 95% CI=0.7-3.6; P=0.268). Conclusions: Although causal relationships are not specified, the data suggest that BAT uptake, glucose levels, BMI, sex, and age are interrelated and the possibility that presence of "detectable" BAT is protective against diabetes and obesity. FDG PET/CT may be a vital tool for further investigations of diabetes and obesity.
FNDC5/irisin is not only a myokine but also an adipokine
PloS one, 2013
Exercise provides clear beneficial effects for the prevention of numerous diseases. However, many of the molecular events responsible for the curative and protective role of exercise remain elusive. The recent discovery of FNDC5/irisin protein that is liberated by muscle tissue in response to exercise might be an important finding with regard to this unsolved mechanism. The most striking aspect of this myokine is its alleged capacity to drive brown-fat development of white fat and thermogenesis. However, the nature and secretion form of this new protein is controversial. The present study reveals that rat skeletal muscle secretes a 25 kDa form of FNDC5, while the 12 kDa/irisin theoretical peptide was not detected. More importantly, this study is the first to reveal that white adipose tissue (WAT) also secretes FNDC5; hence, it may also behave as an adipokine. Our data using rat adipose tissue explants secretomes proves that visceral adipose tissue (VAT), and especially subcutaneous ...
Endogenous FGF21-signaling controls paradoxical obesity resistance of UCP1-deficient mice
Nature Communications
Uncoupling protein 1 (UCP1) executes thermogenesis in brown adipose tissue, which is a major focus of human obesity research. Although the UCP1-knockout (UCP1 KO) mouse represents the most frequently applied animal model to judge the anti-obesity effects of UCP1, the assessment is confounded by unknown anti-obesity factors causing paradoxical obesity resistance below thermoneutral temperatures. Here we identify the enigmatic factor as endogenous FGF21, which is primarily mediating obesity resistance. The generation of UCP1/FGF21 double-knockout mice (dKO) fully reverses obesity resistance. Within mild differences in energy metabolism, urine metabolomics uncover increased secretion of acyl-carnitines in UCP1 KOs, suggesting metabolic reprogramming. Strikingly, transcriptomics of metabolically important organs reveal enhanced lipid and oxidative metabolism in specifically white adipose tissue that is fully reversed in dKO mice. Collectively, this study characterizes the effects of end...
Stem Cells International
There has been an increased interest in mesenchymal stem cells from adipose tissue, due to their abundance and accessibility with no ethical concerns. Their multipotent properties make them appropriate for regenerative clinical applications. It has been shown that adipose-derived stem cells (ASCs) may differ between the origin sites. Moreover, a variety of internal and external factors may affect their biological characteristics, as what we aimed to highlight in this review. It has been demonstrated that ASCs secrete multiple trophic factors that are capable of stimulating cell proliferation and differentiation and migration of various cell types. Particular attention should be given to exosomes, since it is known that they contribute to the paracrine effects of MSCs. Secretion of trophic agents by ASCs is thought to be in a greater importance for regenerative medicine applications, rather than cells engraftment to the site of injury and their differentiation ability. The surface ma...
The Influence of Buddhist Meditation Traditions on the Autonomic System and Attention
Biomed Research International, 2015
Cognitive and neuroscience research from the past several years has shed new light on the influences that meditative traditions have on the meditation practice. Here we review new evidence that shows that types of meditation that developed out of certain traditions such as Vajrayana and Hindu Tantric lead to heightened sympathetic activation and phasic alertness, while types of meditation from other traditions such as Theravada and Mahayana elicit heightened parasympathetic activity and tonic alertness. Such findings validate Buddhist scriptural descriptions of heightened arousal during Vajrayana practices and a calm and alert state of mind during Theravada and Mahayana types of meditation and demonstrate the importance of the cultural and philosophical context out of which the meditation practices develop.
Intracellular thermometry with fluorescent sensors for thermal biology
Pflügers Archiv - European Journal of Physiology
Temperature influences the activities of living organisms at various levels. Cells not only detect environmental temperature changes through their unique temperature-sensitive molecular machineries but also muster an appropriate response to the temperature change to maintain their inherent functions. Despite the fundamental involvement of temperature in physiological phenomena, the mechanism by which cells produce and use heat is largely unknown. Recently, fluorescent thermosensors that function as thermometers in live cells have attracted much attention in biology. These new tools, made of various temperaturesensitive molecules, have allowed for intracellular thermometry at the single-cell level. Intriguing spatiotemporal temperature variations, including organelle-specific thermogenesis, have been revealed with these fluorescent thermosensors, which suggest an intrinsic connection between temperature and cell functions. Moreover, fluorescent thermosensors have shown that intracellular temperature changes at the microscopic level are largely different from those assumed for a water environment at the macroscopic level. Thus, the employment of fluorescent thermosensors will uncover novel mechanisms of intracellular temperature-assisted physiological functions.
Direct Evidence of Brown Adipocytes in Different Fat Depots in Children
PLOS ONE, 2015
Recent studies suggested the persistence of brown adipocytes in adult humans, as opposed to being exclusively present in infancy. In this study, we investigated the presence of brown-like adipocytes in adipose tissue (AT) samples of children and adolescents aged 0 to 18 years and evaluated the association with age, location, and obesity. For this, we analysed AT samples from 131 children and 23 adults by histological, immunohistochemical and expression analyses. We detected brown-like and UCP1 positive adipocytes in 10.3% of 87 lean children (aged 0.3 to 10.7 years) and in one overweight infant, whereas we did not find brown adipocytes in obese children or adults. In our samples, the brown-like adipocytes were interspersed within white AT of perirenal, visceral and also subcutaneous depots. Samples with brown-like adipocytes showed an increased expression of UCP1 (>200fold), PRDM16 (2.8fold), PGC1α and CIDEA while other brown/beige selective markers, such as PAT2, P2RX5, ZIC1, LHX8, TMEM26, HOXC9 and TBX1 were not significantly different between UCP1 positive and negative samples. We identified a positive correlation between UCP1 and PRDM16 within UCP1 positive samples, but not with any other brown/ beige marker. In addition, we observed significantly increased PRDM16 and PAT2 expression in subcutaneous and visceral AT samples with high UCP1 expression in adults. Our data indicate that brown-like adipocytes are present well beyond infancy in subcutaneous depots of non-obese children. The presence was not restricted to typical perirenal locations, but they were also interspersed within WAT of visceral and subcutaneous depots.
Journal of Obesity, 2011
Evidence of active brown adipose tissue in human adults suggests that this may become a pharmacological target to induce negative energy balance. We have explored whole-body indirect calorimetry to detect the metabolic effects of thermogenic drugs through administration of ephedrine hydrochloride and have assessed ephedrine's merits as a comparator compound in the evaluation of novel thermogenic agents. Volunteers randomly given ephedrine hydrochloride 15 mg QID(n=8)or placebo(n=6)were studied at baseline and after 1-2 and 14-15 days of treatment. We demonstrate that overnight or 23-hour, 2% energy expenditure (EE) and 5% fat (FO) or CHO oxidation effects are detectable both acutely and over 14 days. Compared to placebo, ephedrine increased EE and FO rates overnight (EE 63 kJ day 2, EE 105 kJ, FO 190 kJ, day 14), but not over 23 h. We conclude that modest energy expenditure and fat oxidation responses to pharmacological interventions can be confidently detected by calorimetry in...
Journal of Magnetic Resonance Imaging, 2016
To evaluate the volume and changes of human brown adipose tissue (BAT) in vivo following exposure to cold using MRI. Materials and Methods: The clavicular region of 10 healthy volunteers was examined at a 3T MRI system. One volunteer participated twice. A cooling vest that was circulated with temperature-controlled water was used to expose each volunteer to a cold environment. Three different water temperature phases were employed: baseline (23°C, 20 min), cooling (12°C, 90 min) and a final warming phase (37°C, 30 min). Temperatures of the water in the circuit, of the body, and at the back skin of the volunteers were monitored with fiber optic temperature probes. Applying the 2-point DIXON pulse sequence every 5 min, fat fraction (FF) maps were determined and evaluated over time to distinguish between brown and white adipose tissue. Results: Temperature measurements showed a decrease of (3.8 ± 1.0)°C of the back skin temperature, while the body temperature stayed constant at (37.2 ± 0.9)°C. Focusing on the two interscapular BAT depots, a mean FF decrease of (-2.9 ± 2.0)% / h (p < 0.001) was detected during cold stimulation in a mean absolute volume of (1.31 ± 1.43) ml. Also, a correlation of FF decrease to back skin temperature decrease was observed in all volunteers (correlation coefficients: │r│= [0.51; 0.99]). Conclusion: We found that FF decreases in BAT begins immediately with mild cooling of the body and continues during long-time cooling.
Nutrients, 2015
Obesity results in changes in brown adipose tissue (BAT) morphology, leading to fat deposition, inflammation, and alterations in sympathetic nerve activity. Bardoxolone methyl (BARD) has been extensively studied for the treatment of chronic diseases. We present for the first time the effects of oral BARD treatment on BAT morphology and associated changes in the brainstem. Three groups (n = 7) of C57BL/6J mice were fed either a high-fat diet (HFD), a high-fat diet supplemented with BARD (HFD/BARD), or a low-fat diet (LFD) for 21 weeks. BARD was administered daily in drinking water. Interscapular BAT, and ventrolateral medulla (VLM) and dorsal vagal complex (DVC) in the brainstem, were collected for analysis by histology, immunohistochemistry and Western blot. BARD prevented fat deposition in BAT, demonstrated by the decreased accumulation of lipid droplets. When administered BARD, HFD mice had lower numbers of F4/80 and CD11c macrophages in the BAT with an increased proportion of CD2...
Developmental Origins of the Adipocyte Lineage: New Insights from Genetics and Genomics Studies
Stem Cell Reviews and Reports, 2012
The current epidemic of obesity and overweight has caused a surge of interest in the study of adipose tissue formation. Much progress has been made in defining the transcriptional networks controlling the terminal differentiation of adipocyte progenitors into mature adipocytes. However, the early steps of adipocyte development and the embryonic origin of this lineage have been largely disregarded until recently. In mammals, two functionally different types of adipose tissues coexist, which are both involved in energy balance but assume opposite functions. White adipose tissue (WAT) stores energy, while brown adipose tissue (BAT) is specialized in energy expenditure. WAT and BAT can be found as several depots located in various sites of the body. Individual fat depots exhibit different timing of appearance during development, as well as distinct functional properties, suggesting possible differences in their developmental origin. This hypothesis has recently been revisited through large-scale genomics studies and in vivo lineage tracing approaches, which are reviewed in this report. These studies have provided novel fundamental insights into adipocyte biology, pointing out distinct developmental origins for WAT and BAT, as well as for individual WAT depots. They suggest that the adipose tissue is composed of distinct mini-organs, exhibiting developmental and functional differences, as well as variable contribution to obesity-related metabolic diseases. Keywords Adipocytes. Development. Origin. Brown adipose tissue (BAT). White adipose tissue (WAT). Genomics. In vivo lineage tracing
Adiponectin reduces thermogenesis by inhibiting brown adipose tissue activation in mice
Diabetologia, 2014
Aims/hypothesis Adiponectin is an adipocyte-derived hormone that plays an important role in energy homeostasis. The main objective of this study was to investigate whether or not adiponectin regulates brown adipose tissue (BAT) activation and thermogenesis. Methods Core body temperatures (CBTs) of genetic mouse models were monitored at room temperature and during cold exposure. Cultured brown adipocytes and viral vectormediated gene transduction were used to study the regulatory effects of adiponectin on Ucp1 gene expression and the underlying mechanisms. Results The CBTs of adiponectin knockout mice (Adipoq −/−) were significantly higher than those of wild type (WT) mice both at room temperature and during the cold (4°C) challenge. Conversely, reconstitution of adiponectin in Adipoq −/− mice significantly blunted β adrenergic receptor agonist-induced thermogenesis of interscapular BAT. After 10 days of intermittent cold exposure, Adipoq −/− mice exhibited higher UCP1 expression and more brown-like structure in inguinal fat than WT mice. Paradoxically, we found that the anti-thermogenic effect of adiponectin requires neither AdipoR1 nor AdipoR2, two well-known adiponectin receptors. In sharp contrast to the anti-thermogenic effects of adiponectin, AdipoR1 and especially AdipoR2 promote BAT activation. Mechanistically, adiponectin was found to inhibit Ucp1 gene expression by suppressing β 3-adrenergic receptor expression in brown adipocytes. Conclusions/interpretation This study demonstrates that adiponectin suppresses thermogenesis, which is likely to be a mechanism whereby adiponectin reduces energy expenditure. Keywords Adiponectin. Brown adipose tissue. Energy expenditure. Thermogenesis Abbreviations Acrp30 Adipocyte complement-related protein of 30 kDa (adiponectin) Ad-Acrp30 Adenovirus-encoded adipocyte complementrelated protein of 30 kDa (adiponectin) Ad-GFP Adenovirus-encoded green fluorescent protein AMPK AMP-activated protein kinase ATGL Adipose triacylglycerol lipase βAR β-adrenergic receptor BAT Brown adipose tissue CBT Core body temperature GAPDH Glyceraldehyde 3-phosphate dehydrogenase HSL Hormone-sensitive lipase iBAT Interscapular brown adipose tissue ISO Isoprenaline Myf5 Myogenic factor 5 PGC-1α Peroxisome proliferator-activated receptor γ co-activator 1 α PKA Protein kinase A Electronic supplementary material The online version of this article
Frontiers in endocrinology, 2015
In this review, we will first discuss the concept of bone strength and introduce how fat at different locations, including the bone marrow, directly or indirectly regulates bone turnover. We will then review the current literature supporting the mechanistic relationship between marrow fat and bone and our understanding of the relationship between body fat, body weight, and bone with emphasis on its hormonal regulation. Finally, we will briefly discuss the importance and challenges of accurately measuring the fat compartments using non-invasive methods. This review highlights the complex relationship between fat and bone and how these new concepts will impact our diagnostic and therapeutic approaches in the very near future.
Adipogenesis: A Complex Interplay of Multiple Molecular Determinants and Pathways
International Journal of Molecular Sciences
The formation of adipocytes during embryogenesis has been largely understudied. However, preadipocytes appear to originate from multipotent mesenchymal stromal/stem cells which migrate from the mesoderm to their anatomical localization. Most studies on adipocyte formation (adipogenesis) have used preadipocytes derived from adult stem/stromal cells. Adipogenesis consists of two phases, namely commitment and terminal differentiation. This review discusses the role of signalling pathways, epigenetic modifiers, and transcription factors in preadipocyte commitment and differentiation into mature adipocytes, as well as limitations in our understanding of these processes. To date, a limited number of transcription factors, genes and signalling pathways have been described to regulate preadipocyte commitment. One reason could be that most studies on adipogenesis have used preadipocytes already committed to the adipogenic lineage, which are therefore not suitable for studying preadipocyte co...
Syndecan-1 Is Required to Maintain Intradermal Fat and Prevent Cold Stress
PLoS Genetics, 2014
Homeostatic temperature regulation is fundamental to mammalian physiology and is controlled by acute and chronic responses of local, endocrine and nervous regulators. Here, we report that loss of the heparan sulfate proteoglycan, syndecan-1, causes a profoundly depleted intradermal fat layer, which provides crucial thermogenic insulation for mammals. Mice without syndecan-1 enter torpor upon fasting and show multiple indicators of cold stress, including activation of the stress checkpoint p38a in brown adipose tissue, liver and lung. The metabolic phenotype in mutant mice, including reduced liver glycogen, is rescued by housing at thermoneutrality, suggesting that reduced insulation in cool temperatures underlies the observed phenotypes. We find that syndecan-1, which functions as a facultative lipoprotein uptake receptor, is required for adipocyte differentiation in vitro. Intradermal fat shows highly dynamic differentiation, continuously expanding and involuting in response to hair cycle and ambient temperature. This physiology probably confers a unique role for Sdc1 in this adipocyte sub-type. The PPARc agonist rosiglitazone rescues Sdc12/2 intradermal adipose tissue, placing PPARc downstream of Sdc1 in triggering adipocyte differentiation. Our study indicates that disruption of intradermal adipose tissue development results in cold stress and complex metabolic pathology.
Diabetology & Metabolic Syndrome
Objective Melatonin has been shown to increase brown adipose tissue (BAT) mass, which can lead to important metabolic effects, such as bodyweight reduction and glycemic improvement. However, BAT mass can only be measured invasively and. The gold standard for non-invasive measurement of BAT activity is positron emission tomography with 2-deoxy-2-[fluorine-18] fluoro-d-glucose (18F-FDG PET). There is no study, to our knowledge, that has evaluated if melatonin influences BAT activity, measured by this imaging technique in animals. Methods Three experimental groups of Wistar rats (control, pinealectomy, and pinealectomy replaced with melatonin) had an 18F-FDG PET performed at room temperature and after acute cold exposure. The ratio of increased BAT activity after cold exposure/room temperature was called “acute thermogenic capacity” (ATC) We also measured UCP-1 mRNA expression to correlate with the 18F-FDG PET results. Results Pinealectomy led to reduced acute thermogenic capacity, com...
Nutrients, 2018
The aim of this study was to compare the effects of mild energy restriction and resveratrol on thermogenic and oxidative capacity in interscapular brown adipose tissue (IBAT) and in skeletal muscle. Rats were fed a high-fat high-sucrose diet for six weeks, and divided into four experimental groups fed a standard diet: a control group, a resveratrol-treated group, an energy-restricted group and an energy-restricted group treated with resveratrol. Weights of IBAT, gastrocnemius muscle and fat depots were measured. Activities of carnitine palmitoyltransferase (CPT) and citrate synthase (CS), protein levels of sirtuin (SIRT1 and 3), uncoupling proteins (UCP1 and 3), glucose transporter (GLUT4), mitochondrial transcription factor (TFAM), nuclear respiratory factor (NRF1), peroxisome proliferator-activated receptor (PPARα) and AMP activated protein kinase (AMPK) and peroxisome proliferator-activated receptor gamma coactivator (PGC1α) activation were measured. No changes in IBAT and gastro...
Brown and Brite: The Fat Soldiers in the Anti-obesity Fight
Frontiers in Physiology
Brown adipose tissue (BAT) is proposed to maintain thermal homeostasis through dissipation of chemical energy as heat by the uncoupling proteins (UCPs) present in their mitochondria. The recent demonstration of the presence of BAT in humans has invigorated research in this area. The research has provided many new insights into the biology and functioning of this tissue and the biological implications of its altered activities. Another finding of interest is browning of white adipose tissue (WAT) resulting in what is known as beige/brite cells, which have increased mitochondrial proteins and UCPs. In general, it has been observed that the activation of BAT is associated with various physiological improvements such as a reduction in blood glucose levels increased resting energy expenditure and reduced weight. Given the similar physiological functions of BAT and beige/ brite cells and the higher mass of WAT compared to BAT, it is likely that increasing the brite/beige cells in WATs may also lead to greater metabolic benefits. However, development of treatments targeting brown fat or WAT browning would require not only a substantial understanding of the biology of these tissues but also the effect of altering their activity levels on whole body metabolism and physiology. In this review, we present evidence from recent literature on the substrates utilized by BAT, regulation of BAT activity and browning by circulating molecules. We also present dietary and pharmacological activators of brown and beige/brite adipose tissue and the effect of physical exercise on BAT activity and browning.
Nature communications, 2017
Browning of subcutaneous white fat (iWAT) involves several reprograming events, but the underlying mechanisms are incompletely understood. Here we show that the transcription factor Hlx is selectively expressed in brown adipose tissue (BAT) and iWAT, and is translationally upregulated by β3-adrenergic signaling-mediated suppression of the translational inhibitor 4E-BP1. Hlx interacts with and is co-activated by Prdm16 to control BAT-selective gene expression and mitochondrial biogenesis. Hlx heterozygous knockout mice have defects in brown-like adipocyte formation in iWAT, and develop glucose intolerance and high fat-induced hepatic steatosis. Conversely, transgenic expression of Hlx at a physiological level drives a full program of thermogenesis and converts iWAT to brown-like fat, which improves glucose homeostasis and prevents obesity and hepatic steatosis. The adipose remodeling phenotypes are recapitulated by fat-specific injection of Hlx knockdown and overexpression viruses, r...
Adipose stem cells in obesity: challenges and opportunities
Bioscience Reports
Adipose tissue, the storage of excessive energy in the body, secretes various proteins called adipokines, which connect the body’s nutritional status to the regulation of energy balance. Obesity triggers alterations of quantity and quality of various types of cells that reside in adipose tissue, including adipose stem cells (ASCs; referred to as adipose-derived stem/stromal cells in vitro). These alterations in the functionalities and properties of ASCs impair adipose tissue remodeling and adipose tissue function, which induces low-grade systemic inflammation, progressive insulin resistance, and other metabolic disorders. In contrast, the ability of ASCs to recruit new adipocytes when faced with caloric excess leads to healthy adipose tissue expansion, associated with lower amounts of inflammation, fibrosis, and insulin resistance. This review focuses on recent advances in our understanding of the identity of ASCs and their roles in adipose tissue development, homeostasis, expansion...
Multimodal imaging approach to monitor browning of adipose tissue in vivo
Journal of lipid research, 2018
The discovery that white adipocytes can undergo a browning process to become metabolically active beige cells has attracted significant interest in the fight against obesity. However, the study of adipose browning has been impeded by a lack of imaging tools that allow longitudinal and noninvasive monitoring of this process in vivo. Here, we report a preclinical imaging approach to detect development of beige adipocytes during adrenergic stimulation. In this approach, we expressed near-infrared fluorescent protein, iRFP720, driven under an uncoupling protein-1 () promoter in mice by viral transduction, and used multispectral optoacoustic imaging technology with ultrasound tomography (MSOT-US) to assess adipose beiging during adrenergic stimulation. We observed increased photoacoustic signal at 720 nm, coupled with attenuated lipid signals in stimulated animals. As a proof of concept, we validated our approach against hybrid positron emission tomography combined with magnetic resonanc...
International Journal of Obesity
Background Obesity increases the risk of developing impaired glucose tolerance (IGT) and type 2 diabetes (T2D) after myocardial infarction (MI). Brown adipose tissue (BAT) is important to combat obesity and T2D, and increasing BAT mass by transplantation improves glucose metabolism and cardiac function. The objective of this study was to determine if BAT had a protective effect on glucose tolerance and cardiac function in high-fat diet (HFD) fed mice subjected to a mild MI. Methods Male C57BL/6 mice were fed a HFD for eight weeks and then divided into Sham (Sham-operated) and +BAT (mice receiving 0.1 g BAT into their visceral cavity). Sixteen weeks post-transplantation, mice were further subdivided into ±MI (Sham; Sham-MI; +BAT; +BAT-MI) and maintained on a HFD. Cardiac (echocardiography) and metabolic function (glucose and insulin tolerance tests, body composition and exercise tolerance) were assessed throughout 22 weeks post-MI. Quantitative PCR (qPCR) was performed to determine t...
Anti-adipogenic signals at the onset of obesity-related inflammation in white adipose tissue
Cellular and Molecular Life Sciences
Chronic inflammation that affects primarily metabolic organs, such as white adipose tissue (WAT), is considered as a major cause of human obesity-associated co-morbidities. However, the molecular mechanisms initiating this inflammation in WAT are poorly understood. By combining transcriptomics, ChIP-seq and modeling approaches, we studied the global early and late responses to a high-fat diet (HFD) in visceral (vWAT) and subcutaneous (scWAT) AT, the first being more prone to obesity-induced inflammation. HFD rapidly triggers proliferation of adipocyte precursors within vWAT. However, concomitant antiadipogenic signals limit vWAT hyperplastic expansion by interfering with the differentiation of proliferating adipocyte precursors. Conversely, in scWAT, residing beige adipocytes lose their oxidizing properties and allow storage of excessive fatty acids. This phase is followed by tissue hyperplastic growth and increased angiogenic signals, which further enable scWAT expansion without ge...
Effect of Iodothyronines on Thermogenesis: Focus on Brown Adipose Tissue
Frontiers in endocrinology, 2018
Thyroid hormones significantly influence energy expenditure by affecting the activity of metabolic active tissues, among which, mammalian brown adipose tissue (BAT) plays a significant role. For a long time, the modulation of BAT activity by 3,3',5-triiodo-l-thyronine (T3) has been ascribed to its direct actions on this tissue; however, recent evidence indicates that T3, by stimulating specific brain centers, activates the metabolism of BAT the sympathetic nervous system. These distinct mechanisms of action are not mutually exclusive. New evidence indicates that 3,5-diiodo-l-thyronine (3,5-T2), a thyroid hormone derivative, exerts thermogenic effects, by influencing mitochondrial activity in metabolically active tissues, such as liver, skeletal muscle, and BAT. At the moment, due to the absence of experiments finalized to render a clear cut discrimination between peripheral and central effects induced by 3,5-T2, it is not possible to exclude that some of the metabolic effects ex...
Heart hormones fueling a fire in fat
Adipocyte, 2013
O ur view of how adipose tissue metabolism is regulated recently experienced a change in focus and breadth, meaning that some of the key controlling factors were not fully in the picture. The catecholamines of the sympathetic nervous system are wellknown activators of β-adrenergic receptors in adipocytes to increase lipolysis. They also drive energy expenditure in brown adipose tissue and, importantly, the "browning" of cells in white adipose depots. However, this is clearly not the whole story. In earlier work, we established a pathway from β-adrenergic receptors to p38 MAP kinase to drive the transcription of brown adipocyte genes and respiratory uncoupling. Now we recently discovered that cardiac natriuretic peptides (NPs) stimulate a similar "browning" of human and mouse adipocytes. NPs activate the guanylyl cyclase coupled NP receptor A and activation of protein kinase G. Importantly, this pathway also depends upon p38 MAPK. These two pathways work together, additively increasing expression of brown adipocyte marker genes, as well as reflexively controlling each other's components. We discuss these findings and how the control of body fat by these cardiac hormones, in conjunction with the sympathetic nervous system, has implications for obesity as well as cardiovascular disease, including hypertension and heart failure. CoMMentAry CoMMentAry
International Journal of Obesity Supplements, 2014
The catecholamines and the adrenergic receptors have been long known to be vital components in the regulation of fat cell metabolism. Whether in response to stress, cold temperature or diet, the b-adrenergic receptors (bARs) respond to epinephrine/ norepinephrine to activate a signalling cascade that drives triglyceride hydrolysis to free fatty acids for use as fuel for skeletal and cardiac muscle work. The bARs also are well-established activators of brown fat for the conversion of substrate energy to generate heat from the oxidation of glucose and fatty acids. Long thought to be irrelevant to the biology of adult humans, the realization that there is indeed functional brown fat in humans has now created great interest and enthusiasm over the possibility that recruiting brown fat to target obesity and metabolic disease could represent a viable therapeutic option. Coupled with newer evidence that various stimuli independent of the bARs may also be able to increase active brown adipocytes, including the cardiac natriuretic peptides, it is an exciting time to be working in this area. This review will focus on the catecholamines and natriuretic peptides as cooperative actors in promoting fat metabolism, and will consider areas in need of further research.
Adaptive thermogenesis in brown adipose tissue involves activation of pannexin-1 channels
Molecular Metabolism, 2020
Objective Brown adipose tissue (BAT) is specialized in thermogenesis. The conversion of energy into heat in brown adipocytes proceeds via stimulation of β-adrenergic receptor (βAR)-dependent signaling and activation of mitochondrial uncoupling protein 1 (UCP1). We have previously demonstrated a functional role for pannexin-1 (Panx1) channels in white adipose tissue; however, it is not known whether Panx1 channels play a role in the regulation of brown adipocyte function. Here, we tested the hypothesis that Panx1 channels are involved in brown adipocyte activation and thermogenesis. Methods In an immortalized brown pre-adipocytes cell line, Panx1 currents were measured using patch-clamp electrophysiology. Flow cytometry was used for assessment of dye uptake and luminescence assays for adenosine triphosphate (ATP) release, and cellular temperature measurement was performed using a ratiometric fluorescence thermometer. We used RNA interference and expression plasmids to manipulate expr...
Brown adipose tissue growth and development
Scientifica, 2013
Brown adipose tissue is uniquely able to rapidly produce large amounts of heat through activation of uncoupling protein (UCP) 1. Maximally stimulated brown fat can produce 300 watts/kg of heat compared to 1 watt/kg in all other tissues. UCP1 is only present in small amounts in the fetus and in precocious mammals, such as sheep and humans; it is rapidly activated around the time of birth following the substantial rise in endocrine stimulatory factors. Brown adipose tissue is then lost and/or replaced with white adipose tissue with age but may still contain small depots of beige adipocytes that have the potential to be reactivated. In humans brown adipose tissue is retained into adulthood, retains the capacity to have a significant role in energy balance, and is currently a primary target organ in obesity prevention strategies. Thermogenesis in brown fat humans is environmentally regulated and can be stimulated by cold exposure and diet, responses that may be further modulated by phot...
Obesity
This study aimed to compare the associations of positron emission tomography (PET), magnetic resonance (MR), and infrared thermography (IRT) imaging modalities with energy expenditure (EE) after brown adipose tissue (BAT) activation using capsinoid ingestion and cold exposure. Methods: Twenty participants underwent PET-MR, IRT imaging, and whole-body calorimetry after capsinoid ingestion and cold exposure. Standardized uptake values (SUV) and the fat fraction (FF) of the supraclavicular brown adipose tissue regions were estimated. The anterior supraclavicular temperature (Tscv) from IRT at baseline and postintervention was measured. Two-hour post-capsinoid ingestion EE and post-cold exposure EE served as a reference to correlate fluorodeoxyglucose uptake, FF, and Tscv for BAT assessment. IRT images were geometrically transformed to overlay on PET-MR for visualization of the hottest regions. Results: The supraclavicular hot spot identified on IRT closely corresponded to the area of maximal fluorodeoxyglucose uptake on PET images. Controlling for body weight, post-cold exposure Tscv was a significant variable associated with EE (P = 0.025). The SUV was significantly inversely correlated with FF (P = 0.012) and significantly correlated with peak of Tscv during cold exposure in BAT-positive participants (P = 0.022). Conclusions: Tscv correlated positively with EE and was also significantly correlated with SUV after cold exposure. Both IRT and MR FF are promising methods to study BAT activity noninvasively.
Oxidative medicine and cellular longevity, 2013
Hypothermia is a condition in which core temperature drops below the level necessary to maintain bodily functions. The decrease in temperature may disrupt some physiological systems of the body, including alterations in microcirculation and reduction of oxygen supply to tissues. The lack of oxygen can induce the generation of reactive oxygen and nitrogen free radicals (RONS), followed by oxidative stress, and finally, apoptosis and/or necrosis. Furthermore, since the hypothermia is inevitably followed by a rewarming process, we should also consider its effects. Despite hypothermia and rewarming inducing injury, many benefits of hypothermia have been demonstrated when used to preserve brain, cardiac, hepatic, and intestinal function against ischemic injury. This review gives an overview of the effects of hypothermia and rewarming on the oxidant/antioxidant balance and provides hypothesis for the role of reactive oxygen species in therapeutic hypothermia.
Scientific reports, 2016
Current methods for evaluating adipose tissue function are destructive or have low spatial resolution. These limit our ability to assess dynamic changes and heterogeneous responses that occur in healthy or diseased subjects, or during treatment. Here, we demonstrate that intrinsic two-photon excited fluorescence enables functional imaging of adipocyte metabolism with subcellular resolution. Steady-state and time-resolved fluorescence from intracellular metabolic co-factors and lipid droplets can distinguish the functional states of excised white, brown, and cold-induced beige fat. Similar optical changes are identified when white and brown fat are assessed in vivo. Therefore, these studies establish the potential of non-invasive, high resolution, endogenous contrast, two-photon imaging to identify distinct adipose tissue types, monitor their functional state, and characterize heterogeneity of induced responses.
A Novel PET Probe for Brown Adipose Tissue Imaging in Rodents
Molecular Imaging and Biology, 2019
Purpose: Brown adipose tissue (BAT) has emerged as a promising target to counteract obesity and its associated metabolic disorders. However, the detection of this tissue remains one of the major roadblocks. Procedures: In this study, we assess the use of BODIPY 1 as a positron emission tomography (PET) imaging agent to image BAT depots in vivo in two mouse phenotypes: obesity-resistant BALB/c mice and the obesity-prone C57BL/6 mice. [ 18 F]BODIPY 1 is a radioactive dye that processed both radioactivity for PET imaging and fluorescence signal for in vitro mechanism study. Results: Through the co-staining of cancer cells with BODIPY 1 and MitoTracker, we found BODIPY 1 mainly accumulated in cell mitochondria in vitro. Fluorescence imaging of primary brown and white adipocytes further confirmed BODIPY 1 had significantly higher accumulation in primary brown adipocytes compared with primary white adipocytes. We evaluated [ 18 F]BODIPY 1 for BAT imaging in both obesity-resistant BALB/c mice and obesity-prone C57BL/6 mice. Indeed, [ 18 F]BODIPY 1 was efficiently taken up by BAT in both mouse genotypes
Dielectric properties measurements of brown and white adipose tissue in rats from 0.5 to 10 GHz
Biomedical Physics & Engineering Express, 2016
Brown adipose tissue (BAT) plays an important role in whole body metabolism and with appropriate stimulus could potentially mediate weight gain and insulin sensitivity. Although imaging techniques are available to detect subsurface BAT, there are currently no viable methods for continuous acquisition of BAT energy expenditure. Microwave (MW) radiometry is an emerging technology that allows the quantification of tissue temperature variations at depths of several centimeters. Such temperature differentials may be correlated with variations in metabolic rate, thus providing a quantitative approach to monitor BAT metabolism. In order to optimize MW radiometry, numerical and experimental phantoms with accurate dielectric properties are required to develop and calibrate radiometric sensors. Thus, we present for the first time, the characterization of relative permittivity and electrical conductivity of brown (BAT) and white (WAT) adipose tissues in rats across the MW range 0.5-10GHz. Measurements were carried out in situ and post mortem in six female rats of approximately 200g. A Cole-Cole model was used to fit the experimental data into a parametric model that describes the variation of dielectric properties as a function of frequency. Measurements confirm that the dielectric properties of BAT (εr = 14.0-19.4, σ = 0.3-3.3S/m) are significantly higher than those of WAT (εr = 9.1-11.9, σ = 0.1-1.9S/m), in accordance with the higher water content of BAT.
Molecular and cellular biology, 2018
CDP138 is a calcium- and lipid-binding protein that is involved in membrane trafficking. Here we report mice without CDP138 develop obesity under normal chow diet (NCD) or high-fat diet (HFD) conditions. CDP138 mice have lower energy expenditure, oxygen consumption and body temperature in comparison with wild-type (WT) mice. Adrenergic signaling on cyclic adenosine monophosphate (cAMP) formation and hormone sensitive lipase (HSL) phosphorylation induced by cold challenge, were decreased in adipose tissues of CDP138 mice. Cold-induced beige fat browning, fatty acid oxidation, thermogenesis, and related gene expression were reduced in CDP138 mice. CDP138 mice are also prone to HFD-induced insulin resistance assessed by Akt phosphorylation and glucose transport in skeletal muscles. Our data indicates that CDP138 is a regulator of stress response and plays a significant role in adipose tissue browning, energy balance, and insulin sensitivity through regulating catecholamine secretion fr...
The Journal of biological chemistry, 2016
The discovery of brown adipose tissue (BAT) as a key regulator of energy expenditure has sparked interest in identifying novel soluble factors capable of activating inducible BAT (iBAT) to combat obesity. Using a high content cell-based screen, we identified Fibroblast Growth Factor (FGF) 16 as a potent inducer of several physical and transcriptional characteristics analogous to those of both classical BAT and iBAT. Over-expression of Fgf16 in vivo recapitulated several of our in vitro findings, specifically significant induction of Ucp1 gene and UCP1 protein expression in inguinal white adipose tissue (iWAT), a common site for emergent active iBAT. Despite significant UCP1 up-regulation in iWAT and dramatic weight loss, the metabolic improvements observed due to Fgf16 over-expression in vivo were not a result of increased energy expenditure, as measured by indirect calorimetric assessment. Instead, a pattern of reduced food and water intake combined with feces replete with lipid an...
Neuroendocrine Regulation of Energy Metabolism Involving Different Types of Adipose Tissues
International Journal of Molecular Sciences, 2019
Despite tremendous research efforts to identify regulatory factors that control energy metabolism, the prevalence of obesity has been continuously rising, with nearly 40% of US adults being obese. Interactions between secretory factors from adipose tissues and the nervous system innervating adipose tissues play key roles in maintaining energy metabolism and promoting survival in response to metabolic challenges. It is currently accepted that there are three types of adipose tissues, white (WAT), brown (BAT), and beige (BeAT), all of which play essential roles in maintaining energy homeostasis. WAT mainly stores energy under positive energy balance, while it releases fuels under negative energy balance. Thermogenic BAT and BeAT dissipate energy as heat under cold exposure to maintain body temperature. Adipose tissues require neural and endocrine communication with the brain. A number of WAT adipokines and BAT batokines interact with the neural circuits extending from the brain to coo...
ADH5-mediated NO bioactivity maintains metabolic homeostasis in brown adipose tissue
Cell Reports, 2021
Highlights • Thermogenesis induces protein S-nitrosylation modification in the BAT; • ADH5, a major cellular denitrosylase, is required for maintaining BAT metabolic homeostasis under both overnutrition and cold stress conditions; • Diet-induced obesity suppresses HSF1-mediated activation of Adh5 in the BAT; • ADH5 overexpression in BAT improves whole-body glucose homeostasis in obesity.
Effects of Polyphenols on Thermogenesis and Mitochondrial Biogenesis
International Journal of Molecular Sciences, 2018
Obesity is a health problem worldwide, and energy imbalance has been pointed out as one of the main factors responsible for its development. As mitochondria are a key element in energy homeostasis, the development of obesity has been strongly associated with mitochondrial imbalance. Polyphenols are the largest group of phytochemicals, widely distributed in the plant kingdom, abundant in fruits and vegetables, and have been classically described as antioxidants owing to their well-established ability to eliminate free radicals and reactive oxygen species (ROS). During the last decade, however, growing evidence reports the ability of polyphenols to perform several important biological activities in addition to their antioxidant activity. Special attention has been given to the ability of polyphenols to modulate mitochondrial processes. Thus, some polyphenols are now recognized as molecules capable of modulating pathways that regulate mitochondrial biogenesis, ATP synthesis, and thermo...
BMC Cancer, 2015
Background: Irisin is a recently discovered myokine, involved in the browning of white adipose tissue. To date, its function has been mainly associated with energy homeostasis and metabolism, and it has been proposed as a promising therapeutic target for obesity and metabolic diseases. This is the first study investigating the role of irisin in human breast cancer. Methods: Participants included one hundred and one (101) female patients with invasive ductal breast cancer and fifty one (51) healthy women. Serum levels of irisin, leptin, adiponectin and resistin were quantified in duplicates by ELISA. Serum levels of CEA, CA 15-3 and Her-2/neu were measured on an immunology analyzer. The association between irisin and breast cancer was examined by logistic regression analysis. The feasibility of serum irisin in discriminating breast cancer patients was assessed by ROC curve analysis. Potential correlations with demographic, anthropometric and clinical parameters, with markers of adiposity and with breast tumor characteristics were also investigated. Results: Serum levels of irisin were significantly lower in breast cancer patients compared to controls (2.47 ± 0.57 and 3.24 ± 0.66 μg/ml, respectively, p < 0.001). A significant independent association between irisin and breast cancer was observed by univariate and multivariate analysis (p < 0.001). It was estimated that a 1 unit increase in irisin levels leads to a reduction in the probability of breast cancer by almost 90 %. Irisin could effectively discriminate breast cancer patients at a cutoff point of 3.21 μg/ml, with 62.7 % sensitivity and 91.1 % specificity. A positive association with tumor stage and marginal associations with tumor size and lymph node metastasis were observed (p < 0.05, p < 0.01, p < 0.01, respectively). Conclusions: Our novel findings implicate irisin in breast cancer and suggest its potential application as a new diagnostic indicator of the presence of disease.
Endocrine, 2016
Purpose To evaluate whether losartan is able to induce beige adipocytes formation, focusing on the thermogenic gene expression and adipocyte remodeling in the subcutaneous white adipose tissue of diet-induced obese mice. Methods Male C57BL/6 mice received a control diet (10% energy as lipids) or a high-fat diet (50% energy as lipids) for 10 weeks, followed by a 5-week treatment with losartan: control group, control-losartan group (10 mg/Kg/day), highfat group and high-fat-losartan group (10 mg/Kg/day). Biochemical, morphometrical, stereological and molecular approaches were used to evaluate the outcomes. Results The high-fat diet elicited overweight, insulin resistance and adipocyte hypertrophy in the high-fat group, all of which losartan rescued in the high-fat-losartan group. These effects comply with the induction of beige adipocytes within the inguinal fat pads in high-fat-losartan group as they exhibited the greatest energy expenditure among the groups along with the presence uncoupling protein 1 positive multilocular adipocytes with enhanced peroxisome proliferator-activated receptor gamma coactivator 1-alpha and PR domain containing 16 mRNA levels, indicating a significant potential for mitochondrial biogenesis and adaptive thermogenesis. Conclusions Our results show compelling evidence that losartan countered diet-induced obesity in mice by enhancing energy expenditure through beige adipocytes induction. Reduced body mass, increased insulin sensitivity, decreased adipocyte size and marked expression of uncoupling protein 1 by ectopic multilocular adipocytes support these findings. The use of losartan as a coadjutant medicine to tackle obesity and its related disorders merits further investigation.
Caffeine exposure induces browning features in adipose tissue in vitro and in vivo
Scientific Reports, 2019
Brown adipose tissue (BAT) is able to rapidly generate heat and metabolise macronutrients, such as glucose and lipids, through activation of mitochondrial uncoupling protein 1 (UCP1). Diet can modulate UCP1 function but the capacity of individual nutrients to promote the abundance and activity of UCP1 is not well established. Caffeine consumption has been associated with loss of body weight and increased energy expenditure, but whether it can activate UCP1 is unknown. This study examined the effect of caffeine on BAT thermogenesis in vitro and in vivo. Stem cell-derived adipocytes exposed to caffeine (1 mM) showed increased UCP1 protein abundance and cell metabolism with enhanced oxygen consumption and proton leak. These functional responses were associated with browning-like structural changes in mitochondrial and lipid droplet content. Caffeine also increased peroxisome proliferatoractivated receptor gamma coactivator 1-alpha expression and mitochondrial biogenesis, together with a number of BAT selective and beige gene markers. In vivo, drinking coffee (but not water) stimulated the temperature of the supraclavicular region, which co-locates to the main region of BAT in adult humans, and is indicative of thermogenesis. Taken together, these results demonstrate that caffeine can promote BAT function at thermoneutrality and may have the potential to be used therapeutically in adult humans. Brown adipose tissue (BAT) is rapidly activated by diet and cold exposure and has the potential to improve metabolic homeostasis in adults 1-3. This adaptation is characterised by enhanced function of the BAT specific uncoupling protein 1 (UCP1), located on the inner mitochondrial membrane 4. In adult humans, as the amount of BAT decreases with age and is negatively correlated with body mass index (BMI) 5-8 , changing the rate of BAT loss could have marked benefits for metabolic health. This could be achieved through dietary ingredients but, although it has been shown that diet can stimulate BAT function 9 , the extent to which individual nutrients can have comparable effects is not well established. Animal studies indicate that brown and beige cells could be activated through nutrients such as capsaicin analogs 10,11 , and capsinoids exert similar effects in increasing BAT-dependent energy expenditure as cold exposure 12. Caffeine (1,3,7-trimethylxantine), a plant alkaloid found in coffee, tea, cola, and chocolate, is widely consumed, has been associated with weight loss and increased energy expenditure in both human and animal models in vivo, and reduces the risk of type 2 diabetes 13-18. Although caffeine has been reported to upregulate UCP1 in obese mice 19 , the extent to which caffeine (or coffee) may directly stimulate BAT is not known. To elucidate this, we utilised a recently established stem cell model of browning 20 to determine whether a physiological amount of caffeine could change mitochondrial function and lipid handling through promotion of UCP1 function. Based on the recent literature 21-23 , a caffeine concentration of 1 mM was used for in vitro cell culture. A human in vivo study was then undertaken to determine whether the amount of 1 Wolfson centre for Stem cells, tissue engineering and Modelling (SteM), Division of cancer & Stem cells,
Human whole body cold adaptation
Temperature, 2016
Reviews on whole body human cold adaptation generally do not distinguish between population studies and dedicated acclimation studies, leading to confusing results. Population studies show that indigenous black Africans have reduced shivering thermogenesis in the cold and poor cold induced vasodilation in fingers and toes compared to Caucasians and Inuit. About 40,000 y after humans left Africa, natives in cold terrestrial areas seems to have developed not only behavioral adaptations, but also physiological adaptations to cold. Dedicated studies show that repeated whole body exposure of individual volunteers, mainly Caucasians, to severe cold results in reduced cold sensation but no major physiological changes. Repeated cold water immersion seems to slightly reduce metabolic heat production, while repeated exposure to milder cold conditions shows some increase in metabolic heat production, in particular non-shivering thermogenesis. In conclusion, human cold adaptation in the form of increased metabolism and insulation seems to have occurred during recent evolution in populations, but cannot be developed during a lifetime in cold conditions as encountered in temperate and arctic regions. Therefore, we mainly depend on our behavioral skills to live in and survive the cold.
Scoliosis, 2009
Anthropometric data from three groups of adolescent girls-preoperative adolescent idiopathic scoliosis (AIS), screened for scoliosis and normals were analysed by comparing skeletal data between higher and lower body mass index subsets. Unexpected findings for each of skeletal maturation, asymmetries and overgrowth are not explained by prevailing theories of AIS pathogenesis. A speculative pathogenetic theory for girls is formulated after surveying evidence including: (1) the thoracospinal concept for right thoracic AIS in girls; (2) the new neuroskeletal biology relating the sympathetic nervous system to bone formation/resorption and bone growth; (3) white adipose tissue storing triglycerides and the adiposity hormone leptin which functions as satiety hormone and sentinel of energy balance to the hypothalamus for long-term adiposity; and (4) central leptin resistance in obesity and possibly in healthy females. The new theory states that AIS in girls results from developmental disharmony expressed in spine and trunk between autonomic and somatic nervous systems. The autonomic component of this double neuro-osseous theory for AIS pathogenesis in girls involves selectively increased sensitivity of the hypothalamus to circulating leptin (genetically-determined up-regulation possibly involving inhibitory or sensitizing intracellular molecules, such as SOC3, PTP-1B and SH2B1 respectively), with asymmetry as an adverse response (hormesis); this asymmetry is routed bilaterally via the sympathetic nervous system to the growing axial skeleton where it may initiate the scoliosis deformity (leptinhypothalamic-sympathetic nervous system concept = LHS concept). In some younger preoperative AIS girls, the hypothalamic up-regulation to circulating leptin also involves the somatotropic (growth hormone/IGF) axis which exaggerates the sympathetically-induced asymmetric skeletal
PLoS ONE, 2013
We used RNAseq to generate a comprehensive transcriptome of Brown Adipose Tissue (BAT) over the course of a year in the naturally hibernating thirteen-lined ground squirrel, Ictidomys tridecemlineatus. During hibernation ground squirrels do not feed and use fat stored in White Adipose Tissue (WAT) as their primary source of fuel. Stored lipid is consumed at high rates by BAT to generate heat at specific points during the hibernation season. The highest rate of BAT activity occurs during periodic arousals from hypothermic torpor bouts, referred to as Interbout Arousals (IBAs). IBAs are characterized by whole body re-warming (from 5 to 37 °C) in 2-3 hours, and provide a unique opportunity to determine the genes responsible for the highly efficient lipid oxidation and heat generation that drives the arousal process. Illumina HighSeq sequencing identified 14,573 distinct BAT mRNAs and quantified their levels at four points: active ground squirrels in April and October, and hibernating animals during both torpor and IBA. Based on significant changes in mRNA levels across the four collection points, 2,083 genes were shown to be differentially expressed. In addition to providing detail on the expression of nuclear genes encoding mitochondrial proteins, and genes involved in beta-adrenergic and lipolytic pathways, we identified differentially expressed genes encoding various transcription factors and other regulatory proteins which may play critical roles in high efficiency fat catabolism, non-shivering thermogenesis, and transitions into and out of the torpid state.
MKK6 controls T3-mediated browning of white adipose tissue
Nature communications, 2017
Increasing the thermogenic capacity of adipose tissue to enhance organismal energy expenditure is considered a promising therapeutic strategy to combat obesity. Here, we report that expression of the p38 MAPK activator MKK6 is elevated in white adipose tissue of obese individuals. Using knockout animals and shRNA, we show that Mkk6 deletion increases energy expenditure and thermogenic capacity of white adipose tissue, protecting mice against diet-induced obesity and the development of diabetes. Deletion of Mkk6 increases T3-stimulated UC P1 expression in adipocytes, thereby increasing their thermogenic capacity. Mechanistically, we demonstrate that, in white adipose tissue, p38 is activated by an alternative pathway involving AMPK, TAK, and TAB. Our results identify MKK6 in adipocytes as a potential therapeutic target to reduce obesity.Brown and beige adipose tissues dissipate heat via uncoupling protein 1 (UCP1). Here the authors show that the stress activated kinase MKK6 acts as a...
2020
Uncoupling protein 1 (UCP1) is found in the inner mitochondrial membrane of brown adipocyte. In the presence of long-chain fatty acids (LCFA), UCP1 increases the proton conductance, which, in turn, increases fatty acid oxidation and energy release as heat. Several atomic models of UCP1 and UCP2 have been obtained by NMR in dodecylphosphocholine (DPC), a detergent known to inactivate UCP1. Based on NMR titration experiment on UCP1 with LCFA, it has been proposed that K56 and K269 are crucial for LCFA binding and UCP1 activation. Given the numerous controversies on the use of DPC for structure-function analyses of membrane proteins, we revisited those UCP1 mutants in a more physiological context by expressing them in the mitochondria of S. cerevisiae. Mitochondrial respiration, assayed on permeabilized spheroplasts, enables the determination of UCP1 activation and inhibition. The K56S, K269S and K56S/K269S mutants did not display any default in activation, which shows that the NMR exp...
International Journal of Molecular Sciences, 2016
Over the last several years, the increasing prevalence of obesity has favored an intense study of adipose tissue biology and the precise mechanisms involved in adipocyte differentiation and adipogenesis. Adipocyte commitment and differentiation are complex processes, which can be investigated thanks to the development of diverse in vitro cell models and molecular biology techniques that allow for a better understanding of adipogenesis and adipocyte dysfunction associated with obesity. The aim of the present work was to update the different animal and human cell culture models available for studying the in vitro adipogenic differentiation process related to obesity and its co-morbidities. The main characteristics, new protocols, and applications of the cell models used to study the adipogenesis in the last five years have been extensively revised. Moreover, we depict co-cultures and three-dimensional cultures, given their utility to understand the connections between adipocytes and their surrounding cells in adipose tissue.
Targeting skeletal muscle mitochondrial health in obesity
Clinical Science
Metabolic demands of skeletal muscle are substantial and are characterized normally as highly flexible and with a large dynamic range. Skeletal muscle composition (e.g., fiber type and mitochondrial content) and metabolism (e.g., capacity to switch between fatty acid and glucose substrates) are altered in obesity, with some changes proceeding and some following the development of the disease. Nonetheless, there are marked interindividual differences in skeletal muscle composition and metabolism in obesity, some of which have been associated with obesity risk and weight loss capacity. In this review, we discuss related molecular mechanisms and how current and novel treatment strategies may enhance weight loss capacity, particularly in diet-resistant obesity.
Hypothalamic GRP78, a new target against obesity?
Adipocyte, 2017
The chaperone GRP78 (glucose related protein 78), also called BiP (binding immunoglobulin protein) is a key regulator of endoplasmic reticulum (ER) stress. We recently described that over-expression of GRP78 specifically in the ventromedial nucleus of the hypothalamus (VMH) releases hypothalamic ER stress in rodent obese models leading to weight loss, reduced hepatic steatosis and improved insulin and leptin sensitivity. The action of GRP78 is mediated by a feeding-independent mechanism involving increased sympathetic tone, augmented brown adipose tissue (BAT) thermogenesis and induction browning of white adipose tissue (WAT).
Journal of Applied Physiology, 2020
The sympathetic nervous system (SNS) activates cAMP signaling and promotes trophic effects on brown adipose tissue (BAT) through poorly understood mechanisms. Because norepinephrine has been found to induce antiproteolytic effects on muscle and heart, we hypothesized that the SNS could inhibit autophagy in interscapular BAT (IBAT). Here, we describe that selective sympathetic denervation of rat IBAT kept at 25°C induced atrophy, and in parallel dephosphorylated forkhead box class O (FoxO), and increased cathepsin activity, autophagic flux, autophagosome formation, and expression of autophagy-related genes. Conversely, cold stimulus (4°C) for up to 72 h induced thermogenesis and IBAT hypertrophy, an anabolic effect that was associated with inhibition of cathepsin activity, autophagic flux, and autophagosome formation. These effects were abrogated by sympathetic denervation, which also upregulated Gabarapl1 mRNA. In addition, the cold-driven sympathetic activation stimulated the mecha...
Annals of medicine, 2014
Brown adipose tissue (BAT) is a specialized organ responsible for thermogenesis, a process required for maintaining body temperature. BAT is regulated by the sympathetic nervous system (SNS), which activates lipolysis and mitochondrial uncoupling in brown adipocytes. For many years, BAT was considered to be important only in small mammals and newborn humans, but recent data have shown that BAT is also functional in adult humans. On the basis of this evidence, extensive research has been focused on BAT function, where new molecules, such as irisin and bone morphogenetic proteins, particularly BMP7 and BMP8B, as well as novel central factors and new regulatory mechanisms, such as orexins and the canonical ventomedial nucleus of the hypothalamus (VMH) AMP- activated protein kinase (AMPK)-SNS-BAT axis, have been discovered and emerged as potential drug targets to combat obesity. In this review we provide an overview of the complex central regulation of BAT and how different neuronal cel...
Frontiers in Physiology, 2018
Cold induced thermogenesis (CIT) in humans results mainly from the combination of both brown adipose tissue (BAT) and skeletal muscle thermogenic activity. The relative contribution of both tissues to CIT and to cold induced nutrient oxidation rates (CI-NUTox) remains, however, to be elucidated. We investigated the association of BAT and skeletal muscle activity after a personalized cold exposure with CIT and CI-NUTox in 57 healthy adults (23.0 ± 2.4 years old; 25.1 ± 4.6 kg/m 2 ; 35 women). BAT and skeletal muscle (paracervical, sternocleidomastoid, scalene, longus colli, trapezius, parathoracic, supraspinatus, subscapular, deltoid, pectoralis major, and triceps brachii) metabolic activity were assessed by means of a 18 Fluorodeoxyglucose positron emission tomography-computed tomography scan preceded by a personalized cold exposure. The cold exposure consisted in remaining in a mild cold room for 2 h at 19.5-20 • C wearing a water perfused cooling vest set at 3.8 • C above the individual shivering threshold. On a separate day, we estimated CIT and CI-NUTox by indirect calorimetry under fasting conditions for 1 h of personalized cold exposure. There was no association of BAT volume or activity with CIT or CI-NUTox (all P > 0.2). Similarly, the skeletal muscle metabolic activity was not associated either with CIT or CI-NUTox (all P > 0.2). The results persisted after controlling for sex, the time of the day, and the date when CIT was assessed. Our results suggest that human BAT activity and skeletal muscle 18 F-FDG activity are not associated to CIT in young healthy adults. Inherent limitations of the available radiotracers for BAT detection and muscle activity quantification may explain why we failed to detect a physiologically plausible association.
Nature communications, 2018
Obesity has emerged as an alarming health crisis due to its association with metabolic risk factors such as diabetes, dyslipidemia, and hypertension. Recent work has demonstrated the multifaceted roles of lncRNAs in regulating mouse adipose development, but their implication in human adipocytes remains largely unknown. Here we present a catalog of 3149 adipose active lncRNAs, of which 909 are specifically detected in brown adipose tissue (BAT) by performing deep RNA-seq on adult subcutaneous, omental white adipose tissue and fetal BATs. A total of 169 conserved human lncRNAs show positive correlation with their nearby mRNAs, and knockdown assay supports a role of lncRNAs in regulating their nearby mRNAs. The knockdown of one of those, lnc-dPrdm16, impairs brown adipocyte differentiation in vitro and a significant reduction of BAT-selective markers in in vivo. Together, our work provides a comprehensive human adipose catalog built from diverse fat depots and establishes a roadmap to ...
Browning Epicardial Adipose Tissue: Friend or Foe?
Cells, 2022
The epicardial adipose tissue (EAT) is the visceral fat depot of the heart which is highly plastic and in direct contact with myocardium and coronary arteries. Because of its singular proximity with the myocardium, the adipokines and pro-inflammatory molecules secreted by this tissue may directly affect the metabolism of the heart and coronary arteries. Its accumulation, measured by recent new non-invasive imaging modalities, has been prospectively associated with the onset and progression of coronary artery disease (CAD) and atrial fibrillation in humans. Recent studies have shown that EAT exhibits beige fat-like features, and express uncoupling protein 1 (UCP-1) at both mRNA and protein levels. However, this thermogenic potential could be lost with age, obesity and CAD. Here we provide an overview of the physiological and pathophysiological relevance of EAT and further discuss whether its thermogenic properties may serve as a target for obesity therapeutic management with a specif...
Microbiome‐immune‐metabolic axis in the epidemic of childhood obesity: Evidence and opportunities
Obesity Reviews, 2019
Obesity epidemic responsible for increase in diabetes, heart diseases, infections and cancer shows no signs of abating. Obesity in children is also on rise, indicating the urgent need of strategies for prevention and intervention that must begin in early life. While originally posited that obesity results from the simple concept of consuming more calories, or genetics, emerging research suggests that the bacteria living in our gut (gut microbiome) and its interactions with immune cells and metabolic organs including adipose tissues (microbiome-immune-metabolic axis) play significant role in obesity development in childhood. Specifically, abnormal changes (dysbiosis) in the gut microbiome, stimulation of inflammatory cytokines, and shifts in the metabolic functions of brown adipose tissue and the browning of white adipose tissue are associated with increased obesity. Many factors from as early as gestation appear to contribute in obesity, such as maternal health, diet, antibiotic use by mother and/or child, and birth and feeding methods. Herein, using evidence from animal and human studies, we discuss how these factors impact microbiome-immune-metabolic axis and cause obesity epidemic in children, and describe the gaps in knowledge that are warranted for future research.
GeroScience, 2020
Adipose tissue plays an essential role in metabolic health. Ames dwarf mice are exceptionally longlived and display metabolically beneficial phenotypes in their adipose tissue, providing an ideal model for studying the intersection between adipose tissue and longevity. To this end, we assessed the metabolome and lipidome of adipose tissue in Ames dwarf mice. We observed distinct lipid profiles in brown versus white adipose tissue of Ames dwarf mice that are consistent with increased thermogenesis and insulin sensitivity, such as increased cardiolipin and decreased ceramide concentrations. Moreover, we identified 5hydroxyeicosapentaenoic acid (5-HEPE), an ω-3 fatty acid metabolite, to be increased in Ames dwarf brown adipose tissue (BAT), as well as in circulation. Importantly, 5-HEPE is increased in other models of BAT activation and is negatively correlated with body weight, insulin resistance, and circulating triglyceride concentrations in humans. Together, these data represent a novel lipid signature of adipose tissue in a mouse model of extreme longevity.
Journal of Lipid Research, 2018
acid (ARA), and 3 -linolenic acid, a precursor of 3 EPA and DHA. These long-chain PUFAs trigger a variety of biological responses, particularly in adipose tissue, and are required for healthy development (1, 2). New dietary recommendations take into account the insufficient intake of 3 PUFAs and the excess of 6 PUFAs, which correlate with overweight/obesity (3-5). Indeed, high 6:3 ratios are positively associated with adiposity of infants at 6 months and 3 and 4 years of age (6-8), and ARA intake correlates positively with BMI and the associated metabolic syndrome (9-13). In fact, diets exhibiting a high 6:3 ratio result in higher ARA bioavailability for the synthesis of 6 derived oxylipins due to an insufficient compensatory effect of EPA and DHA (14). These 6 oxygenated derivatives are known to favor inflammatory responses (15), promote energy storage (16), and inhibit energy expenditure (17). These effects are mainly triggered by oxylipins arising from the cyclooxygenase (COX) pathway. In contrast to the white adipose tissue (WAT) involved in energy storage and release, brown adipose tissue (BAT) is endowed with thermogenic activity and regulates body temperature by dissipating energy through nonshivering thermogenesis (18). This mechanism is mediated by uncoupling protein 1 (UCP1), which uncouples mitochondrial oxygen consumption from energy production. Interestingly, a further population of UCP1-positive adipocytes is present in WAT and is termed brite for "brown in white" or beige adipocytes (19-21). In vivo, brite adipocytes stem from progenitors or emerge by direct conversion of mature white Abstract The recent characterization of functional brown adipose tissue in adult humans has opened new perspectives for regulation of energy expenditure with respect to obesity and diabetes. Furthermore, dietary recommendations have taken into account the insufficient dietary intake of 3 PUFAs and the concomitant excessive intake of 6 PUFA associated with the occurrence of overweight/obesity. We aimed to study whether 3 PUFAs could play a role in the recruitment and function of energy-dissipating brown/brite adipocytes. We show that 3 PUFA supplementation has a beneficial effect on the thermogenic function of adipocytes. In vivo, a low dietary 6:3 ratio improved the thermogenic response of brown and white adipose tissues to 3-adrenergic stimulation. This effect was recapitulated in vitro by PUFA treatment of hMADS adipocytes. We pinpointed the 6derived eicosanoid prostaglandin (PG)F2 as the molecular origin because the effects were mimicked with a specific PGF2 receptor agonist. PGF2 level in hMADS adipocytes was reduced in response to 3 PUFA supplementation. The recruitment of thermogenic adipocytes is influenced by the local quantity of individual oxylipins, which is controlled by the 6:3 ratio of available lipids. In human nutrition, energy homeostasis may thus benefit from the implementation of a more balanced dietary 6:3 ratio.-Ghandour, R.
Fatty acid metabolism and the basis of brown adipose tissue function
Adipocyte, 2016
Obesity has reached epidemic proportions, leading to severe associated pathologies such as insulin resistance, cardiovascular disease, cancer and type 2 diabetes. Adipose tissue has become crucial due to its involvement in the pathogenesis of obesity-induced insulin resistance, and traditionally white adipose tissue has captured the most attention. However in the last decade the presence and activity of heat-generating brown adipose tissue (BAT) in adult humans has been rediscovered. BAT decreases with age and in obese and diabetic patients. It has thus attracted strong scientific interest, and any strategy to increase its mass or activity might lead to new therapeutic approaches to obesity and associated metabolic diseases. In this review we highlight the mechanisms of fatty acid uptake, trafficking and oxidation in brown fat thermogenesis. We focus on BAT's morphological and functional characteristics and fatty acid synthesis, storage, oxidation and use as a source of energy.
PLOS ONE, 2016
The discovery of active brown adipose tissue (BAT) in adult humans and the fact that it is reduced in obese and diabetic patients have put a spotlight on this tissue as a key player in obesity-induced metabolic disorders. BAT regulates energy expenditure through thermogenesis; therefore, harnessing its thermogenic fat-burning power is an attractive therapeutic approach. We aimed to enhance BAT thermogenesis by increasing its fatty acid oxidation (FAO) rate. Thus, we expressed carnitine palmitoyltransferase 1AM (CPT1AM), a permanently active mutant form of CPT1A (the rate-limiting enzyme in FAO), in a rat brown adipocyte (rBA) cell line through adenoviral infection. We found that CPT1AM-expressing rBA have increased FAO, lipolysis, UCP1 protein levels and mitochondrial activity. Additionally, enhanced FAO reduced the palmitate-induced increase in triglyceride content and the expression of obese and inflammatory markers. Thus, CPT1AM-expressing rBA had enhanced fat-burning capacity and improved lipid-induced derangements. This indicates that CPT1AM-mediated increase in brown adipocytes FAO may be a new approach to the treatment of obesity-induced disorders.
Neck adipose tissue – tying ties in metabolic disorders
Hormone Molecular Biology and Clinical Investigation, 2018
Upper body adipose tissue accumulation has been associated with clustering of metabolic disorders and increased cardiovascular risk. Neck circumference (NC) indicated that subcutaneous adipose tissue (SAT) in that region is an independent pathogenic depot that might account for the additional risk missed by visceral adipose tissue (VAT). Neck adipose tissue (NAT) is not only one more ectopic depot but has several particular features that might modulate its metabolic role. Besides a controversial impact on obstructive apnea syndrome, neck fat encompasses carotid arteries as an important perivascular adipose tissue (PVAT) depot. With dysfunctional changes in obesity, physiologic vascular regulation is lost and inflammatory signals accelerate atherogenesis. Unexpected was the discovery of brown and beige adipocytes in the neck of human adults. When stimulated, brown adipose tissue (BAT) dissipates energy through thermogenesis and it is associated with other favorable metabolic effects....
2019
Atrial natriuretic peptide (ANP) is a cardiac hormone controlling blood volume and arterial pressure in mammals. It is unclear whether and how ANP controls cold-induced thermogenesis in vivo. Here we show that acute cold exposure induces cardiac ANP secretion in mice and humans. Genetic inactivation of ANP promotes cold intolerance and suppresses about half of cold-induced brown adipose tissue (BAT) activation in mice. While white adipocytes are resistant to ANP-mediated lipolysis at thermoneutral temperature in mice, cold exposure renders white adipocytes fully responsive to ANP to activate lipolysis and a thermogenic program, a physiological response which is dramatically suppressed in ANP null mice. ANP deficiency also blunts liver triglycerides and glycogen metabolism thus impairing fuel availability for BAT thermogenesis. ANP directly increases mitochondrial uncoupling and thermogenic genes expression in human white and brown adipocytes. Together, these results indicate that AN...
The Journal of Experimental Biology, 2018
The aim of this study was to determine the effects of long-term sucrose overfeeding on functional capacity and ultrastructural characteristics of the rat brown adipose tissue (BAT). For the study, sixteen male Wistar rats, chow-fed and kept under standard laboratory conditions were divided into 2 equal groups. The rats from a control group drank tap water, while those from a sucrose overfed group were allowed to drink 10% sucrose solution for 21 days. Structural changes of BAT were analysed at the level of light and electron microscopy on routinely prepared tissue sections or using immunohistochemical staining, in combination with stereological methods. Obtained results have shown that significantly increased energy intake in sucrose overfed rats did not result in elevated body mass gain. The light microscopy analysis revealed that the BAT acquired the appearance of a thermogenically active tissue, with intensified vascularisation, reduced size of brown adipocytes and increased mult...
Unique Genetic and Histological Signatures of Mouse Pericardial Adipose Tissue
Nutrients, 2020
Obesity is a major risk factor for a plethora of metabolic disturbances including diabetes and cardiovascular disease. Accumulating evidence is showing that there is an adipose tissue depot-dependent relationship with obesity-induced metabolic dysfunction. While some adipose depots, such as subcutaneous fat, are generally metabolically innocuous, others such as visceral fat, are directly deleterious. A lesser known visceral adipose depot is the pericardial adipose tissue depot. We therefore set out to examine its transcriptional and morphological signature under chow and high-fat fed conditions, in comparison with other adipose depots, using a mouse model. Our results revealed that under chow conditions pericardial adipose tissue has uncoupling-protein 1 gene expression levels which are significantly higher than classical subcutaneous and visceral adipose depots. We also observed that under high-fat diet conditions, the pericardial adipose depot exhibits greatly upregulated transcri...
International Journal of Molecular Sciences, 2018
Adipose-derived stromal/stem cells (ASCs) seems to be a promising regenerative therapeutic agent due to the minimally invasive approach of their harvest and multi-lineage differentiation potential. The harvested adipose tissues are further digested to extract stromal vascular fraction (SVF), which is cultured, and the anchorage-dependent cells are isolated in order to characterize their stemness, surface markers, and multi-differentiation potential. The differentiation potential of ASCs is directed through manipulating culture medium composition with an introduction of growth factors to obtain the desired cell type. ASCs have been widely studied for its regenerative therapeutic solution to neurologic, skin, wound, muscle, bone, and other disorders. These therapeutic outcomes of ASCs are achieved possibly via autocrine and paracrine effects of their secretome comprising of cytokines, extracellular proteins and RNAs. Therefore, secretome-derivatives might offer huge advantages over ce...
Nature Communications, 2018
Activation of brown adipose tissue-mediated thermogenesis is a strategy for tackling obesity and promoting metabolic health. BMP8b is secreted by brown/beige adipocytes and enhances energy dissipation. Here we show that adipocyte-secreted BMP8b contributes to adrenergic-induced remodeling of the neuro-vascular network in adipose tissue (AT). Overexpression of bmp8b in AT enhances browning of the subcutaneous depot and maximal thermogenic capacity. Moreover, BMP8b-induced browning, increased sympathetic innervation and vascularization of AT were maintained at 28 °C, a condition of low adrenergic output. This reinforces the local trophic effect of BMP8b. Innervation and vascular remodeling effects required BMP8b signaling through the adipocytes to 1) secrete neuregulin-4 (NRG4), which promotes sympathetic axon growth and branching in vitro, and 2) induce a pro-angiogenic transcriptional and secretory profile that promotes vascular sprouting. Thus, BMP8b and NRG4 can be considered as i...
Brown versus White Adipose Tissue: A Mini-Review
Gerontology, 2012
Background: Brown adipose tissue (BAT) is abundant in small mammals and in newborns and helps them to survive cold temperatures. In adults, it had long been considered to be absent or at least of no relevance. Recent investigations, however, have fuelled interest in adult BAT. Objective: We aimed at (1) summarizing structural and physiological characteristics of BAT versus white adipose tissue (WAT); (2) discussing the development of the two adipose tissue types; (3) reviewing the data available from human studies on BAT, and (4) discussing the impact of aging. Methods: We summarize recent descriptions of BAT and WAT based on the original literature and reviews in the field, with emphasis on human BAT. Results: WAT and BAT have essentially antagonistic functions: WAT stores excess energy as triglycerides and BAT is specialized in the dissipation of energy through the production of heat. Considerable amounts of BAT are present in a substantial proportion of adult humans and relativel...
Scientific Reports, 2016
Histone acetylation depends on the abundance of nucleo-cytoplasmic acetyl-CoA. Here, we present a novel route for cytoplasmic acetyl-CoA production in brown adipocytes. N-acetylaspartate (NAA) is a highly abundant brain metabolite catabolized by aspartoacylase yielding aspartate and acetate. The latter can be further used for acetyl-CoA production. Prior to this work, the presence of NAA has not been described in adipocytes. Here, we show that accumulation of NAA decreases the brown adipocyte phenotype. We increased intracellular NAA concentrations in brown adipocytes via media supplementation or knock-down of aspartoacylase and measured reduced lipolysis, thermogenic gene expression and oxygen consumption. Combinations of approaches to increase intracellular NAA levels showed additive effects on lipolysis and gene repression, nearly abolishing the expression of Ucp1, Cidea, Prdm16 and Ppara. Transcriptome analyses of aspartoacylase knock-down cells indicate deficiencies in acetyl-C...
Mediators of Inflammation, 2017
Obesity is marked by chronic, low-grade inflammation. Here, we examined whether intrinsic differences between white and brown adipocytes influence the inflammatory status of macrophages. White and brown adipocytes were characterized by transcriptional regulation of UCP-1, PGC1α, PGC1β, and CIDEA and their level of IL-6 secretion. The inflammatory profile of PMA-differentiated U937 and THP-1 macrophages, in resting state and after stimulation with LPS/IFN-gamma and IL-4, was assessed by measuring IL-6 secretion and transcriptional regulation of a panel of inflammatory genes after mono- or indirect coculture with white and brown adipocytes. White adipocyte monocultures show increased IL-6 secretion compared to brown adipocytes. White adipocytes cocultured with U937 and THP-1 macrophages induced a greater increase in IL-6 secretion compared to brown adipocytes cocultured with both macrophages. White adipocytes cocultured with macrophages increased inflammatory gene expression in both t...
Investigation of the Relationship between MR-Based Supraclavicular Fat Fraction and Thyroid Hormones
Obesity Facts, 2020
Purpose: Brown adipose tissue (BAT) plays a potential role in energy and glucose metabolism in humans. Thyroid hormones (TH) are main regulators of BAT development and function. However, it remains unknown how the magnetic resonance (MR)-based proton density fat fraction (PDFF) of supraclavicular adipose tissue used as a surrogate marker for BAT presence relates to TH. Therefore, the purpose of this analysis was to investigate the relationship between supraclavicular PDFF and serum levels of TH. Methods: In total, 96 adult volunteers from a large cross-sectional study who underwent additional MR examination of the neck and pelvis were included in this analysis. Segmented PDFF maps of the supraclavicular and gluteal subcutaneous adipose tissue were generated. Delta PDFF was calculated as the difference between gluteal and supraclavicular PDFF and grouped as high (≥12%) or low (<12%) based on the median and the clinical rationale of a high versus low probability of BAT being presen...
Insulin selectively reduces mitochondrial uncoupling in brown adipose tissue in mice
The Biochemical journal, 2018
The purpose of the present study was to determine the effects of prolonged hyperinsulinemia on mitochondrial respiration and uncoupling in distinct adipose tissue depots. Sixteen-week-old male mice were injected daily with placebo or insulin to induce an artificial hyperinsulinemia for 28 days. Following the treatment period, mitochondrial respiration and degree of uncoupling were determined in permeabilized perirenal, inguinal, and interscapular adipose tissue. White adipose tissue (WAT) mitochondria (inguinal and perirenal) respire at substantially lower rates compared with brown adipose tissue (BAT). Insulin treatment resulted in a significant reduction in mitochondrial respiration in inguinal WAT (iWAT) and interscapular BAT (iBAT), but not in perirenal WAT (pWAT). Furthermore, these changes were accompanied by an insulin-induced reduction in UCP-1 (uncoupling protein 1) and PGC-1α in iWAT and iBAT only, but not in pWAT or skeletal muscle. Compared with adipose tissue mitochondr...
Sex differences in thermoregulation in mammals: Implications for energy homeostasis
Frontiers in Endocrinology
Thermal homeostasis is a fundamental process in mammals, which allows the maintenance of a constant internal body temperature to ensure an efficient function of cells despite changes in ambient temperature. Increasing evidence has revealed the great impact of thermoregulation on energy homeostasis. Homeothermy requires a fine regulation of food intake, heat production, conservation and dissipation and energy expenditure. A great interest on this field of research has re-emerged following the discovery of thermogenic brown adipose tissue and browning of white fat in adult humans, with a potential clinical relevance on obesity and metabolic comorbidities. However, most of our knowledge comes from male animal models or men, which introduces unwanted biases on the findings. In this review, we discuss how differences in sex-dependent characteristics (anthropometry, body composition, hormonal regulation, and other sexual factors) influence numerous aspects of thermal regulation, which imp...
Adaptive thermogenesis in mice requires adipocyte light-sensing via Opsin 3
2019
SummaryAlmost all life forms can decode light information for adaptive advantage. Examples include the visual system, where photoreceptor signals are interpreted as images, and the circadian system, where light entrains a physiological clock. Here we describe a local, non-visual light response in mice that employs encephalopsin (OPN3, a 480 nm, blue light responsive opsin) to regulate the function of adipocytes. Germ line null and adipocyte-specific conditional null mice show a deficit in thermogenesis that is phenocopied in mice under blue-light deficient conditions. We show that blue light stimulation of adipocytes activates hormone sensitive lipase, the rate limiting enzyme in the lipolysis pathway, and that this is OPN3-dependent. Opn3 adipocyte conditional null mice also use reduced levels of fat mass when fasted and cold exposed further suggesting a lipolysis deficit. These data suggest the hypothesis that in mice, a local, OPN3-dependent light response in adipocytes is a mech...
Hormone and Metabolic Research, 2020
Polycystic ovary syndrome (PCOS) is a chronic dysfunction associated with obesity and metabolic disorders that can be ameliorated by treatment with metformin. Brown adipose tissue (BAT) has been recently identified in adult humans, and irisin is a myokine that induces BAT formation. The aim of this randomized controlled trial was to evaluate whether a short term treatment with metformin alters BAT activity and plasma irisin levels in women with PCOS. The participants were randomly assigned to receive metformin (1500 mg/day, n=21) or placebo (n=24) during 60 days. BAT activity was assessed by 18F-FDG positron emission tomography-computed tomography (PET-CT) and plasma irisin levels were measured by enzyme immunoassay. The groups were similar in age, body measures, metabolic profile and PCOS phenotypes. BAT activity did not change significantly in the women treated with metformin (median Δ SUVmax=–0.06 g/ml, interquartile interval –2.81 to 0.24 g/ml, p=0.484, Wilcoxon’s test) or place...
Genes & Nutrition, 2013
Induction of brown-like adipocytes (brite) in white adipose tissues may allow the conversion of lipid storage cells in fat-burning cells. Little is known concerning browning potential in males compared with females. In this study, we aimed to analyse whether gender differences were present in gene expression of ''brite'' markers as well as the impact of dietary manipulation at both early stages and adulthood in rats. We have determined the expression of brite markers and genes associated with lipid and energy metabolism in inguinal adipose tissue in adult male and female rats. We have analysed the impact of high-fat (HF) diet in adult life and of early leucine supplementation (2 %) during lactation. Results show that although both genders have the potential to induce brite genes in inguinal adipose tissue, males expressed higher levels (CIDEA, HOXC9 and SHOX2), which would imply a higher browning capacity in comparison with females. Minor impact of HF diet in adult life was observed in most of the genes studied. Interestingly, results showed that early Leu was able to compromise the metabolic fate of white and brite adipocytes later in adult life. Leucine supplementation programmed higher expression of cell death-inducing DFFA-like effector, accompanied with induction of sterol regulatory element binding transcription 1c factor and lower UPC2 expression, particularly in females. In addition, Leucine supplementation was associated with higher expression of leptin and PPARc and decreased carnitine palmitoyl transferase in both genders. Although the exact role of these adaptations needs further comprehensive analysis, dietary Leu supplementation at early age programmed inguinal adipose tissue in a gender specific manner.
Biomedicines, 2021
Fat grafting is a frequently applied procedure in plastic surgery for volume reconstruction. Moreover, the transplantation of white adipose tissue (WAT) and brown adipose tissue (BAT) increasingly gains interest in preclinical research for the treatment of obesity-related metabolic defects. Therefore, we herein directly compared the vascularization capacity and survival of WAT and BAT grafts. For this purpose, size-matched grafts isolated from the inguinal WAT pad and the interscapular BAT depot of C57BL/6N donor mice were syngeneically transplanted into the dorsal skinfold chamber of recipient animals. The vascularization and survival of the grafts were analyzed by means of intravital fluorescence microscopy, histology, and immunohistochemistry over an observation period of 14 days. WAT grafts showed an identical microvascular architecture and functional microvessel density as native WAT. In contrast, BAT grafts developed an erratic microvasculature with a significantly lower funct...
Nuclear medicine and molecular imaging, 2013
To study the (18)F-FDG uptake pattern in brown adipose tissue (BAT) over an extended time period, by multiple-time-point fluorodeoxyglucose positron emission tomography (FDG-PET) imaging. The primary objective for this kind of research was that it could form a basis and may have further implications for obesity research, metabolic diseases and for cachexia of both malignant and benign origin. A total of 12 patients who had undergone routine FDG-PET for disease evaluation and had demonstrated prominent BAT uptake in their baseline scans were selected. The patients with the diagnosis of neuroendocrine tumors were excluded. Maximum standardized uptake values (SUVmax) were calculated in the BAT of the supraclavicular and paravertebral areas of either side, and were analyzed separately to examine their behavior individually. Time activity curves (TACs) were generated for [A] BAT SUVmax values and [B] SUVmax ratio of BAT/lung (B/L SUVmax ratio) at various time points. Ten out of the 12 pa...
Role of Epicardial Adipose Tissue in Health and Disease: A Matter of Fat?
Comprehensive Physiology, 2017
Running head Role of epicardial fat in health and disease Didactic synopsis Major teaching points:" followed by a bulleted list of 5-10 summary statements. EAT is an ectopic fat depot located between myocardium and the visceral pericardium with no fascia separating the tissues, allowing local interaction and cellular cross-talk between myocytes and adipocytes Given the lack of standard terminology, it is necessary to make a distinction between epicardial and pericardial fat to avoid confusion in the use of terms. The pericardial fat refers to the combination of epicardial fat and paracardial fat (located on the external surface of the parietal pericardium) Imaging techniques such as echocardiography, computed tomography or magnetic resonance imaging are necessary to study EAT distribution in humans Very little amount of EAT is found in rodents compared to humans EAT displays high rate of fatty acids metabolism (lipogenesis and lipolysis), thermogenic (beiging features), and mechanical properties (protective framework for cardiac autonomic nerves and vessels) Compared to visceral fat, EAT is likely to have predominant local effects EAT secretes numerous bioactive factors including adipokines, fibrokines, growth factors and cytokines that could either be protective or harmful depending on the local microenvironement Human EAT has a unique transcriptome enriched in genes implicated in extracellular matrix remodeling, inflammation, immune signaling, beiging, thrombosis and apoptosis pathways Epicardial adipocytes have a mesothelial origin and derive mainly from epicardium. Cells originating from the Wt1+ mesothelial lineage, can differentiate into EAT and this "epicardium-to-fat transition" fate could be reactivated after myocardial infarction Factors leading to cardiac ectopic fat deposition may include dysfunctional subcutaneous adipose tissue, fibrosis, inflammation, hypoxia, and aging Periatrial EAT has a specific transcriptomic signature and its amount is associated with atrial fibrillation EAT is likely to play a role in the pathogenesis of cardiovascular disease and coronary artery disease EAT amount is a strong independent predictor of future coronary events EAT is increased in obesity, type 2 diabetes, hypertension, metabolic syndrome, nonalcoholic fatty liver disease, and obstructive sleep apnea (OSA)
Apolipoprotein A4 Elevates Sympathetic Activity and Thermogenesis in Male Mice
Nutrients
Long-chain fatty acids induce apolipoprotein A4 (APOA4) production in the small intestine and activate brown adipose tissue (BAT) thermogenesis. The increase in BAT thermogenesis enhances triglyceride clearance and insulin sensitivity. Acute administration of recombinant APOA4 protein elevates BAT thermogenesis in chow-fed mice. However, the physiological role of continuous infusion of recombinant APOA4 protein in regulating sympathetic activity, thermogenesis, and lipid and glucose metabolism in low-fat-diet (LFD)-fed mice remained elusive. The hypothesis of this study was that continuous infusion of mouse APOA4 protein would increase sympathetic activity and thermogenesis in BAT and subcutaneous inguinal white adipose tissue (IWAT), attenuate plasma lipid levels, and improve glucose tolerance. To test this hypothesis, sympathetic activity, BAT temperature, energy expenditure, body weight, fat mass, caloric intake, glucose tolerance, and levels of BAT and IWAT thermogenic and lipol...
In vivo isotope tracing reveals the versatility of glucose as a brown adipose tissue substrate
Cell Reports, 2021
In vivo isotope tracing reveals the versatility of glucose as a brown adipose tissue substrate Graphical abstract Highlights d In vivo BAT glucose fluxes vary with the degree and duration of cold exposure d BAT uses glucose to support auxiliary pathways beyond glycolysis and the TCA cycle d Cold-adapted BAT rapidly synthesizes fatty acids de novo for acyl-carnitine production d N-acetylated amino acids are markers of thermogenesis
Role of Epicardial Adipose Tissue Secretome on Cardiovascular Diseases
Biomedicines
Obesity and insulin resistance are associated with the inflamed and defective adipose tissue (AT) phenotype, and are established risk factors for cardiovascular diseases (CVDs). Extracellular vesicles (EVs) are a heterogeneous group of cell-derived lipid membrane vesicles involved in the onset and development of many pathologies, including insulin resistance, diabetes, and CVDs. The inflammation associated with overweight and obesity triggers the transition of the AT secretome from healthy to pathological, with a consequent increased expression of pro-inflammatory mediators. Epicardial adipose tissue (EAT) is a specialized fat depot that surrounds the heart, in direct contact with the myocardium. Recently, the role of EAT in regulating the physiopathology of many heart diseases has been increasingly explored. In particular, the EAT phenotype and derived EVs have been associated with the onset and exacerbation of CVDs. In this review, we will focus on the role of the AT secretome in ...
Fatty Acid Metabolite Profiling Reveals Oxylipins as Markers of Brown but Not Brite Adipose Tissue
Frontiers in Endocrinology, 2020
Metabolites of omega-6 and omega-3 polyunsaturated fatty acids are important signaling molecules implicated in the control of adipogenesis and energy balance regulation. Some of these metabolites belonging to the group of oxylipins have been associated with non-shivering thermogenesis in mice mediated by brown or brite adipose tissue. We aimed to identify novel molecules with thermogenic potential and to clarify the relevance of these findings in a translational context. Therefore, we characterized and compared the oxylipin profiles of murine and human adipose tissues with different abundance of brown or brite adipocytes. A broad panel of 36 fatty acid metabolites was quantified in brown and white adipose tissues of C57BL/6J mice acclimatized to different ambient temperatures and in biopsies of human supraclavicular brown and white adipose tissue. The oxylipin profile of murine brite adipose tissue was not distinguishable from white adipose tissue, suggesting that adipose tissue browning in vivo is not associated with major changes in the oxylipin metabolism. Human brown and white adipose tissue also exhibited similar metabolite profiles. This is in line with previous studies proposing human brown adipose tissue to resemble the nature of murine brite adipose tissue representing a heterogeneous mixture of brite and white adipocytes. Although the global oxylipin profile served as a marker for the abundance of thermogenic adipocytes in bona fide brown but not white adipose tissue, we identified 5-HETE and 5,6-EET as individual compounds consistently associated with the abundance of brown or brite adipocytes in human BAT and murine brite fat. Further studies need to establish whether these candidates are mere markers or functional effectors of thermogenic capacity.
Effects of Fatty Acid Metabolites on Adipocytes Britening: Role of Thromboxane A2
Cells
Obesity is a complex disease highly related to diet and lifestyle and is associated with low amount of thermogenic adipocytes. Therapeutics that regulate brown adipocyte recruitment and activity represent interesting strategies to fight overweight and associated comorbidities. Recent studies suggest a role for several fatty acids and their metabolites, called lipokines, in the control of thermogenesis. The purpose of this work was to analyze the role of several lipokines in the control of brown/brite adipocyte formation. We used a validated human adipocyte model, human multipotent adipose-derived stem cell model (hMADS). In the absence of rosiglitazone, hMADS cells differentiate into white adipocytes, but convert into brite adipocytes upon rosiglitazone or prostacyclin 2 (PGI2) treatment. Gene expression was quantified using RT-qPCR and protein levels were assessed by Western blotting. We show here that lipokines such as 12,13-diHOME, 12-HEPE, 15dPGJ2 and 15dPGJ3 were not able to in...
ADH5-mediated NO Bioactivity Maintains Metabolic Homeostasis in Brown Adipose Tissue
bioRxiv (Cold Spring Harbor Laboratory), 2020
Highlights • Thermogenesis induces protein S-nitrosylation modification in the BAT; • ADH5, a major cellular denitrosylase, is required for maintaining BAT metabolic homeostasis under both overnutrition and cold stress conditions; • Diet-induced obesity suppresses HSF1-mediated activation of Adh5 in the BAT; • ADH5 overexpression in BAT improves whole-body glucose homeostasis in obesity.
Adiponectin: a pleiotropic hormone with multifaceted roles
Problemy e̊ndokrinologii, 2021
Adipose tissue mostly composed of different types of fat is one of the largest endocrine organs in the body playing multiple intricate roles including but not limited to energy storage, metabolic homeostasis, generation of heat, participation in immune functions and secretion of a number of biologically active factors known as adipokines. The most abundant of them is adiponectin. This adipocite-derived hormone exerts pleiotropic actions and exhibits insulin-sensitizing, antidiabetic, anti-obesogenic, anti-inflammatory, antiatherogenic, cardio- and neuroprotective properties. Contrariwise to its protective effects against various pathological events in different cell types, adiponectin may have links to several systemic diseases and malignances. Reduction in adiponectin levels has an implication in COVID-19-associated respiratory failure, which is attributed mainly to a phenomenon called ‘adiponectin paradox’. Ample evidence about multiple functions of adiponectin in the body was obtained from animal, mostly rodent studies. Our succinct review is entirely about multifaceted roles of adiponectin and mechanisms of its action in different physiological and pathological states.Жировая ткань, состоящая из различных видов жира, является в организме одним из самых больших эндокринных органов, играющим множество ролей, которые включают, но не ограничиваются сохранением энергетических запасов, метаболическим гомеостазом, продукцией тепла, участием в иммунных функциях и секрецией целого ряда биологически активных факторов, называемых адипокинами. Самым обильно секретируемым из адипокинов является адипонектин. Этот вырабатываемый адипоцитами гормон оказывает плейотропное действие и обладает способностью повышать чувствительность к инсулину, а также демонстрирует антидиабетические свойства и эффекты противодействия развитию ожирения, воспаления, атеросклероза и, кроме того, еще и проявляет кардио- и нейропротективные свойства. С другой стороны, помимо вышеперечисленных защитных свойств и возможности предотвращения развития различных патологических процессов в разных типах клеток, адипонектин может быть связан с развитием ряда системных заболеваний и злокачественных опухолей. Снижение уровней адипонектина, как оказалось, наблюдается в том числе при дыхательной недостаточности, связанной с коронавирусной инфекцией COVID-19, что обусловлено в основном развитием феномена, называемого «адипонектиновый парадокс». Многочисленные доказательства многоликости функций адипонектина в организме были получены в ходе исследований на животных моделях, больше всего на грызунах. Наш краткий обзор полностью посвящен многофункциональной роли адипонектина и механизмам его действия при различных физиологических и патологических состояниях.
International journal of experimental pathology, 2017
Fat storage changes throughout life and affects body metabolism. Ageing impact on brown (BAT) and white adipose tissue (WAT) deserves attention, especially in females, because they are less prone to age-induced weight gain. While in male mice the impact of ageing on adipose tissue remodelling is well characterized, the effects in female mice remain largely unclear. Thus, we investigated BAT and WAT remodelling during ageing in female C57BL/6 mice. At 3 months, body weight was 24 ± 0.3 g (mean±SD), and it increased from 6 to 9 months of age (+20%, P < 0.0001). Oral glucose tolerance test showed no disturbance of glucose metabolism. All WAT depots became heavier, and white adipocytes hypertrophied. The subcutaneous and visceral WAT had clusters of beige cells in younger mice, but they were progressively lost by ageing, indicating loss of WAT browning. Older mice had hypertrophied classic brown adipocytes that had larger cytoplasmic lipid droplets than younger mice. Pearson's co...
Biomedicines
Obesity is associated with an increased risk of non-alcoholic fatty liver disease (NAFLD), which is initiated by adipocyte-macrophage crosstalk. Among the possible molecules regulating this crosstalk, we focused on neuropeptide Y (NPY), which is known to be involved in hypothalamic appetite and adipose tissue inflammation and metabolism. In this study, the NPY−/− mice showed a marked decrease in body weight and adiposity, and lower free fatty acid and adipose inflammation without food intake alteration during a high fat diet (HFD). Moreover, NPY deficiency increased the thermogenic genes expression in brown adipose tissue. Notably, NPY-mRNA expression was upregulated in macrophages from the HFD mice compared to that from the mice on a standard diet. The NPY-mRNA expression also positively correlated with the liver mass/body weight ratio. NPY deletion alleviated HFD-induced adipose inflammation and liver steatosis. Hence, our findings point toward a novel intracellular mechanism of N...
Reduced Diet-induced Thermogenesis in Apolipoprotein A-IV Deficient Mice
International Journal of Molecular Sciences, 2019
In the presence of dietary lipids, both apolipoprotein A-IV (ApoA-IV) production and brown adipose tissue (BAT) thermogenesis are increased. The effect of dietary lipid-induced AproA-IV on BAT thermogenesis and energy expenditure remains unknown. In the present study, we hypothesized that ApoA-IV knockout (ApoA-IV-KO) mice exhibited decreased BAT thermogenesis to affect energy homeostasis. To test this hypothesis, BAT thermogenesis in wildtype (WT) and ApoA-IV-KO mice fed either a standard low-fat chow diet or a high-fat diet (HFD) was investigated. When fed a chow diet, energy expenditure and food intake were comparable between WT and ApoA-IV-KO mice. After 1 week of HFD consumption, ApoA-IV-KO mice had comparable energy intake but produced lower energy expenditure relative to their WT controls in the dark phase. After an acute feeding of dietary lipids or 1-week HFD feeding, ApoA-IV-KO mice produced lower levels of uncoupling protein 1 (UCP1) and exhibited reduced expression of th...
Obesity, 2016
ObjectiveTo analyze whether a combination of quercetin (Q) and resveratrol (RSV) would induce a white adipose tissue (WAT) browning effect.MethodsThirty‐six rats were fed an obesogenic diet and divided into four groups: control, treated with RSV (15 mg/kg body weight/day; RSV group), treated with Q (30 mg/kg body weight/day; Q group), or treated with both polyphenols (RSV + Q group).ResultsAfter 6 weeks, body and WAT weights were significantly reduced in the RSV + Q group. In perirenal WAT of the control, RSV, and Q groups, white unilocular adipocytes appeared in the majority of cells, while in the RSV + Q group numerous multilocular adipocytes with positive immunostaining for UCP1 were observed. The presence of UCP1 was confirmed by Western blot. This group also revealed increased mRNA levels of Cidea, Hocx9, Bmp4, Slc27a1, Pat2, Atgl, and Atp5d. Interscapular brown adipose tissue weight showed no differences between groups, but the Cidea mRNA level was increased in the RSV group, ...
Proceedings of the National Academy of Sciences of the United States of America, 2016
The incidence of obesity, which is recognized by the American Medical Association as a disease, has nearly doubled since 1980, and obesity-related comorbidities have become a major threat to human health. Given that adipose tissue expansion and transformation require active growth of new blood vasculature, angiogenesis offers a potential target for the treatment of obesity-associated disorders. Here we construct two peptide-functionalized nanoparticle (NP) platforms to deliver either Peroxisome Proliferator-Activated Receptor gamma (PPARgamma) activator rosiglitazone (Rosi) or prostaglandin E2 analog (16,16-dimethyl PGE2) to adipose tissue vasculature. These NPs were engineered through self-assembly of a biodegradable triblock polymer composed of end-to-end linkages between poly(lactic-coglycolic acid)-b-poly(ethylene glycol) (PLGA-b-PEG) and an endothelial-targeted peptide. In this system, released Rosi promotes both transformation of white adipose tissue (WAT) into brown-like adip...
2021
1Cold and nutrient activated brown adipose tissue (BAT) is capable of increasing systemic energy expenditure via uncoupled respiration and secretion of endocrine factors thereby protecting mice against diet-induced obesity and improving insulin response and glucose tolerance in men. Long non-coding RNAs (lncRNAs) have recently been identified as fine tuning regulators of cellular function. While certain lncRNAs have been functionally characterised in adipose tissue, their overall contribution in the activation of BAT remains elusive. We identified lncRNAs correlating to inter-scapular brown adipose tissue (iBAT) function in high fat diet (HFD) and cold stressed mice. We focused on Gm15551 which has an adipose tissue specific expression profile, is highly upregulated during adipogenesis and downregulated by β-adrenergic activation in mature adipocytes. Albeit we performed comprehensive transcriptional and adipocyte physiology profiling in vitro and in vivo, we could not detect an eff...
Exercise Increases and Browns Muscle Lipid in High-Fat Diet-Fed Mice
Frontiers in endocrinology, 2016
Muscle lipid increases with high-fat feeding and diabetes. In trained athletes, increased muscle lipid is not associated with insulin resistance, a phenomenon known as the athlete's paradox. To understand if exercise altered the phenotype of muscle lipid, female C57BL/6 mice fed CTL or high-fat diet (HFD for 6 or 18 weeks) were further divided into sedentary or exercising groups (CTL-E or HFD-E) with voluntary access to running wheels for the last 6 weeks of experiments, running 6 h/night. Diet did not affect running time or distance. HFD mice weighed more than CTL after 18 weeks (p < 0.01). Quadriceps muscle TG was increased in running animals and in sedentary mice fed HFD for 18 weeks (p < 0.05). In exercised animals, markers of fat, Plin1, aP2, FSP27, and Fasn, were increased significantly in HFD groups. Ucp1 and Pgc1a, markers for brown fat, increased with exercise in the setting of high fat feeding. Fndc5, which encodes irisin, and CytC were sensitive to exercise rega...
Frontiers in Pharmacology
Obesity affects more than 10% of the adult population globally. Despite the introduction of diverse medications aimed at combating fat accumulation and obesity, a significant number of these pharmaceutical interventions are linked to substantial occurrences of severe adverse events, occasionally leading to their withdrawal from the market. Natural products serve as attractive sources for anti-obesity agents as many of them can alter the host metabolic processes and maintain glucose homeostasis via metabolic and thermogenic stimulation, appetite regulation, pancreatic lipase and amylase inhibition, insulin sensitivity enhancing, adipogenesis inhibition and adipocyte apoptosis induction. In this review, we shed light on the biological processes that control energy balance and thermogenesis as well as metabolic pathways in white adipose tissue browning, we also highlight the anti-obesity potential of natural products with their mechanism of action. Based on previous findings, the cruci...
Cell discovery, 2018
Pericardial adipose tissue, which comprises both epicardial adipose tissue (EAT) and paracardial adipose tissue (PAT), has recently been recognized as a novel factor in the pathophysiology of cardiovascular diseases, especially coronary artery disease (CAD). The goal of this study was to evaluate differences in the brown-like characteristic and proteome among human EAT, PAT, and subcutaneous adipose tissue (SAT) to identify candidate molecules causing CAD. Uncoupling protein 1 (UCP-1) and other brown-related proteins were highly expressed in pericardial adipose tissue but was weakly expressed in SAT from the same non-CAD patient. Moreover, pericardial adipose tissues displayed a higher thermogenesis than SAT. However, brown-related genes were lower in CAD pericardial fat. Remarkably, there were lower levels of metabolic enzymes involved in glycolysis, tricarboxylic acid cycle, and fatty acid metabolism in pericardial adipose tissues of CAD. EAT is an organ adjacent to aortic root wi...
Frontiers in Nutrition, 2021
The potential ability of nutritional compounds to induce or enhance the browning of adipocytes has attracted large interest as a workable means of combatting the obesity epidemic. Green tea compounds are discussed as such inducers of an enhanced thermogenic capacity and activity. However, the cell-autonomous effects of green tea compounds on adipocytes have until now only been demonstrated in adipogenic cell lines (3T3-L1 and 3T3-F442A), i.e., cells of undefined tissue lineage. In this study, we examine the ability of green tea compounds to cell-autonomously induce thermogenic recruitment in authentic brown and brite/beige adipocytes in vitro. In primary brown adipocytes, the green tea compounds suppressed basal UCP1 gene expression, and there was no positive interaction between the compounds and adrenergic stimulation. In white adipocytes, green tea compounds decreased both basal and norepinephrine-induced UCP1 mRNA levels, and this was associated with the suppression of cell differentiation, indicated by reduced lipogenic gene expression and lipid accumulation. A lack of interaction between rosiglitazone and green tea compounds suggests that the green tea compounds do not directly interact with the PPARγ pathway. We conclude that there is a negative effect of the green tea compounds on basal UCP1 gene expression, in both brown and white primary adipocytes, in contrast to the positive effects earlier reported from studies in adipogenic cell lines. We posit that the epigenetic status of the adipogenic cell lines is fundamentally different from that of genuine brown and white adipocytes, reflected, e.g., in several-thousand-fold differences in UCP1 gene expression levels. Thus, results obtained with adipogenic cell lines cannot unreservedly be extrapolated as being relevant for authentic effects in brown and white adipocytes. We suggest that this conclusion can be of general concern for studies attempting to establish physiologically relevant cell-autonomous effects.
Science China-life Sciences, 2023
Aging biomarkers are a combination of biological parameters to (i) assess age-related changes, (ii) track the physiological aging process, and (iii) predict the transition into a pathological status. Although a broad spectrum of aging biomarkers has been developed, their potential uses and limitations remain poorly characterized. An immediate goal of biomarkers is to help us answer the following three fundamental questions in aging research: How old are we? Why do we get old? And how can we age slower? This review aims to address this need. Here, we summarize our current knowledge of biomarkers developed for cellular, organ, and organismal levels of aging, comprising six pillars: physiological characteristics, medical imaging, histological features, cellular alterations, molecular changes, and secretory factors. To fulfill all these requisites, we propose that aging biomarkers should qualify for being specific, systemic, and clinically relevant.
Evolutionary Human Sciences, 2021
Functional benefits of the morphologies described by Bergmann's and Allen's rules in human males have recently been reported. However, the functional implications of ecogeographical patterning in females remain poorly understood. Here, we report the findings of preliminary work analysing the association between body shape and performance in female ultramarathon runners (n = 36) competing in hot and cold environments. The body shapes differed between finishers of hot and cold races, and also between hot race finishers and non-finishers. Variability in race performance across different settings supports the notion that human phenotype is adapted to different thermal environments as ecogeographical patterns have reported previously. This report provides support for the recent hypothesis that the heightened thermal strain associated with prolonged physical activity in hot/cold environments may have driven the emergence of thermally adaptive phenotypes in our evolutionary past. These results also tentatively suggest that the relationship between morphology and performance may be stronger in female vs. male athletes. This potential sex difference is discussed with reference to the evolved unique energetic context of human female reproduction. Further work, with a larger sample size, is required to investigate the observed potential sex differences in the strength of the relationship between phenotype and performance.
Increased BAT Thermogenesis in Male Mouse Apolipoprotein A4 Transgenic Mice
International Journal of Molecular Sciences, 2023
Dietary lipids induce apolipoprotein A4 (APOA4) production and brown adipose tissue (BAT) thermogenesis. Administration of exogenous APOA4 elevates BAT thermogenesis in chow-fed mice, but not high-fat diet (HFD)-fed mice. Chronic feeding of HFD attenuates plasma APOA4 production and BAT thermogenesis in wildtype (WT) mice. In light of these observations, we sought to determine whether steady production of APOA4 could keep BAT thermogenesis elevated, even in the presence of HFD consumption, with an aim toward eventual reduction of body weight, fat mass and plasma lipid levels. Transgenic mice with overexpression of mouse APOA4 in the small intestine (APOA4-Tg mice) produce greater plasma APOA4 than their WT controls, even when fed an atherogenic diet. Thus, we used these mice to investigate the correlation of levels of APOA4 and BAT thermogenesis during HFD consumption. The hypothesis of this study was that overexpression of mouse APOA4 in the small intestine and increased plasma APOA4 production would increase BAT thermogenesis and consequently reduce fat mass and plasma lipids of HFD-fed obese mice. To test this hypothesis, BAT thermogenic proteins, body weight, fat mass, caloric intake, and plasma lipids in male APOA4-Tg mice and WT mice fed either a chow diet or a HFD were measured. When fed a chow diet, APOA4 levels were elevated, plasma triglyceride (TG) levels were reduced, and BAT levels of UCP1 trended upward, while body weight, fat mass, caloric intake, and plasma lipids were comparable between APOA4-Tg and WT mice. After a four-week feeding of HFD, APOA4-Tg mice maintained elevated plasma APOA4 and reduced plasma TG, but UCP1 levels in BAT were significantly elevated in comparison to WT controls; body weight, fat mass and caloric intake were still comparable. After 10-week consumption of HFD, however, while APOA4-Tg mice still exhibited increased plasma APOA4, UCP1 levels and reduced TG levels, a reduction in body weight, fat mass and levels of plasma lipids and leptin were finally observed in comparison to their WT controls and independent of caloric intake. Additionally, APOA4-Tg mice exhibited increased energy expenditure at several time points when measured during the 10-week HFD feeding. Thus, overexpression of APOA4 in the small intestine and maintenance of elevated levels of plasma APOA4 appear to correlate with elevation of UCP1-dependent BAT thermogenesis and subsequent protection against HFD-induced obesity in mice.
FEBS Journal, 2020
Uncoupling protein 1 (UCP1) is found in the inner mitochondrial membrane of brown adipocyte. In the presence of long-chain fatty acids (LCFA), UCP1 increases the proton conductance, which, in turn, increases fatty acid oxidation and energy release as heat. Several atomic models of UCP1 and UCP2 have been obtained by NMR in dodecylphosphocholine (DPC), a detergent known to inactivate UCP1. Based on NMR titration experiment on UCP1 with LCFA, it has been proposed that K56 and K269 are crucial for LCFA binding and UCP1 activation. Given the numerous controversies on the use of DPC for structure-function analyses of membrane proteins, we revisited those UCP1 mutants in a more physiological context by expressing them in the mitochondria of S. cerevisiae. Mitochondrial respiration, assayed on permeabilized spheroplasts, enables the determination of UCP1 activation and inhibition. The K56S, K269S and K56S/K269S mutants did not display any default in activation, which shows that the NMR experiments in DPC detergent are not relevant to understand UCP1 function.