Supplemental text: Yin et al. Cell Metabolism 2013 (original) (raw)
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miR-133a Regulates Adipocyte Browning In Vivo
PLoS Genetics, 2013
Prdm16 determines the bidirectional fate switch of skeletal muscle/brown adipose tissue (BAT) and regulates the thermogenic gene program of subcutaneous white adipose tissue (SAT) in mice. Here we show that miR-133a, a microRNA that is expressed in both BAT and SATs, directly targets the 39 UTR of Prdm16. The expression of miR-133a dramatically decreases along the commitment and differentiation of brown preadipocytes, accompanied by the upregulation of Prdm16. Overexpression of miR-133a in BAT and SAT cells significantly inhibits, and conversely inhibition of miR-133a upregulates, Prdm16 and brown adipogenesis. More importantly, double knockout of miR-133a1 and miR-133a2 in mice leads to elevations of the brown and thermogenic gene programs in SAT. Even 75% deletion of miR-133a (a1 2/2 a2 +/2) genes results in browning of SAT, manifested by the appearance of numerous multilocular UCP1-expressing adipocytes within SAT. Additionally, compared to wildtype mice, miR-133a1 2/2 a2 +/2 mice exhibit increased insulin sensitivity and glucose tolerance, and activate the thermogenic gene program more robustly upon cold exposure. These results together elucidate a crucial role of miR-133a in the regulation of adipocyte browning in vivo.
Cell Metabolism, 2013
Brown adipose tissue (BAT) is an energy-dispensing thermogenic tissue that plays an important role in balancing energy metabolism. Lineage-tracing experiments indicate that brown adipocytes are derived from myogenic progenitors during embryonic development. However, adult skeletal muscle stem cells (satellite cells) have long been considered uniformly determined toward the myogenic lineage. Here, we report that adult satellite cells give rise to brown adipocytes and that microRNA-133 regulates the choice between myogenic and brown adipose determination by targeting the 3 0 UTR of Prdm16. Antagonism of microRNA-133 during muscle regeneration increases uncoupled respiration, glucose uptake, and thermogenesis in local treated muscle and augments whole-body energy expenditure, improves glucose tolerance, and impedes the development of diet-induced obesity. Finally, we demonstrate that miR-133 levels are downregulated in mice exposed to cold, resulting in de novo generation of satellite cell-derived brown adipocytes. Therefore, microRNA-133 represents an important therapeutic target for the treatment of obesity.
MiR-193b and miR-365-1 are not required for the development and function of brown fat in the mouse
RNA Biology, 2013
Generating heat and maintaining body temperature is the primary function of brown adipose tissue (Bat). Previous studies have implicated micrornas, including miR-193b and miR-365-1, in Bat differentiation. We used mouse genetics to further understand the specific contributions of these two mirs. Bat function in mice with an inactivated miR-193b-365-1 locus, as determined by their response to the selective β3 adrenergic receptor agonist CL316.243 and their tolerance to cold exposure, was normal and expression of genes associated with functional Bat, including Prdm16 and Ucp1, was unaffected. in addition, genome-wide expression profiles of mirnas and mrnas in Bat in the presence and absence of miR-193b-365-1 were determined. in summary, these data demonstrate, in contrast to earlier work, that the development, differentiation, and function of Bat do not require the presence of miR-193b and miR-365-1.
miR-125b affects mitochondrial biogenesis and impairs brite adipocyte formation and function
Molecular Metabolism, 2016
Objective: In rodents and humans, besides brown adipose tissue (BAT), islands of thermogenic adipocytes, termed "brite" (brown-in-white) or beige adipocytes, emerge within white adipose tissue (WAT) after cold exposure or b3-adrenoceptor stimulation, which may protect from obesity and associated diseases. microRNAs are novel modulators of adipose tissue development and function. The purpose of this work was to characterize the role of microRNAs in the control of brite adipocyte formation. Methods/Results: Using human multipotent adipose derived stem cells, we identified miR-125b-5p as downregulated upon brite adipocyte formation. In humans and rodents, miR-125b-5p expression was lower in BAT than in WAT. In vitro, overexpression and knockdown of miR-125b-5p decreased and increased mitochondrial biogenesis, respectively. In vivo, miR-125b-5p levels were downregulated in subcutaneous WAT and interscapular BAT upon b3-adrenergic receptor stimulation. Injections of an miR-125b-5p mimic and LNA inhibitor directly into WAT inhibited and increased b3-adrenoceptor-mediated induction of UCP1, respectively, and mitochondrial brite adipocyte marker expression and mitochondriogenesis. Conclusion: Collectively, our results demonstrate that miR-125b-5p plays an important role in the repression of brite adipocyte function by modulating oxygen consumption and mitochondrial gene expression.
Expression Change of miR-214 and miR-135 during Muscle Differentiation
Cell Journal (Yakhteh), 2015
Objective MicroRNAs (miRNAs) are a class of small non-coding RNAs that play pivotal roles in many biological processes such as regulating skeletal muscle development where alterations in miRNA expression are reported during myogenesis. In this study, we aimed to investigate the impact of predicted miRNAs and their target genes on the myoblast to myocyte differentiation process. Materials and Methods This experimental study was conducted on the C2C12 cell line. Using a bioinformatics approach, miR-214 and miR-135 were selected according to their targets as potential factors in myoblast to myocyte differentiation induced by 3% horse serum. Immunocytochemistry (ICC) was undertaken to confirm the differentiation process and quantitative real-time polymerase chain reaction (PCR) to determine the expression level of miRNAs and their targets. Results During myoblast to myocyte differentiation, miR-214 was significantly down- regulated while miRNA-135, Irs2, Akt2 and Insr were overexpressed...
Journal of Biological Chemistry, 2008
UCP2 and UCP3, two novel uncoupling proteins, are important regulators of energy expenditure and thermogenesis in various organisms. The striking disparity between UCP2 mRNA and protein levels in muscle tissues prompted initial speculation that microRNAs are implicated in the regulatory pathway of UCP2. We found, for the first time, that the repression of UCP2 expression in cardiac and skeletal muscle resulted from its targeting by a muscle-specific microRNA, miR-133a. Moreover, our findings illustrate a novel function of UCP2 as a brake for muscle development. We also show that MyoD can remove the braking role of UCP2 via direct up-regulation of miR-133a during myogenic differentiation. Taken together, our current work delineates a novel regulatory network employing MyoD, microRNA, and uncoupling proteins to fine-tune the balance between muscle differentiation and proliferation during myogenesis.
BMC Developmental Biology, 2011
Background: MicroRNAs (miRNAs) are small RNA molecules that post-transcriptionally regulate gene expression and have been shown to play an important role during development. miR-1, miR-133a, miR-133b and miR-206 are expressed in muscle tissue and induced during muscle cell differentiation, a process that directs myoblasts to differentiate into mature myotubes, which are organized into myofibers. Although miR-1, miR-133a, miR-133b and miR-206 are well-studied in muscle, there is no information about their expression and function during human development. The purpose of this study was to determine the profile of these miRNAs in muscle cells isolated from different stages of human development. Results: We examined the levels of miR-1, miR-133a, miR-133b and miR-206 during the development of human foetus. All four miRNA levels were found increased during late stages of human foetal muscle development. Increases in the expression levels of these miRNAs were proportional to the capacity of myoblasts to form myotubes. Changes in miRNA levels during human foetal development were accompanied by endogenous alterations in their known targets and also in their inducer, MyoD. Ectopic MyoD expression caused an induction of muscle cell differentiation in vitro, accompanied by an increase in the levels of miR-1, miR-133a, miR-133b and miR-206.
miR-206, miR-1a-1 and miR-1a-2 are induced during differentiation of skeletal myoblasts and promote myogenesis in vitro. miR-206 is required for skeletal muscle regeneration in vivo. Although this microRNA family is hypothesized to play an essential role in differentiation, a triple knockout of the three genes has not been done to test this hypothesis. We report that triple KO C2C12 myoblasts generated using CRISPR/Cas9 method differentiate despite the expected de-repression of the microRNA targets. Surprisingly, their mitochondrial function is diminished. Triple KO mice demonstrate partial embryonic lethality, most likely due to the role of miR-1a in cardiac muscle differentiation. Two triple KO mice survive and grow normally to adulthood with smaller myofiber diameter and diminished physical performance. Thus, unlike other microRNAs important in other differentiation pathways, the miR-206 family is not absolutely essential for myogenesis and is instead a modulator of optimal diffe...
bta-miR-23a involves in adipogenesis of progenitor cells derived from fetal bovine skeletal muscle
Scientific reports, 2017
Intramuscular fat deposition or marbling is essential for high quality beef. The molecular mechanism of adipogenesis in skeletal muscle remains largely unknown. In this study, we isolated Platelet-derived growth factor receptor α (PDGFRα) positive progenitor cells from fetal bovine skeletal muscle and induced into adipocytes. Using miRNAome sequencing, we revealed that bta-miR-23a was an adipogenic miRNA mediating bovine adipogenesis in skeletal muscle. The expression of bta-miR-23a was down-regulated during differentiation of PDGFRα(+) progenitor cells. Forced expression of bta-miR-23a mimics reduced lipid accumulation and inhibited the key adipogenic transcription factor peroxisome proliferative activated receptor gamma (PPARγ) and CCAAT/enhancer binding protein alpha (C/EBPα). Whereas down-regulation of bta-miR-23a by its inhibitors increased lipid accumulation and expression of C/EBPα, PPARγ and fatty acid-binding protein 4 (FABP4). Target prediction analysis revealed that ZNF42...
Dicer1-miR-328-Bace1 signalling controls brown adipose tissue differentiation and function
Activation of brown adipose tissue (BAT) controls energy homeostasis in rodents and humans and has emerged as an innovative strategy for the treatment of obesity and type 2 diabetes mellitus 1-4. Here we show that ageing-and obesity-associated dysfunction of brown fat coincides with global microRNA downregulation due to reduced expression of the microRNA-processing node Dicer1. Consequently, heterozygosity of Dicer1 in BAT aggravated diet-induced-obesity (DIO)-evoked deterioration of glucose metabolism. Analyses of differential microRNA expression during preadipocyte commitment and mouse models of progeria, longevity and DIO identified miR-328 as a regulator of BAT differentiation. Reducing miR-328 blocked preadipocyte commitment, whereas miR-328 overexpression instigated BAT differentiation and impaired muscle progenitor commitment-partly through silencing of the β-secretase Bace1. Loss of Bace1 enhanced brown preadipocyte specification in vitro and was overexpressed in BAT of obese and progeroid mice. In vivo Bace1 inhibition delayed DIO-induced weight gain and improved glucose tolerance and insulin sensitivity. These experiments reveal Dicer1-miR-328-Bace1 signalling as a determinant of BAT function, and highlight the potential of Bace1 inhibition as a therapeutic approach to improve not only neurodegenerative diseases but also ageing-and obesity-associated impairments of BAT function. Obesity is rising across all socioeconomic strata, with >1.4 billion adults now diagnosed as overweight (BMI > 25) and >500 million considered obese (BMI > 30, WHO 2008). Weight-lowering approaches, for instance reducing food intake or surgical interventions, fail to reduce body weight owing to adaptive reductions in energy expenditure 5. Approaches that increase basal metabolic rates in contrast harbour great potential as anti-obesity regimens 6. Activated brown adipose tissue (BAT) received increasing attention owing to its capacity of converting chemical energy stored in carbohydrates and lipids into heat through uncoupling of the mito-chondrial proton gradient, for example, on prolonged cold exposure (a process termed 'non-shivering thermogenesis' 1). Interestingly, the amount and activity of BAT inversely correlates with age and BMI (refs 2,3) and functionally ablating BAT renders mice obese 7 , whereas cold-induced BAT activation in humans reduces adiposity by age-and BMI-independent increases in energy expenditure 4. This underscores the hope that brown fat recruitment or restoration of BAT activity could materialize into new and effective anti-obesity approaches. In contrast to protein-coding regulators 8,9 , the role of microRNA-evoked post-transcriptional silencing begins to become apparent only in the context of BAT biology. MicroRNAs are small, 21-22-nucleotide non-coding RNAs that regulate stability and/or translational capacity of target messenger RNAs through incomplete base-pairing to their 3 untranslated region 10 (UTR). In fact, in vitro evidence revealed that microRNAs can regulate BAT differentiation and mesenchymal progenitor commitment towards the brown adipogenic lineage 11-13. Yet these studies largely relied on cell culture experiments and information regarding the role of microRNAs and their target genes in BAT control of glucose homeostasis in vivo remains scarce. Recent reports and our own findings in old C57BL/6 mice (Supplementary Fig. 1a) demonstrate that BAT homeostasis