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Papers by susan aja

Research paper thumbnail of Anaplerotic Triheptanoin Diet Enhances Mitochondrial Substrate Use to Remodel the Metabolome and Improve Lifespan, Motor Function, and Sociability in MeCP2-Null Mice

PLoS ONE, 2014

Rett syndrome (RTT) is an autism spectrum disorder (ASD) caused by mutations in the X-linked MECP... more Rett syndrome (RTT) is an autism spectrum disorder (ASD) caused by mutations in the X-linked MECP2 gene that encodes methyl-CpG binding protein 2 (MeCP2). Symptoms range in severity and include psychomotor disabilities, seizures, ataxia, and intellectual disability. Symptom onset is between 6-18 months of age, a critical period of brain development that is highly energy-dependent. Notably, patients with RTT have evidence of mitochondrial dysfunction, as well as abnormal levels of the adipokines leptin and adiponectin, suggesting overall metabolic imbalance. We hypothesized that one contributor to RTT symptoms is energy deficiency due to defective nutrient substrate utilization by the TCA cycle. This energy deficit would lead to a metabolic imbalance, but would be treatable by providing anaplerotic substrates to the TCA cycle to enhance energy production. We show that dietary therapy with triheptanoin significantly increased longevity and improved motor function and social interaction in male mice hemizygous for Mecp2 knockout. Anaplerotic therapy in Mecp2 knockout mice also improved indicators of impaired substrate utilization, decreased adiposity, increased glucose tolerance and insulin sensitivity, decreased serum leptin and insulin, and improved mitochondrial morphology in skeletal muscle. Untargeted metabolomics of liver and skeletal muscle revealed increases in levels of TCA cycle intermediates with triheptanoin diet, as well as normalizations of glucose and fatty acid biochemical pathways consistent with the improved metabolic phenotype in Mecp2 knockout mice on triheptanoin. These results suggest that an approach using dietary supplementation with anaplerotic substrate is effective in improving symptoms and metabolic health in RTT.

Research paper thumbnail of Increasing Fatty Acid Oxidation Remodels the Hypothalamic Neurometabolome to Mitigate Stress and Inflammation

PLoS ONE, 2014

Modification of hypothalamic fatty acid (FA) metabolism can improve energy homeostasis and preven... more Modification of hypothalamic fatty acid (FA) metabolism can improve energy homeostasis and prevent hyperphagia and excessive weight gain in diet-induced obesity (DIO) from a diet high in saturated fatty acids. We have shown previously that C75, a stimulator of carnitine palmitoyl transferase-1 (CPT-1) and fatty acid oxidation (FAOx), exerts at least some of its hypophagic effects via neuronal mechanisms in the hypothalamus. In the present work, we characterized the effects of C75 and another anorexigenic compound, the glycerol-3-phosphate acyltransferase (GPAT) inhibitor FSG67, on FA metabolism, metabolomics profiles, and metabolic stress responses in cultured hypothalamic neurons and hypothalamic neuronal cell lines during lipid excess with palmitate. Both compounds enhanced palmitate oxidation, increased ATP, and inactivated AMP-activated protein kinase (AMPK) in hypothalamic neurons in vitro. Lipidomics and untargeted metabolomics revealed that enhanced catabolism of FA decreased palmitate availability and prevented the production of fatty acylglycerols, ceramides, and cholesterol esters, lipids that are associated with lipotoxicity-provoked metabolic stress. This improved metabolic signature was accompanied by increased levels of reactive oxygen species (ROS), and yet favorable changes in oxidative stress, overt ER stress, and inflammation. We propose that enhancing FAOx in hypothalamic neurons exposed to excess lipids promotes metabolic remodeling that reduces local inflammatory and cell stress responses. This shift would restore mitochondrial function such that increased FAOx can produce hypothalamic neuronal ATP and lead to decreased food intake and body weight to improve systemic metabolism.

Research paper thumbnail of CTRP1 protein enhances fatty acid oxidation via AMP-activated protein kinase (AMPK) activation and acetyl-CoA carboxylase (ACC) inhibition

The Journal of biological chemistry, Jan 6, 2012

We previously described the adipokine CTRP1, which has up-regulated expression following exposure... more We previously described the adipokine CTRP1, which has up-regulated expression following exposure to the anti-diabetic drug rosiglitazone and increased circulating levels in adiponectin-null mice (Wong, G. W., Krawczyk, S. A., Kitidis-Mitrokostas, C., Revett, T., Gimeno, R., and Lodish, H. F. (2008) Biochem. J. 416, 161-177). Although recombinant CTRP1 lowers blood glucose in mice, its physiological function, mechanisms of action, and roles in metabolic stress remain unknown. Here, we show that circulating levels of CTRP1 are strikingly reduced in diet-induced obese mice. Overexpressing CTRP1 in transgenic mice improved insulin sensitivity and decreased high-fat diet-induced weight gain. Reduced adiposity resulted from enhanced fatty acid oxidation and energy expenditure, effects mediated by AMP-activated protein kinase (AMPK). In skeletal muscle of transgenic mice, AMPKα and its downstream target, acetyl-CoA carboxylase (ACC), were hyperphosphorylated, indicative of AMPK activation and ACC inhibition. Inactivation of ACC promotes mitochondrial fat oxidation. Consistent with the direct effect of CTRP1 on AMPK signaling, recombinant CTRP1 administration acutely stimulated muscle AMPKα and ACC phosphorylation in vivo. In isolated soleus muscle, recombinant CTRP1 activated AMPK signaling to increase fatty acid oxidation ex vivo, an effect abrogated by an AMPK inhibitor. These results provide the first in vivo evidence that CTRP1 is a novel regulator of fatty acid metabolism.

Research paper thumbnail of Neuroprotective role of Sirt1 in mammalian models of Huntington's disease through activation of multiple Sirt1 targets

Research paper thumbnail of Metabolic consequences of high-fat diet are attenuated by suppression of HIF-1α

PloS one, 2012

Obesity is associated with tissue hypoxia and the up-regulation of hypoxia inducible factor 1 alp... more Obesity is associated with tissue hypoxia and the up-regulation of hypoxia inducible factor 1 alpha . Prior studies in transgenic mice have shown that HIF-1a plays a role in the metabolic dysfunction associated with obesity. Therefore, we hypothesized that, after the development of diet-induced obesity (DIO), metabolic function could be improved by administration of HIF-1a antisense oligonucleotides (ASO). DIO mice were treated with HIF-1a ASO or with control ASO for 8 weeks and compared with an untreated group. We found that HIF-1a ASO markedly suppressed Hif-1a gene expression in adipose tissue and the liver. HIF-1a ASO administration induced weight loss. Final body weight was 41.661.4 g in the HIF-1a ASO group vs 46.760.9 g in the control ASO group and 47.960.8 g in untreated mice (p,0.001). HIF-1a ASO increased energy expenditure (13.360.6 vs 1260.1 and 11.960.4 kcal/kg/hr, respectively, p,0.001) and decreased the respiratory exchange ratio (0.7160.01 vs 0.7560.01 and 0.7660.01, respectively, p,0.001), which suggested switching metabolism to fat oxidation. In contrast, HIF-1a ASO had no effect on food intake or activity. HIF-1a ASO treatment decreased fasting blood glucose (195.568.4 mg/dl vs 23967.8 mg/dl in the control ASO group and 22268.2 mg/dl in untreated mice, p,0.01), plasma insulin, hepatic glucose output, and liver fat content. These findings demonstrate that the metabolic consequences of DIO are attenuated by HIF-1a ASO treatment.

Research paper thumbnail of Targeted deletion of C1q/TNF-related protein 9 increases food intake, decreases insulin sensitivity, and promotes hepatic steatosis in mice

American journal of physiology. Endocrinology and metabolism, 2014

Transgenic overexpression of CTRP9, a secreted hormone downregulated in obesity, confers striking... more Transgenic overexpression of CTRP9, a secreted hormone downregulated in obesity, confers striking protection against diet-induced obesity and type 2 diabetes. However, the physiological relevance of this adiponectin-related plasma protein remains undefined. Here, we used gene targeting to establish the metabolic function of CTRP9 in a physiological context. Mice lacking CTRP9 were obese and gained significantly more body weight when fed standard laboratory chow. Increased food intake, due in part to upregulated expression of hypothalamic orexigenic neuropeptides, contributed to greater adiposity in CTRP9 knockout mice. Although the frequency of food intake remained unchanged, CTRP9 knockout mice increased caloric intake by increasing meal size and decreasing satiety ratios. The absence of CTRP9 also resulted in peripheral tissue insulin resistance, leading to increased fasting insulin levels, impaired hepatic insulin signaling, and reduced insulin tolerance. Increased expression of lipogenic genes, combined with enhanced caloric intake, contributed to hepatic steatosis in CTRP9 knockout mice. Loss of CTRP9 also resulted in reduced skeletal muscle AMPK activation and mitochondrial content. Together, these results provide the genetic evidence for a physiological role of CTRP9 in controlling energy balance via central and peripheral mechanisms.

Research paper thumbnail of Hypothalamic neuron derived neurotrophic factor (NENF) regulates food intake

Research paper thumbnail of disease ri sk, respectively. She will also test for gene-gene interactions between variants in multiple genes in the lipolytic pathway. Core facilities used: Genetics, Genomics, Genetic Epidemiology Core. Regulation of systemic energy balance by AMP-activated protein kinase in select

Research paper thumbnail of Synphilin-1 induces hyperphagia-mediated obesity in mice

Appetite, 2008

Synphilin-1, a synaptic vesicle protein with unclear function, was originally identified as a pro... more Synphilin-1, a synaptic vesicle protein with unclear function, was originally identified as a protein that can interact with alpha-synuclein and parkin. Synphilin-1 is shown to promote the formation of intracellular inclusions and may play a protective role in Parkinson's disease. We found that expression of synphilin-1 in neurons in mice by a PrP promoter resulted in increased body weight, body fat and elevated plasma levels of insulin and leptin, and insulin insensitivity. We further found that the obesity in synphilin-1 mice likely results from increased energy intake as synphilin-1 mice had increased daily food intake but no changes in daily activity compared with none transgenic mice. Pair feeding synphilin-1 mice to amounts consumed by intact non-transgenic mice normalizes body weight, body fat and elevated insulin and leptin levels. We have identified high levels of synphilin-1 expression in the anterior hypothalamus, arcuate and paraventricular nuclei suggesting that the altered food intake derives from alterations in hypothalamic function. These data identify a novel potential role for synphilin-1 in energy balance.

Research paper thumbnail of WITHDRAWN: Hypothalamic acetyl CoA carboxylase in arcuate nucleus is a mediator of AMP kinase actions in the control of food intake

Appetite, 2006

The publisher regrets that this article is an accidental duplication of an article that has alrea... more The publisher regrets that this article is an accidental duplication of an article that has already been published, doi:10.1016/j.appet.2006.03.001. The duplicate article has therefore been withdrawn.

Research paper thumbnail of Intraperitoneal injections of low doses of C75 elicit a behaviorally specific and vagal afferent-independent inhibition of eating in rats

American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2008

Central and intraperitoneal C75, an inhibitor of fatty acid synthase and stimulator of carnitine ... more Central and intraperitoneal C75, an inhibitor of fatty acid synthase and stimulator of carnitine palmitoyl-transferase-1, inhibits eating in mice and rats. Mechanisms involved in feeding inhibition after central C75 have been identified, but little is yet known about how systemic C75 might inhibit eating. One issue is whether intraperitoneal C75 reduces food intake in rats by influencing normal physiological controls of food intake or acts nonselectively, for example by eliciting illness or aversion. Another issue relates to whether intraperitoneal C75 acts centrally or, similar to some other peripheral metabolic controls of eating, activates abdominal vagal afferents to inhibit eating. To further address these questions, we investigated the effects of intraperitoneal C75 on spontaneous meal patterns and the formation of conditioned taste aversion (CTA). We also tested whether the eating inhibitory effect of intraperitoneal C75 is vagally mediated by testing rats after either total subdiaphragmatic vagotomy (TVX) or selective subdiaphragmatic vagal deafferentations (SDA). Intraperitoneal injection of 3.2 and 7.5 mg/kg of C75 significantly reduced food intake 3, 12, and 24 h after injection by reducing the number of meals without affecting meal size, whereas 15 mg/kg of C75 reduced both meal number and meal size. The two smaller doses of C75 failed to induce a CTA, but 15 mg/kg C75 did. The eating inhibitory effect of C75 was not diminished in either TVX or SDA rats. We conclude that intraperitoneal injections of low doses of C75 inhibit eating in a behaviorally specific manner and that this effect does not require abdominal vagal afferents.

Research paper thumbnail of AMP-activated protein kinase in the brain

International Journal of Obesity, 2008

Since its discovery as an important regulator of fuel utilization in the periphery, AMP-activated... more Since its discovery as an important regulator of fuel utilization in the periphery, AMP-activated protein kinase (AMPK) has become a contender for many important cell-intrinsic and organismal roles regarding energy balance in the central nervous system. The challenge will be to delineate the mechanisms by which neuronal AMPK can respond to cellular energy requirements as well as whole body energy demands. Thus, under physiological conditions in the brain, hypothalamic AMPK responds to changes in energy balance/food intake, whereas under pathological conditions, AMPK responds globally in the brain to energy challenge. Modulation of fatty acid metabolism affects energy balance in a context-specific manner and may provide an insight into other mechanisms for selective activation or inhibition of AMPK activity for therapeutic applications.

Research paper thumbnail of Knockdown of NPY Expression in the Dorsomedial Hypothalamus Promotes Development of Brown Adipocytes and Prevents Diet-Induced Obesity

Cell Metabolism, 2011

Hypothalamic neuropeptide Y (NPY) has been implicated in control of energy balance, but the physi... more Hypothalamic neuropeptide Y (NPY) has been implicated in control of energy balance, but the physiological importance of NPY in the dorsomedial hypothalamus (DMH) remains unclear. Here we report that knockdown of NPY expression in the DMH by adeno-associated virus-mediated RNAi reduced fat depots in rats fed regular chow and ameliorated high-fat diet-induced hyperphagia and obesity. DMH NPY knockdown resulted in development of brown adipocytes in inguinal white adipose tissue through the sympathetic nervous system. This knockdown increased uncoupling protein 1 expression in both inguinal fat and interscapular brown adipose tissue (BAT). Consistent with the activation of BAT, DMH NPY knockdown increased energy expenditure and enhanced the thermogenic response to a cold environment. This knockdown also increased locomotor activity, improved glucose homeostasis, and enhanced insulin sensitivity. Together, these results demonstrate critical roles of DMH NPY in body weight regulation through affecting food intake, body adiposity, thermogenesis, energy expenditure, and physical activity.► Knockdown of dorsomedial hypothalamic (DMH) NPY affects body weight regulation ► DMH NPY knockdown promotes development of brown adipocytes in white fat depots ► DMH NPY knockdown increases energy expenditure and cold-induced thermogenesis ► DMH NPY knockdown improves glucose homeostasis and enhanced insulin sensitivity

Research paper thumbnail of Serotonin3 receptors in gastric mechanisms of cholecystokinin-induced satiety

American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2006

OUR UNDERSTANDING OF THE CONTROLS of food intake has increased substantially during the last 30 y... more OUR UNDERSTANDING OF THE CONTROLS of food intake has increased substantially during the last 30 years. Important in this has been the recognition of the meal as a controlled, physiologically relevant unit of energy intake. During a meal, ingested nutrients accumulate in the stomach and gradually pass to the small intestine. The gastrointestinal presence of nutrients stimulates the release of peptides and neurotransmitters that coordinate gastrointestinal secretion and motility to facilitate digestion. These events can individually, and in concert, produce signals to the brain that lead to meal termination or satiety (28) and thus determine individual meal size. The gut-brain peptide cholecystokinin (CCK) and the monoamine serotonin (5-HT) are two long-recognized agents of satiation. In this issue of the American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, Hayes et al. (16) present important new information about how CCK and 5-HT systems interact to promote peripheral mechanisms of satiety.

Research paper thumbnail of Leptin modulation of peripheral controls of meal size

Physiology & Behavior, 2006

Leptin reduces food intake through a specific effect on meal size. Investigations into how this w... more Leptin reduces food intake through a specific effect on meal size. Investigations into how this within meal effect of leptin is mediated have demonstrated that leptin increases the ability of within meal inhibitory feedback signaling to limit intake and activate neurons within the nucleus of the solitary tract (NTS). Leptin's effects on neural activation can be demonstrated both as an increase in c-fos activation and as increase in electrophysiolgoical activity in response to peripheral stimuli. Leptin can exert these effects through interactions at hypothalamic sites and activation of a descending pathway. NPY has opposite effect suggesting a role for reduced NPY signaling in the actions of leptin. Forebrain ventricular administration of a melanocortin agonist does not mimic the actions of leptin. As well as modulating within meal signaling through a descending pathway leptin, NPY and melanocortins could work directly at hindbrain integrative sites suggesting the possibility of distributed controls of meal size by anorexigenic and orexigenic signaling.

Research paper thumbnail of Basolateral and central amygdaloid lesions leave aversion to dietary amino acid imbalance intact

Physiology & Behavior, 2000

Expression of c-fos is increased in the central amygdaloid nucleus (CE) of rats ingesting a diet ... more Expression of c-fos is increased in the central amygdaloid nucleus (CE) of rats ingesting a diet with a severely imbalanced essential amino acid profile (IMB), at a time associated with development of a conditioned taste aversion (CTA). The CE and the basolateral amygdaloid nucleus (BL) both are reported to be involved in the development of CTA. Large amygdaloid lesions involving CE and BL mitigate the normal decrease in intake of IMB; this treatment also impairs CTA to a flavor cue associated with gastrointestinal discomfort. To differentiate their potential roles in aversive responses to IMB, we electrolytically lesioned CE and BL separately. Neither lesion attenuated IMB-induced anorexia, or prevented the avoidance of flavored solutions previously paired with IMB. In contrast, after saccharin–LiCl pairing, CE-lesioned animals showed attenuated CTA to saccharin solution in a two-bottle test. We conclude that neither the CE nor the BL is essential for the reduction of IMB intake, or for CTA associated with IMB. Furthermore, these results suggest that the aversive consequences of IMB intake do not involve gastrointestinal malaise-evoked neurotransmission involving the CE.

Research paper thumbnail of Fourth Ventricular CART Reduces Food and Water Intake and Produces a Conditioned Taste Aversion in Rats

Behavioral Neuroscience, 2002

Cocaine- and amphetamine-regulated transcript peptide (CART) reduces rats&amp... more Cocaine- and amphetamine-regulated transcript peptide (CART) reduces rats' intake of liquid diet if the peptide reaches the 4th ventricle (4V). To test for specificity of 4V CART effects on feeding, the authors compared its ability to reduce intakes of liquid diet and water and tested for conditioned taste aversion (CTA). CART reduced 30-min intakes of both water and Ensure at a threshold of 1 microg. Lithium chloride (0.15 M, 20 ml/kg i.p.) and 4V CART (1 microg) paired with novel saccharin solution reduced saccharin preferences similarly in subsequent 2-bottle tests, compared with saline. Thus, CART can produce CTA. These data demonstrate that 4V CART's actions in ingestive behavior are not specific to nutrients and suggest that aspects of 4V CART's actions in reducing intake may be secondary to the production of an aversive state.

Research paper thumbnail of Fourth ventricular CART reduces food and water intake and produces a conditioned taste aversion in rats

Behavioral Neuroscience, 2002

Cocaine- and amphetamine-regulated transcript peptide (CART) reduces rats&amp... more Cocaine- and amphetamine-regulated transcript peptide (CART) reduces rats' intake of liquid diet if the peptide reaches the 4th ventricle (4V). To test for specificity of 4V CART effects on feeding, the authors compared its ability to reduce intakes of liquid diet and water and tested for conditioned taste aversion (CTA). CART reduced 30-min intakes of both water and Ensure at a threshold of 1 microg. Lithium chloride (0.15 M, 20 ml/kg i.p.) and 4V CART (1 microg) paired with novel saccharin solution reduced saccharin preferences similarly in subsequent 2-bottle tests, compared with saline. Thus, CART can produce CTA. These data demonstrate that 4V CART's actions in ingestive behavior are not specific to nutrients and suggest that aspects of 4V CART's actions in reducing intake may be secondary to the production of an aversive state.

Research paper thumbnail of WITHDRAWN: “Intracerebroventricular administration of either C89b, a stimulator of carnitinepalmitoyl-transferase-1 (CPT1s), or cerulenin, an inhibitor of fatty acid synthase (FASi), reduces food intake and body weight in mice”

Research paper thumbnail of AMPK in the brain: its roles in energy balance and neuroprotection

Journal of Neurochemistry, 2009

Adenosine monophosphate-activated protein kinase (AMPK) senses metabolic stress and integrates di... more Adenosine monophosphate-activated protein kinase (AMPK) senses metabolic stress and integrates diverse physiological signals to restore energy balance. Multiple functions are indicated for AMPK in the CNS. While all neurons sense their own energy status, some integrate neuro-humoral signals to assess organismal energy balance. A variety of disease states may involve AMPK, so determining the underlying mechanisms is important. We review the impact of altered AMPK activity under physiological (hunger, satiety) and pathophysiological (stroke) conditions, as well as therapeutic manipulations of AMPK that may improve energy balance.

Research paper thumbnail of Anaplerotic Triheptanoin Diet Enhances Mitochondrial Substrate Use to Remodel the Metabolome and Improve Lifespan, Motor Function, and Sociability in MeCP2-Null Mice

PLoS ONE, 2014

Rett syndrome (RTT) is an autism spectrum disorder (ASD) caused by mutations in the X-linked MECP... more Rett syndrome (RTT) is an autism spectrum disorder (ASD) caused by mutations in the X-linked MECP2 gene that encodes methyl-CpG binding protein 2 (MeCP2). Symptoms range in severity and include psychomotor disabilities, seizures, ataxia, and intellectual disability. Symptom onset is between 6-18 months of age, a critical period of brain development that is highly energy-dependent. Notably, patients with RTT have evidence of mitochondrial dysfunction, as well as abnormal levels of the adipokines leptin and adiponectin, suggesting overall metabolic imbalance. We hypothesized that one contributor to RTT symptoms is energy deficiency due to defective nutrient substrate utilization by the TCA cycle. This energy deficit would lead to a metabolic imbalance, but would be treatable by providing anaplerotic substrates to the TCA cycle to enhance energy production. We show that dietary therapy with triheptanoin significantly increased longevity and improved motor function and social interaction in male mice hemizygous for Mecp2 knockout. Anaplerotic therapy in Mecp2 knockout mice also improved indicators of impaired substrate utilization, decreased adiposity, increased glucose tolerance and insulin sensitivity, decreased serum leptin and insulin, and improved mitochondrial morphology in skeletal muscle. Untargeted metabolomics of liver and skeletal muscle revealed increases in levels of TCA cycle intermediates with triheptanoin diet, as well as normalizations of glucose and fatty acid biochemical pathways consistent with the improved metabolic phenotype in Mecp2 knockout mice on triheptanoin. These results suggest that an approach using dietary supplementation with anaplerotic substrate is effective in improving symptoms and metabolic health in RTT.

Research paper thumbnail of Increasing Fatty Acid Oxidation Remodels the Hypothalamic Neurometabolome to Mitigate Stress and Inflammation

PLoS ONE, 2014

Modification of hypothalamic fatty acid (FA) metabolism can improve energy homeostasis and preven... more Modification of hypothalamic fatty acid (FA) metabolism can improve energy homeostasis and prevent hyperphagia and excessive weight gain in diet-induced obesity (DIO) from a diet high in saturated fatty acids. We have shown previously that C75, a stimulator of carnitine palmitoyl transferase-1 (CPT-1) and fatty acid oxidation (FAOx), exerts at least some of its hypophagic effects via neuronal mechanisms in the hypothalamus. In the present work, we characterized the effects of C75 and another anorexigenic compound, the glycerol-3-phosphate acyltransferase (GPAT) inhibitor FSG67, on FA metabolism, metabolomics profiles, and metabolic stress responses in cultured hypothalamic neurons and hypothalamic neuronal cell lines during lipid excess with palmitate. Both compounds enhanced palmitate oxidation, increased ATP, and inactivated AMP-activated protein kinase (AMPK) in hypothalamic neurons in vitro. Lipidomics and untargeted metabolomics revealed that enhanced catabolism of FA decreased palmitate availability and prevented the production of fatty acylglycerols, ceramides, and cholesterol esters, lipids that are associated with lipotoxicity-provoked metabolic stress. This improved metabolic signature was accompanied by increased levels of reactive oxygen species (ROS), and yet favorable changes in oxidative stress, overt ER stress, and inflammation. We propose that enhancing FAOx in hypothalamic neurons exposed to excess lipids promotes metabolic remodeling that reduces local inflammatory and cell stress responses. This shift would restore mitochondrial function such that increased FAOx can produce hypothalamic neuronal ATP and lead to decreased food intake and body weight to improve systemic metabolism.

Research paper thumbnail of CTRP1 protein enhances fatty acid oxidation via AMP-activated protein kinase (AMPK) activation and acetyl-CoA carboxylase (ACC) inhibition

The Journal of biological chemistry, Jan 6, 2012

We previously described the adipokine CTRP1, which has up-regulated expression following exposure... more We previously described the adipokine CTRP1, which has up-regulated expression following exposure to the anti-diabetic drug rosiglitazone and increased circulating levels in adiponectin-null mice (Wong, G. W., Krawczyk, S. A., Kitidis-Mitrokostas, C., Revett, T., Gimeno, R., and Lodish, H. F. (2008) Biochem. J. 416, 161-177). Although recombinant CTRP1 lowers blood glucose in mice, its physiological function, mechanisms of action, and roles in metabolic stress remain unknown. Here, we show that circulating levels of CTRP1 are strikingly reduced in diet-induced obese mice. Overexpressing CTRP1 in transgenic mice improved insulin sensitivity and decreased high-fat diet-induced weight gain. Reduced adiposity resulted from enhanced fatty acid oxidation and energy expenditure, effects mediated by AMP-activated protein kinase (AMPK). In skeletal muscle of transgenic mice, AMPKα and its downstream target, acetyl-CoA carboxylase (ACC), were hyperphosphorylated, indicative of AMPK activation and ACC inhibition. Inactivation of ACC promotes mitochondrial fat oxidation. Consistent with the direct effect of CTRP1 on AMPK signaling, recombinant CTRP1 administration acutely stimulated muscle AMPKα and ACC phosphorylation in vivo. In isolated soleus muscle, recombinant CTRP1 activated AMPK signaling to increase fatty acid oxidation ex vivo, an effect abrogated by an AMPK inhibitor. These results provide the first in vivo evidence that CTRP1 is a novel regulator of fatty acid metabolism.

Research paper thumbnail of Neuroprotective role of Sirt1 in mammalian models of Huntington's disease through activation of multiple Sirt1 targets

Research paper thumbnail of Metabolic consequences of high-fat diet are attenuated by suppression of HIF-1α

PloS one, 2012

Obesity is associated with tissue hypoxia and the up-regulation of hypoxia inducible factor 1 alp... more Obesity is associated with tissue hypoxia and the up-regulation of hypoxia inducible factor 1 alpha . Prior studies in transgenic mice have shown that HIF-1a plays a role in the metabolic dysfunction associated with obesity. Therefore, we hypothesized that, after the development of diet-induced obesity (DIO), metabolic function could be improved by administration of HIF-1a antisense oligonucleotides (ASO). DIO mice were treated with HIF-1a ASO or with control ASO for 8 weeks and compared with an untreated group. We found that HIF-1a ASO markedly suppressed Hif-1a gene expression in adipose tissue and the liver. HIF-1a ASO administration induced weight loss. Final body weight was 41.661.4 g in the HIF-1a ASO group vs 46.760.9 g in the control ASO group and 47.960.8 g in untreated mice (p,0.001). HIF-1a ASO increased energy expenditure (13.360.6 vs 1260.1 and 11.960.4 kcal/kg/hr, respectively, p,0.001) and decreased the respiratory exchange ratio (0.7160.01 vs 0.7560.01 and 0.7660.01, respectively, p,0.001), which suggested switching metabolism to fat oxidation. In contrast, HIF-1a ASO had no effect on food intake or activity. HIF-1a ASO treatment decreased fasting blood glucose (195.568.4 mg/dl vs 23967.8 mg/dl in the control ASO group and 22268.2 mg/dl in untreated mice, p,0.01), plasma insulin, hepatic glucose output, and liver fat content. These findings demonstrate that the metabolic consequences of DIO are attenuated by HIF-1a ASO treatment.

Research paper thumbnail of Targeted deletion of C1q/TNF-related protein 9 increases food intake, decreases insulin sensitivity, and promotes hepatic steatosis in mice

American journal of physiology. Endocrinology and metabolism, 2014

Transgenic overexpression of CTRP9, a secreted hormone downregulated in obesity, confers striking... more Transgenic overexpression of CTRP9, a secreted hormone downregulated in obesity, confers striking protection against diet-induced obesity and type 2 diabetes. However, the physiological relevance of this adiponectin-related plasma protein remains undefined. Here, we used gene targeting to establish the metabolic function of CTRP9 in a physiological context. Mice lacking CTRP9 were obese and gained significantly more body weight when fed standard laboratory chow. Increased food intake, due in part to upregulated expression of hypothalamic orexigenic neuropeptides, contributed to greater adiposity in CTRP9 knockout mice. Although the frequency of food intake remained unchanged, CTRP9 knockout mice increased caloric intake by increasing meal size and decreasing satiety ratios. The absence of CTRP9 also resulted in peripheral tissue insulin resistance, leading to increased fasting insulin levels, impaired hepatic insulin signaling, and reduced insulin tolerance. Increased expression of lipogenic genes, combined with enhanced caloric intake, contributed to hepatic steatosis in CTRP9 knockout mice. Loss of CTRP9 also resulted in reduced skeletal muscle AMPK activation and mitochondrial content. Together, these results provide the genetic evidence for a physiological role of CTRP9 in controlling energy balance via central and peripheral mechanisms.

Research paper thumbnail of Hypothalamic neuron derived neurotrophic factor (NENF) regulates food intake

Research paper thumbnail of disease ri sk, respectively. She will also test for gene-gene interactions between variants in multiple genes in the lipolytic pathway. Core facilities used: Genetics, Genomics, Genetic Epidemiology Core. Regulation of systemic energy balance by AMP-activated protein kinase in select

Research paper thumbnail of Synphilin-1 induces hyperphagia-mediated obesity in mice

Appetite, 2008

Synphilin-1, a synaptic vesicle protein with unclear function, was originally identified as a pro... more Synphilin-1, a synaptic vesicle protein with unclear function, was originally identified as a protein that can interact with alpha-synuclein and parkin. Synphilin-1 is shown to promote the formation of intracellular inclusions and may play a protective role in Parkinson's disease. We found that expression of synphilin-1 in neurons in mice by a PrP promoter resulted in increased body weight, body fat and elevated plasma levels of insulin and leptin, and insulin insensitivity. We further found that the obesity in synphilin-1 mice likely results from increased energy intake as synphilin-1 mice had increased daily food intake but no changes in daily activity compared with none transgenic mice. Pair feeding synphilin-1 mice to amounts consumed by intact non-transgenic mice normalizes body weight, body fat and elevated insulin and leptin levels. We have identified high levels of synphilin-1 expression in the anterior hypothalamus, arcuate and paraventricular nuclei suggesting that the altered food intake derives from alterations in hypothalamic function. These data identify a novel potential role for synphilin-1 in energy balance.

Research paper thumbnail of WITHDRAWN: Hypothalamic acetyl CoA carboxylase in arcuate nucleus is a mediator of AMP kinase actions in the control of food intake

Appetite, 2006

The publisher regrets that this article is an accidental duplication of an article that has alrea... more The publisher regrets that this article is an accidental duplication of an article that has already been published, doi:10.1016/j.appet.2006.03.001. The duplicate article has therefore been withdrawn.

Research paper thumbnail of Intraperitoneal injections of low doses of C75 elicit a behaviorally specific and vagal afferent-independent inhibition of eating in rats

American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2008

Central and intraperitoneal C75, an inhibitor of fatty acid synthase and stimulator of carnitine ... more Central and intraperitoneal C75, an inhibitor of fatty acid synthase and stimulator of carnitine palmitoyl-transferase-1, inhibits eating in mice and rats. Mechanisms involved in feeding inhibition after central C75 have been identified, but little is yet known about how systemic C75 might inhibit eating. One issue is whether intraperitoneal C75 reduces food intake in rats by influencing normal physiological controls of food intake or acts nonselectively, for example by eliciting illness or aversion. Another issue relates to whether intraperitoneal C75 acts centrally or, similar to some other peripheral metabolic controls of eating, activates abdominal vagal afferents to inhibit eating. To further address these questions, we investigated the effects of intraperitoneal C75 on spontaneous meal patterns and the formation of conditioned taste aversion (CTA). We also tested whether the eating inhibitory effect of intraperitoneal C75 is vagally mediated by testing rats after either total subdiaphragmatic vagotomy (TVX) or selective subdiaphragmatic vagal deafferentations (SDA). Intraperitoneal injection of 3.2 and 7.5 mg/kg of C75 significantly reduced food intake 3, 12, and 24 h after injection by reducing the number of meals without affecting meal size, whereas 15 mg/kg of C75 reduced both meal number and meal size. The two smaller doses of C75 failed to induce a CTA, but 15 mg/kg C75 did. The eating inhibitory effect of C75 was not diminished in either TVX or SDA rats. We conclude that intraperitoneal injections of low doses of C75 inhibit eating in a behaviorally specific manner and that this effect does not require abdominal vagal afferents.

Research paper thumbnail of AMP-activated protein kinase in the brain

International Journal of Obesity, 2008

Since its discovery as an important regulator of fuel utilization in the periphery, AMP-activated... more Since its discovery as an important regulator of fuel utilization in the periphery, AMP-activated protein kinase (AMPK) has become a contender for many important cell-intrinsic and organismal roles regarding energy balance in the central nervous system. The challenge will be to delineate the mechanisms by which neuronal AMPK can respond to cellular energy requirements as well as whole body energy demands. Thus, under physiological conditions in the brain, hypothalamic AMPK responds to changes in energy balance/food intake, whereas under pathological conditions, AMPK responds globally in the brain to energy challenge. Modulation of fatty acid metabolism affects energy balance in a context-specific manner and may provide an insight into other mechanisms for selective activation or inhibition of AMPK activity for therapeutic applications.

Research paper thumbnail of Knockdown of NPY Expression in the Dorsomedial Hypothalamus Promotes Development of Brown Adipocytes and Prevents Diet-Induced Obesity

Cell Metabolism, 2011

Hypothalamic neuropeptide Y (NPY) has been implicated in control of energy balance, but the physi... more Hypothalamic neuropeptide Y (NPY) has been implicated in control of energy balance, but the physiological importance of NPY in the dorsomedial hypothalamus (DMH) remains unclear. Here we report that knockdown of NPY expression in the DMH by adeno-associated virus-mediated RNAi reduced fat depots in rats fed regular chow and ameliorated high-fat diet-induced hyperphagia and obesity. DMH NPY knockdown resulted in development of brown adipocytes in inguinal white adipose tissue through the sympathetic nervous system. This knockdown increased uncoupling protein 1 expression in both inguinal fat and interscapular brown adipose tissue (BAT). Consistent with the activation of BAT, DMH NPY knockdown increased energy expenditure and enhanced the thermogenic response to a cold environment. This knockdown also increased locomotor activity, improved glucose homeostasis, and enhanced insulin sensitivity. Together, these results demonstrate critical roles of DMH NPY in body weight regulation through affecting food intake, body adiposity, thermogenesis, energy expenditure, and physical activity.► Knockdown of dorsomedial hypothalamic (DMH) NPY affects body weight regulation ► DMH NPY knockdown promotes development of brown adipocytes in white fat depots ► DMH NPY knockdown increases energy expenditure and cold-induced thermogenesis ► DMH NPY knockdown improves glucose homeostasis and enhanced insulin sensitivity

Research paper thumbnail of Serotonin3 receptors in gastric mechanisms of cholecystokinin-induced satiety

American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2006

OUR UNDERSTANDING OF THE CONTROLS of food intake has increased substantially during the last 30 y... more OUR UNDERSTANDING OF THE CONTROLS of food intake has increased substantially during the last 30 years. Important in this has been the recognition of the meal as a controlled, physiologically relevant unit of energy intake. During a meal, ingested nutrients accumulate in the stomach and gradually pass to the small intestine. The gastrointestinal presence of nutrients stimulates the release of peptides and neurotransmitters that coordinate gastrointestinal secretion and motility to facilitate digestion. These events can individually, and in concert, produce signals to the brain that lead to meal termination or satiety (28) and thus determine individual meal size. The gut-brain peptide cholecystokinin (CCK) and the monoamine serotonin (5-HT) are two long-recognized agents of satiation. In this issue of the American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, Hayes et al. (16) present important new information about how CCK and 5-HT systems interact to promote peripheral mechanisms of satiety.

Research paper thumbnail of Leptin modulation of peripheral controls of meal size

Physiology & Behavior, 2006

Leptin reduces food intake through a specific effect on meal size. Investigations into how this w... more Leptin reduces food intake through a specific effect on meal size. Investigations into how this within meal effect of leptin is mediated have demonstrated that leptin increases the ability of within meal inhibitory feedback signaling to limit intake and activate neurons within the nucleus of the solitary tract (NTS). Leptin's effects on neural activation can be demonstrated both as an increase in c-fos activation and as increase in electrophysiolgoical activity in response to peripheral stimuli. Leptin can exert these effects through interactions at hypothalamic sites and activation of a descending pathway. NPY has opposite effect suggesting a role for reduced NPY signaling in the actions of leptin. Forebrain ventricular administration of a melanocortin agonist does not mimic the actions of leptin. As well as modulating within meal signaling through a descending pathway leptin, NPY and melanocortins could work directly at hindbrain integrative sites suggesting the possibility of distributed controls of meal size by anorexigenic and orexigenic signaling.

Research paper thumbnail of Basolateral and central amygdaloid lesions leave aversion to dietary amino acid imbalance intact

Physiology & Behavior, 2000

Expression of c-fos is increased in the central amygdaloid nucleus (CE) of rats ingesting a diet ... more Expression of c-fos is increased in the central amygdaloid nucleus (CE) of rats ingesting a diet with a severely imbalanced essential amino acid profile (IMB), at a time associated with development of a conditioned taste aversion (CTA). The CE and the basolateral amygdaloid nucleus (BL) both are reported to be involved in the development of CTA. Large amygdaloid lesions involving CE and BL mitigate the normal decrease in intake of IMB; this treatment also impairs CTA to a flavor cue associated with gastrointestinal discomfort. To differentiate their potential roles in aversive responses to IMB, we electrolytically lesioned CE and BL separately. Neither lesion attenuated IMB-induced anorexia, or prevented the avoidance of flavored solutions previously paired with IMB. In contrast, after saccharin–LiCl pairing, CE-lesioned animals showed attenuated CTA to saccharin solution in a two-bottle test. We conclude that neither the CE nor the BL is essential for the reduction of IMB intake, or for CTA associated with IMB. Furthermore, these results suggest that the aversive consequences of IMB intake do not involve gastrointestinal malaise-evoked neurotransmission involving the CE.

Research paper thumbnail of Fourth Ventricular CART Reduces Food and Water Intake and Produces a Conditioned Taste Aversion in Rats

Behavioral Neuroscience, 2002

Cocaine- and amphetamine-regulated transcript peptide (CART) reduces rats&amp... more Cocaine- and amphetamine-regulated transcript peptide (CART) reduces rats' intake of liquid diet if the peptide reaches the 4th ventricle (4V). To test for specificity of 4V CART effects on feeding, the authors compared its ability to reduce intakes of liquid diet and water and tested for conditioned taste aversion (CTA). CART reduced 30-min intakes of both water and Ensure at a threshold of 1 microg. Lithium chloride (0.15 M, 20 ml/kg i.p.) and 4V CART (1 microg) paired with novel saccharin solution reduced saccharin preferences similarly in subsequent 2-bottle tests, compared with saline. Thus, CART can produce CTA. These data demonstrate that 4V CART's actions in ingestive behavior are not specific to nutrients and suggest that aspects of 4V CART's actions in reducing intake may be secondary to the production of an aversive state.

Research paper thumbnail of Fourth ventricular CART reduces food and water intake and produces a conditioned taste aversion in rats

Behavioral Neuroscience, 2002

Cocaine- and amphetamine-regulated transcript peptide (CART) reduces rats&amp... more Cocaine- and amphetamine-regulated transcript peptide (CART) reduces rats' intake of liquid diet if the peptide reaches the 4th ventricle (4V). To test for specificity of 4V CART effects on feeding, the authors compared its ability to reduce intakes of liquid diet and water and tested for conditioned taste aversion (CTA). CART reduced 30-min intakes of both water and Ensure at a threshold of 1 microg. Lithium chloride (0.15 M, 20 ml/kg i.p.) and 4V CART (1 microg) paired with novel saccharin solution reduced saccharin preferences similarly in subsequent 2-bottle tests, compared with saline. Thus, CART can produce CTA. These data demonstrate that 4V CART's actions in ingestive behavior are not specific to nutrients and suggest that aspects of 4V CART's actions in reducing intake may be secondary to the production of an aversive state.

Research paper thumbnail of WITHDRAWN: “Intracerebroventricular administration of either C89b, a stimulator of carnitinepalmitoyl-transferase-1 (CPT1s), or cerulenin, an inhibitor of fatty acid synthase (FASi), reduces food intake and body weight in mice”

Research paper thumbnail of AMPK in the brain: its roles in energy balance and neuroprotection

Journal of Neurochemistry, 2009

Adenosine monophosphate-activated protein kinase (AMPK) senses metabolic stress and integrates di... more Adenosine monophosphate-activated protein kinase (AMPK) senses metabolic stress and integrates diverse physiological signals to restore energy balance. Multiple functions are indicated for AMPK in the CNS. While all neurons sense their own energy status, some integrate neuro-humoral signals to assess organismal energy balance. A variety of disease states may involve AMPK, so determining the underlying mechanisms is important. We review the impact of altered AMPK activity under physiological (hunger, satiety) and pathophysiological (stroke) conditions, as well as therapeutic manipulations of AMPK that may improve energy balance.