Hypothalamic mTOR Research Articles

Kappa-Opioid Receptor Blockade Ameliorates Obesity Caused by Estrogen Withdrawal via Promotion of Energy Expenditure through mTOR Pathway.

Weight gain is a hallmark of decreased estradiol (E2) levels because of menopause or following surgical ovariectomy (OVX) at younger ages. Of note, this weight gain tends to be around the abdomen, which is frequently associated with impaired metabolic homeostasis and greater cardiovascular risk in both rodents and humans. However, the molecular underpinnings and the neuronal basis for these effects remain to be elucidated. The aim of this study is to elucidate whether the kappa-opioid receptor (k-OR) system is involved in mediating body weight changes associated with E2 withdrawal. Here, we document that body weight gain induced by OVX occurs, at least partially, in a k-OR dependent manner, by modulation of energy expenditure independently of food intake as assessed in Oprk1−/−global KO mice. These effects were also observed following central pharmacological blockade of the k-OR system using the k-OR-selective antagonist PF-04455242 in wild type mice, in which we also observed a decrease in OVX-induced weight gain associated with increased UCP1 positive immunostaining in brown adipose tissue (BAT) and browning of white adipose tissue (WAT). Remarkably, the hypothalamic mTOR pathway plays an important role in regulating weight gain and adiposity in OVX mice. These findings will help to define new therapies to manage metabolic disorders associated with low/null E2 levels based on the modulation of central k-OR signaling.

Leucine sensing in rainbow trout hypothalamus is direct but separate from mTOR signalling in the regulation of food intake

In prior studies, we evidenced the presence in fish hypothalamus of different systems sensing changes in leucine levels to relate them to food intake control. To assess whether or not those effects are due to a direct action of leucine, we evaluated in the present in vitro study if rainbow trout (Oncorhynchus mykiss) hypothalamus respond to changes in leucine levels in a way comparable to that observed in vivo. Thus, we incubated hypothalamus in vitro with increased leucine concentrations (1, 5 and 25 mM). Then, we evaluated parameters related to mechanisms of amino acid sensing as well as transcription factors, and neuropeptides. Amino acid sensing systems related to metabolism of BCAA and glutamine and GCN2 kinase are activated by the presence of leucine, in a way comparable to that observed in vivo thus supporting a direct action of leucine on them. However, the activation of these systems did not trigger mTOR signalling pathway including downstream protein targets of mTOR, transcription factors, and mRNA abundance of neuropeptides involved in food intake the regulation of food intake. Therefore, the activation of hypothalamic mTOR observed after leucine administration in vivo is not a direct response to leucine but indirect. The absence in vitro of connections between hypothalamus and other brain areas and/or the lack of changes in levels of hormones, particularly insulin, could be responsible of this differential response.

The AMPK-mTOR signaling pathway is involved in regulation of food intake in the hypothalamus of stressed chickens

Glucocorticoids (GCs) can stimulate the appetite and AMPK in broilers. The activation of hypothalamic mTOR has been proposed as an important anorexigenic signal. However, inhibitory effect of AMPK activity on appetite and AMPK downstream signaling pathway under stress has not been reported. In this study, we performed an intracerebroventricular (icv) injection of compound C, an AMPK inhibitor, in GC-treated birds to explore the regulatory mechanism on appetite and AMPK downstream signaling pathway. A total of 48 7-day-old broilers, which had received an icv cannula, were randomly subjected to one of two treatments: subcutaneous injection of dexamethasone (DEX) or saline. After 3 days of continuous DEX injection, chicks of each group received an icv injection with either compound C (6 μg/2 μL) or vehicle (dimethyl sulfoxide, 2 μL). The results showed that body weight gain was reduced by the DEX treatment. Compared with the control, icv injection of compound C reduced feed intake at 0.5–1.5 h. In the DEX-treated group, the inhibitory effect of compound C on appetite remained apparent at 0.5–1 h. The DEX treatment increased the gene expression of liver kinase B1 (LKB1), neuropeptide Y (NPY), and decreased p-mTOR protein level. In stressed broilers, inhibition of AMPK relieved the decreased mTOR activity. A significant interaction was noted in DEX and compound C on protein expression of phospho-AMPK. Taken together, in stressed broilers, the central injection of compound C could inhibit central AMPK activity and reduce appetite, in which the AMPK/mTOR signaling pathway might be involved.

Very-low-protein diets lead to reduced food intake and weight loss, linked to inhibition of hypothalamic mTOR signaling, in mice

The protein leverage hypothesis predicts that low dietary protein should increase energy intake and cause adiposity. We designed 10 diets varying from 1% to 20% protein combined with either 60% or 20% fat. Contrasting the expectation, very low protein did not cause increased food intake. Although these mice had activated hunger signaling, they ate less food, resulting in decreased body weight and improved glucose tolerance but not increased frailty, even under 60% fat. Moreover, they did not show hyperphagia when returned to a 20% protein diet, which could be mimicked by treatment with rapamycin. Intracerebroventricular injection of AAV-S6K1 significantly blunted the decrease in both food intake and body weight in mice fed 1% protein, an effect not observed with inhibition of eIF2a, TRPML1, and Fgf21 signaling. Hence, the 1% protein diet induced decreased food intake and body weight via a mechanism partially dependent on hypothalamic mTOR signaling.

Adipocyte-derived extracellular vesicles modulate appetite and weight through mTOR signalling in the hypothalamus.

Type 2 diabetes and obesity are diseases related to surplus energy in the body. Abnormal interaction between the hypothalamus and adipose tissues is a key trigger of energy metabolism dysfunction. Extracellular vesicles (EVs) regulate intercellular communication by transporting intracellular cargo to recipient cells thereby altering the function of recipient cells. This study aimed to evaluate whether adipocyte-derived EVs can act on hypothalamic neurons to modulate energy intake and to identify the EV-associated non-coding RNAs. Confocal imaging was used to trace the uptake of labelled adipocyte-derived exosomes by hypothalamic anorexigenic POMC neurons. The effects of adipocyte-derived EVs on the mammalian target of rapamycin (mTOR) signalling pathway in POMC neurons were evaluated based on mRNA and protein expression in vitro using quantitative real-time PCR and western blotting. In addition, adipocyte-derived EVs were injected into recipient mice, and changes in mice body weight and daily food intake were monitored. The biological effects of the EV-associated MALAT1 on POMC neurons were explored. Adipocyte-derived EVs were successfully transferred into POMC neurons in vitro. Results showed that adipocytes of obese mice secreted MALAT1-containing EVs, which increased appetite and weight when administered to lean mice. Conversely, adipocyte-derived EVs from lean mice decreased food intake and weight when administered to obese mice. Adipocyte-derived EVs play important roles in mediating the interaction between adipocytes and hypothalamic neurons. Adipocyte-derived EVs can regulate POMC expression through the hypothalamic mTOR signalling in vivo and in vitro, thereby affecting body energy intake.

Fluoxetine Modulates the Activity of Hypothalamic POMC Neurons via mTOR Signaling.

Hypothalamic proopiomelanocortin (POMC) neurons are important players in the regulation of energy homeostasis; we previously demonstrated that environmental stimulation excites arcuate nucleus circuits to undergo plastic remodeling, leading to altered ratio between excitatory and inhibitory synaptic contacts on these neurons. The widely used selective serotonin reuptake inhibitor fluoxetine (FLX) is known to affect body weight. On the other hand, FLX administration mimics the effects of environmental stimulation on synaptic plasticity in the hippocampus and cortex. The mammalian target of rapamycin (mTOR) pathway is instrumental in these phenomena. Thus, we aimed at investigating whether and how FLX affects POMC neurons activity and hypothalamic mTOR function. Adult mice expressing green fluorescent protein (GFP) under the POMC promoter were treated with FLX for 3weeks resulting in diminished body weight. Patch clamp recordings performed on POMC neurons indicate that FLX increases their firing rate and the excitatory AMPA-mediated transmission, and reduces the inhibitory GABAergic currents at presynaptic level. Immunofluorescence studies indicate that FLX increases the ratio between excitatory and inhibitory synaptic contacts on POMC neurons. These changes are associated with an increased activity of the hypothalamic mTOR pathway. Use of the mTOR inhibitor rapamycin blunts the effects of FLX on body weight and on functional and structural plasticity of POMC neurons. Our findings indicate that FLX is able to remodel POMC neurons, and that this may be partly mediated by the mTOR signaling pathway.

Changes of Ghrelin/GOAT axis and mTOR pathway in the hypothalamus after sleeve gastrectomy in obese type-2 diabetes rats.

AIMTo examine the changes of the ghrelin/ghrelin O-acyltransferase (GOAT) axis and the mammalian target of rapamycin (mTOR) pathway in the hypothalamus after sleeve gastrectomy.METHODSA total of 30 obese type-2 diabetes Sprague-Dawley (SD) rats, 6 wk of age, fed with high-sugar and high-fat fodder for 2 mo plus intraperitoneal injection of streptozotocin were randomly divided into three groups: non-operation group (S0 group, n = 10), sham operation group (Sh group, n = 10) and sleeve gastrectomy group (SG group, n = 10). Data of body mass, food intake, oral glucose tolerance test (OGTT), acylated ghrelin (AG) and total ghrelin (TG) were collected and measured at the first day (when the rats were 6 wk old), preoperative day 3 and postoperative week 8. The mRNA expression of preproghrelin, GOAT and neuropeptide Y (NPY), and protein expression of ghrelin, GOAT, GHSR and the mTOR pathway (p-Akt, p-mTOR and p-S6) were measured in the hypothalamus.RESULTSSG can significantly improve metabolic symptoms by reducing body mass and food intake. The obese rats showed lower serum TG levels and no change in AG, but the ratio of AG/TG was increased. When compared with the S0 and Sh groups, the SG group showed decreased TG (1482.03 ± 26.55, 1481.49 ± 23.30 and 1206.63 ± 52.02 ng/L, respectively, P < 0.05), but unchanged AG (153.06 ± 13.74, 155.37 ± 19.30 and 144.44 ± 16.689 ng/L, respectively, P > 0.05). As a result, the ratio of AG/TG further increased in the SG group (0.103 ± 0.009, 0.105 ± 0.013 and 0.12 ± 0.016, respectively, P < 0.05). When compared with the S0 group, SG suppressed mRNA and protein levels of preproghrelin (0.63 ± 0.12 vs 0.5 ± 0.11, P < 0.05) and GOAT (0.96 ± 0.09 vs 0.87 ± 0.08, P < 0.05), but did not change NPY mRNA expression (0.61 ± 0.04 vs 0.65 ± 0.07, P > 0.05) in the hypothalamus. The protein levels of p-Akt, p-mTOR and p-S6 were higher in the SG group, which indicated that the hypothalamic mTOR pathway was activated after SG at the postoperative week 8.CONCLUSIONThe reduction of ghrelin expression and activation of the mTOR pathway might have opposite effects on food intake, as SG improves obesity and T2DM.

Effect of Nourishing "Yin" Removing "Fire" Chinese Herbal Mixture on Hypothalamic Mammalian Target of Rapamycin Expression during Onset of Puberty in Female Rats.

Aim. The present study aims to investigate the effects of nourishing “Yin” removing “Fire” (NYRF) Chinese herbal mixture on puberty onset and hypothalamic mTOR expression in female rats. Materials and Methods. Forty female 20-day-old Sprague-Dawley rats were randomly divided into Chinese herbal mixture (CHM) and normal saline (NS) groups. Rats in CHM and NS were treated with NYRF mixture and normal saline, respectively, from d22. Rats in each group were sacrificed on d28, d31, and d34. Serum luteinizing hormone (LH), follicle stimulating hormone (FSH), and estradiol (E2) levels were analyzed by ELISA. Hypothalamic mTOR mRNA expression levels were determined by RT-PCR and hypothalamic p-mTOR protein levels were assayed by western blot. Results. The vaginal opening time in CHM group was significantly delayed (P < 0.05). On d31, in comparison with NS group, the coefficients of uteri and ovaries, levels of serum LH and E2, and the expression levels of hypothalamic mTOR mRNA and p-mTOR protein were significantly lower in CHM group (P < 0.05). Conclusion. The mechanism by which the nourishing “Yin” removing “Fire” Chinese herbal mixture delays puberty onset may be associated with the inhibition of the hypothalamic mTOR signaling.

Hypothalamic mTOR: The Rookie Energy Sensor

Optimal cellular function and therefore organism's survival is determined by the sensitive and accurate convergence of energy and nutrient abundance to cell growth and division. Among other factors, this integration is coupled by the target of rapamycin (TOR) pathway, which is able to sense nutrient, energy and oxygen availability and also growth factor signaling. Indeed, TOR signaling regulates cell energy homeostasis by coordinating anabolic and catabolic processes for survival. TOR, named mTOR in mammals, is a conserved serine/threonine kinase that exists in two different complexes, mTORC1 and mTORC2. Recently, studies are suggesting that alterations of those complexes promote disease and disrupted phenotypes, such as aging, obesity and related disorders and even cancer. The evidences linking mTOR to energy and metabolic homeostasis included the following. At central level mTOR regulates food intake and body weight being involved in the mechanism by which signals such as leptin and ghrelin exert its effects. At peripheral level it influences adipogenesis and lipogenesis in different tissues including the liver. Noteworthy chronic nutritional activation of mTOR signaling has been implicated in the development of beta cell mass expansion and on insulin resistance. Understanding of mTOR and other molecular switches, such as AMP-activated protein kinase (AMPK), as well as their interrelationship is crucial to know how organisms maintain optimal homeostasis. This review summarizes the role of hypothalamic TOR complex in cellular energy sensing, evidenced in the last years, focusing on the metabolic pathways where it is involved and the importance of this metabolic sensor in cellular and whole body energy management. Understanding the exact role of hypothalamic mTOR may provide new cues for therapeutic intervention in diseases.

Oral Leucine Supplementation Is Sensed by the Brain but neither Reduces Food Intake nor Induces an Anorectic Pattern of Gene Expression in the Hypothalamus

Leucine activates the intracellular mammalian target of the rapamycin (mTOR) pathway, and hypothalamic mTOR signaling regulates food intake. Although central infusion of leucine reduces food intake, it is still uncertain whether oral leucine supplementation is able to affect the hypothalamic circuits that control energy balance. We observed increased phosphorylation of p70s6k in the mouse hypothalamus after an acute oral gavage of leucine. We then assessed whether acute oral gavage of leucine induces the activation of neurons in several hypothalamic nuclei and in the brainstem. Leucine did not induce the expression of Fos in hypothalamic nuclei, but it increased the number of Fos-immunoreactive neurons in the area postrema. In addition, oral gavage of leucine acutely increased the 24 h food intake of mice. Nonetheless, chronic leucine supplementation in the drinking water did not change the food intake and the weight gain of ob/ob mice and of wild-type mice consuming a low- or a high-fat diet. We assessed the hypothalamic gene expression and observed that leucine supplementation increased the expression of enzymes (BCAT1, BCAT2 and BCKDK) that metabolize branched-chain amino acids. Despite these effects, leucine supplementation did not induce an anorectic pattern of gene expression in the hypothalamus. In conclusion, our data show that the brain is able to sense oral leucine intake. However, the food intake is not modified by chronic oral leucine supplementation. These results question the possible efficacy of leucine supplementation as an appetite suppressant to treat obesity.

The effect of high fat diet and saturated fatty acids on insulin signaling in the amygdala and hypothalamus of rats

Insulin injections into the central nucleus of the amygdala (CeA) inhibit food intake but this response is lost quickly on feeding a high fat diet. The purpose of the studies described in this manuscript was to identify the potential mechanism for the development of this insulin resistance. High fat diets (HFD) induced PKCθ activation and blocked the stimulation of Akt but not mTOR phosphorylation in the amygdala in response to CeA insulin injections. Infusions of palmitic acid onto the CeA had identical effects to HFD on PKCθ expression and insulin signaling in the amygdala. CeA insulin also induced an increase in Akt phosphorylation in the hypothalamus but had no effect on hypothalamic mTOR phosphorylation. Feeding HFD but not CeA palmitate infusions reversed the hypothalamic Akt signaling response to CeA insulin. These data, which show the independence of Akt and mTOR signaling responses to insulin in the amygdala and the effect of insulin signaling in the CeA on hypothalamic Akt signaling, suggest that the amygdala might also have a significant role in regulating hypothalamic responses to dietary fat.

MTOR and regulation of energy homeostasis in humans

Patients treated with the mammalian or mechanistic target of rapamycin (mTOR) inhibitor everolimus in order to slow progression of autosomal-dominant polycystic kidney disease (ADPKD) showed a significant reduction of body weight. Although the detailed mechanism of how mTOR inhibition interferes with body weight regulation is rather unclear, present data suggest that this effect is mediated by both central and peripheral mechanisms. These findings in ADPKD patients are in contrast to well-documented effects of hypothalamic mTOR on regulation of energy homeostasis and eating behavior in rodents. In a number of rodent models, the mTOR inhibitor rapamycin induces increased food intake, which is accompanied by increased body weight. However, animal data are inconsistent. This review highlights some of the regulatory signals and key mechanisms that are important for balancing energy intake and energy expenditure with a special focus on adipose tissue-derived adipokines and their interaction with mTOR regarding local regulation of tissue perfusion and metabolism and overall systemic energy homeostasis. Specifically, clinical aspects of an impaired mTOR signaling pathway regarding the development of obesity and type-2 diabetes mellitus will be discussed.

Hypothalamic mTOR pathway mediates neuronal actions of insulin

Insulin action in the mediobasal hypothalamus (MBH) influences energy balance and sympathetic nerve activity (SNA). Recently, hypothalamic mechanistic target of rapamycin (mTOR) has emerged as a critical regulator of energy homeostasis and SNA. Here, we tested the importance of mTOR pathway in mediating the hypothalamic actions of insulin. In hypothalamic neuron GT1–7, we found that insulin significantly activated mTOR pathway as indicated by 1.5 and 1.4‐fold change in phosphorylated S6K and S6, respectively. Importantly, pre‐treatment with an mTOR inhibitor, rapamycin (RAP), abolished the activation of S6K and S6. In mice, intracerebroventricular (ICV) administration of insulin activated mTOR pathway in MBH (3.6‐fold increase in S6 phosphorylation), whereas ICV RAP pre‐treatment blunted this effect. Finally, we tested the physiological significance of hypothalamic mTOR activation by insulin in mice. ICV RAP reversed (P&lt;0.05) the anorectic and body weight‐reducing effects of ICV insulin. Similarly, pre‐treatment with ICV RAP attenuated (P&lt;0.05) insulin‐induced increase in SNA to brown adipose tissue, hindlimb and kidney. These results demonstrate that hypothalamic mTOR pathway is critically involved in insulin receptor signaling in MBH and regulation of physiological processes by central action of insulin.

Hypothalamic mTORC1 Signaling Controls Sympathetic Nerve Activity and Arterial Pressure and Mediates Leptin Effects

The fundamental importance of the hypothalamus in the regulation of autonomic and cardiovascular functions is well established. However, the molecular processes involved are not well understood. Here, we show that the mammalian (or mechanistic) target of rapamycin (mTOR) signaling in the hypothalamus is tied to the activity of the sympathetic nervous system and to cardiovascular function. Modulation of mTOR complex 1 (mTORC1) signaling caused dramatic changes in sympathetic traffic, blood flow, and arterial pressure. Our data also demonstrate the importance of hypothalamic mTORC1 signaling in transducing the sympathetic and cardiovascular actions of leptin. Moreover, we show that the PI3K pathway links the leptin receptor to mTORC1 signaling and that changes in its activity impact sympathetic traffic and arterial pressure. These findings establish mTORC1 activity in the hypothalamus as a key determinant of sympathetic and cardiovascular regulation and suggest that dysregulated hypothalamic mTORC1 activity may influence the development of cardiovascular diseases.

Hypothalamic mTOR Signaling Mediates the Orexigenic Action of Ghrelin

Current evidence suggests that ghrelin, a stomach derived peptide, exerts its orexigenic action through specific modulation of Sirtuin1 (SIRT1)/p53 and AMP-activated protein kinase (AMPK) pathways, which ultimately increase the expression of agouti-related protein (AgRP) and neuropeptide Y (NPY) in the arcuate nucleus of the hypothalamus (ARC). However, there is a paucity of data about the possible action of ghrelin on alternative metabolic pathways at this level. Here, we demonstrate that ghrelin elicits a marked upregulation of the hypothalamic mammalian target of rapamycin (mTOR) signaling pathway. Of note, central inhibition of mTOR signaling with rapamycin decreased ghrelin’s orexigenic action and normalized the mRNA expression of AgRP and NPY, as well as their key downstream transcription factors, namely cAMP response-element binding protein (pCREB) and forkhead box O1 (FoxO1, total and phosphorylated). Taken together, these data indicate that, in addition to previous reported mechanisms, ghrelin also promotes feeding through modulation of hypothalamic mTOR pathway.

Leucine Improves Glucose and Lipid Status in Offspring from Obese Dams, Dependent on Diet Type, but not Caloric Intake

Previously, we showed that offspring from obese rat dams were hyperphagic, with increased adiposity, hyperlipidaemia and glucose intolerance associated with increased orexigenic neuropeptide expression after fasting. Mammalian target of rapamycin (mTOR) can inhibit food intake through a hypothalamic action. As we previously showed that maternal obesity down-regulated hypothalamic mTOR, in the present study, we hypothesised that dietary leucine supplementation would activate hypothalamic mTOR to reduce food intake, thus limiting metabolic disorders in offspring from obese dams, regardless of postweaning diet. Obesity was induced in Sprague-Dawley females by high-fat diet (HFD) for 5 weeks before mating, throughout gestation and lactation. Male pups from HFD-fed mothers were weaned onto chow or HFD; within each dietary group, half were supplied with leucine via drinking water (1.5%) versus water control for 10 weeks. Those from chow-fed mothers were fed chow and water. Maternal obesity led to increased adiposity in chow-fed offspring. Postweaning HFD consumption exaggerated adiposity, hyperglycaemia, hyperinsulinaemia and hyperlipidaemia. Supplementation with leucine doubled leucine intake and increased hypothalamic mTOR activation; however, appetite regulation was not affected. A reduction in blood lipid levels was observed in offspring regardless of diet, as well as improved glucose tolerance in HFD-fed rats. In HFD-fed rats, up-regulated carnitine palmitoyl-transferase-1 and peroxisome-proliferator-activated receptor-γ coactivator-1α in muscle and glucose transporter 4 in fat suggested that leucine improved peripheral fat oxidation and glucose transport. Leucine is able to improve peripheral glucose and lipid metabolism independent of appetite and weight regulation, suggesting its potential application in the management of metabolic disorders.

Hypothalamic mTOR pathway mediates thyroid hormone‐induced hyperphagia in hyperthyroidism

Hyperthyroidism is characterized in rats by increased energy expenditure and marked hyperphagia. Alterations of thermogenesis linked to hyperthyroidism are associated with dysregulation of hypothalamic AMPK and fatty acid metabolism; however, the central mechanisms mediating hyperthyroidism-induced hyperphagia remain largely unclear. Here, we demonstrate that hyperthyroid rats exhibit marked up-regulation of the hypothalamic mammalian target of rapamycin (mTOR) signalling pathway associated with increased mRNA levels of agouti-related protein (AgRP) and neuropeptide Y (NPY), and decreased mRNA levels of pro-opiomelanocortin (POMC) in the arcuate nucleus of the hypothalamus (ARC), an area where mTOR co-localizes with thyroid hormone receptor-α (TRα). Central administration of thyroid hormone (T3) or genetic activation of thyroid hormone signalling in the ARC recapitulated hyperthyroidism effects on feeding and the mTOR pathway. In turn, central inhibition of mTOR signalling with rapamycin in hyperthyroid rats reversed hyperphagia and normalized the expression of ARC-derived neuropeptides, resulting in substantial body weight loss. The data indicate that in the hyperthyroid state, increased feeding is associated with thyroid hormone-induced up-regulation of mTOR signalling. Furthermore, our findings that different neuronal modulations influence food intake and energy expenditure in hyperthyroidism pave the way for a more rational design of specific and selective therapeutic compounds aimed at reversing the metabolic consequences of this disease.

Outstanding Scientific Achievement Award Lecture 2010: Deconstructing Leptin: From Signals to Circuits

Martin G. Myers Jr., MD, PhD, received the American Diabetes Association's prestigious 2010 Outstanding Scientific Achievement Award at the Association's 70th Scientific Sessions in Orlando, Florida, on 28 June 2010. The Outstanding Scientific Achievement Award recognizes outstanding scientific achievement in the field of diabetes, taking into consideration independence of thought and originality.Currently the Marilyn H. Vincent Professor of Diabetes Research at the University of Michigan, Ann Arbor, and Associate Professor in internal medicine and in molecular and integrative physiology at the University of Michigan Medical School, Dr. Myers began his impressive track record in diabetes research as a graduate student in the laboratory of Dr. Morris White at the Joslin Diabetes Center/Harvard Medical School. There, Dr. Myers deciphered many of the insulin signaling pathways engaged by insulin receptor substrate proteins.Following his graduation from the Harvard MD-PhD Program in 1997, Dr. Myers was promoted to instructor in medicine at the Joslin Diabetes Center/Harvard Medical School. He began his independent work by building a molecular framework for understanding the mechanisms of leptin signaling, including how individual phosphorylation sites on the leptin receptor recruit distinct signaling molecules. He was promoted to assistant professor at Harvard in 1999.In 2004, Dr. Myers moved to the University of Michigan, where he built upon the molecular framework of leptin signaling to probe the regulation of metabolism by individual leptin signals. Dr. Myers' laboratory revealed the specificity of leptin signals in metabolic control, including the role for leptin-STAT3 signaling in the regulation of energy balance and glucose homeostasis. His group also defined roles for leptin receptor feedback inhibition and hypothalamic mTor signaling in metabolism.Dr. Myers' laboratory has recently developed novel molecular approaches to elucidate the leptin-regulated brain circuits that contribute to metabolic control, enabling the discovery of novel brain systems and their functions.In 1998, Dr. Myers received the American Diabetes Association's Career Development Award for his scientific abilities. Dr. Myers' current support includes the National Institute of Diabetes and Digestive and Kidney Diseases MERIT Award.

Critical Role for Hypothalamic mTOR Activity in Energy Balance

The mammalian target of rapamycin (mTOR) promotes anabolic cellular processes in response to growth factors and metabolic cues. The TSC1 and TSC2 tumor suppressors are major upstream inhibitory regulators of mTOR signaling. Mice with Rip2/Cre-mediated deletion of Tsc1 (Rip-Tsc1cKO mice) developed hyperphagia and obesity, suggesting that hypothalamic disruption (for which Rip2/Cre is well known) of Tsc1 may dysregulate feeding circuits via mTOR activation. Indeed, Rip-Tsc1cKO mice displayed increased mTOR signaling and enlarged neuron cell size in a number of hypothalamic populations, including Pomc neurons. Furthermore, Tsc1 deletion with Pomc/Cre (Pomc-Tsc1cKO mice) resulted in dysregulation of Pomc neurons and hyperphagic obesity. Treatment with the mTOR inhibitor, rapamycin, ameliorated the hyperphagia, obesity, and the altered Pomc neuronal morphology in developing or adult Pomc-Tsc1cKO mice, and cessation of treatment reinstated these phenotypes. Thus, ongoing mTOR activation in Pomc neurons blocks the catabolic function of these neurons to promote nutrient intake and increased adiposity.

Fatty acid synthase inhibitors modulate energy balance via mammalian target of rapamycin complex 1 signaling in the central nervous system.

OBJECTIVE—Evidence links the hypothalamic fatty acid synthase (FAS) pathway to the regulation of food intake and body weight. This includes pharmacological inhibitors that potently reduce feeding and body weight. The mammalian target of rapamycin (mTOR) is an intracellular fuel sensor whose activity in the hypothalamus is also linked to the regulation of energy balance. The purpose of these experiments was to determine whether hypothalamic mTOR complex 1 (mTORC1) signaling is involved in mediating the effects of FAS inhibitors.RESEARCH DESIGN AND METHODS—We measured the hypothalamic phosphorylation of two downstream targets of mTORC1, S6 kinase 1 (S6K1) and S6 ribosomal protein (S6), after administration of the FAS inhibitors C75 and cerulenin in rats. We evaluated food intake in response to FAS inhibitors in rats pretreated with the mTOR inhibitor rapamycin and in mice lacking functional S6K1 (S6K1−/−). Food intake and phosphorylation of S6K1 and S6 were also determined after C75 injection in rats maintained on a ketogenic diet.RESULTS—C75 and cerulenin increased phosphorylation of S6K1 and S6, and their anorexic action was reduced in rapamycin-treated rats and in S6K1−/− mice. Consistent with our previous findings, C75 was ineffective at reducing caloric intake in ketotic rats. Under ketosis, C75 was also less efficient at stimulating mTORC1 signaling.CONCLUSIONS—These findings collectively indicate an important interaction between the FAS and mTORC1 pathways in the central nervous system for regulating energy balance, possibly via modulation of neuronal glucose utilization.