The Role of Hypothalamic mTORC1 Signaling in Insulin Regulation of Food Intake, Body Weight, and Sympathetic Nerve Activity in Male Mice

Muta, Kenjiro; Morgan, Donald A.; Rahmouni, Kamal

doi:10.1210/en.2014-1660

Cited by 42 publications

(43 citation statements)

References 55 publications

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“…Over the last years, several groups have shown that the mTOR pathway, a signaling node that is highly sensitive to nutritional cues, plays key roles in the regulation of energy balance and glucose metabolism (3,7,9,16,28,29,35). In two recent studies (5, 6), we have demonstrated that DEPTOR, an endogenous inhibitor of mTOR, is widely expressed in the brain, with high levels being found in the MBH.…”

Section: Discussionmentioning

confidence: 94%

DEPTOR in POMC neurons affects liver metabolism but is dispensable for the regulation of energy balance

Caron

Labbé

Mouchiroud

et al. 2016

American Journal of Physiology-Regulatory, Integrative and Comp

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-We have recently demonstrated that specific overexpression of DEP-domain containing mTOR-interacting protein (DEPTOR) in the mediobasal hypothalamus (MBH) protects mice against high-fat diet-induced obesity, revealing DEPTOR as a significant contributor to energy balance regulation. On the basis of evidence that DEPTOR is expressed in the proopiomelanocortin (POMC) neurons of the MBH, the present study aimed to investigate whether these neurons mediate the metabolic effects of DEPTOR. Here, we report that specific DEPTOR overexpression in POMC neurons does not recapitulate any of the phenotypes observed when the protein was overexpressed in the MBH. Unlike the previous model, mice overexpressing DEPTOR only in POMC neurons 1) did not show differences in feeding behavior, 2) did not exhibit changes in locomotion activity and oxygen consumption, 3) did not show an improvement in systemic glucose metabolism, and 4) were not resistant to high-fat diet-induced obesity. These results support the idea that other neuronal populations are responsible for these phenotypes. Nonetheless, we observed a mild elevation in fasting blood glucose, insulin resistance, and alterations in liver glucose and lipid homeostasis in mice overexpressing DEP-TOR in POMC neurons. Taken together, these results show that DEPTOR overexpression in POMC neurons does not affect energy balance regulation but could modulate metabolism through a brainliver connection. DEPTOR; mTOR; POMC; energy balance; glucose metabolism THE CONTROL OF FOOD INTAKE and energy expenditure is ensured by neurons of several brain regions, including the mediobasal hypothalamus (MBH), which has emerged as a major center of integration for nutrient and hormonal cues (26,33). MBH hosts several neuronal populations, including the proopiomelanocortin (POMC) and neuropeptide Y (NPY)/agouti-related protein (AgRP)/GABA-producing neurons of the arcuate nucleus, as well as steroidogenic factor 1 (SF1) neurons of the ventromedial hypothalamus. Over the years, these neurons were shown to play critical roles in the regulation of systemic metabolic homeostasis (17, 21). Intensive efforts are currently being made to better understand the molecular mechanisms by which MBH neurons control energy balance and systemic metabolism (11, 15).The mechanistic target of rapamycin (mTOR) plays an important role in the hypothalamic regulation of energy balance and glucose homeostasis (3,8,9). mTOR is a serine/threonine kinase that nucleates two protein complexes named mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) (20). These complexes are part of a well-conserved anabolic pathway that modulates growth and metabolism in response to nutrients and growth factors. They include several proteins, including DEP-domain containing mTOR-interacting protein (DEPTOR), a component of both mTORC1 and mTORC2 (31). Recently, we have characterized the expression of Deptor in the rat and mouse brain and have shown that this gene is highly expressed in several structures involved in energy balance regulation, i...

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Section: Discussionmentioning

confidence: 94%

DEPTOR in POMC neurons affects liver metabolism but is dispensable for the regulation of energy balance

Caron

Labbé

Mouchiroud

et al. 2016

American Journal of Physiology-Regulatory, Integrative and Comp

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“…In line with these findings, icv administration of insulin also activates the mTORC1 pathway in mouse ARC via a PI3K/Akt-dependent mechanism (48). On the other hand, rapamycin-induced inhibition of hypothalamic mTORC1 reverses the effects of insulin on food intake and body weight (48). Hypothalamic insulin signaling is known to be an important regulator of hepatic glucose production (HGP) in rodents (17,51).…”

Section: E996 Hypothalamic Mtorc1 Regulates Energy Homeostasismentioning

confidence: 85%

“…Similarly, adenoviral-mediated hypothalamic constitutive activation of S6K1 decreases leucine deprivation-stimulated energy expenditure, and the effect is mediated by modulation of corticotropin-releasing hormone (CRH) expression in a MC4R-dependent manner (80). Very recently, Muta et al (48) demonstrated that hypothalamic mTORC1 is also involved in insulin action on the SNS. Inhibition of hypothalamic mTORC1 with rapamycin not only reverses the suppressing central effects of insulin on food intake and body weight gain, but also abolishes insulin-stimulated lumbar SNA (48).…”

Section: Roles Of Hypothalamic Mtorc1 Signaling In the Regulation Of mentioning

confidence: 99%

“…Very recently, Muta et al (48) demonstrated that hypothalamic mTORC1 is also involved in insulin action on the SNS. Inhibition of hypothalamic mTORC1 with rapamycin not only reverses the suppressing central effects of insulin on food intake and body weight gain, but also abolishes insulin-stimulated lumbar SNA (48). Because the SNS mediates the central leptin or insulin action on BAT thermogenesis, it is reasonable to postulate that hypothalamic mTORC1 may mediate the action of anorexigenic hormones on BAT function and WAT browning by regulating the SNS.…”

Section: Roles Of Hypothalamic Mtorc1 Signaling In the Regulation Of mentioning

confidence: 99%

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Hypothalamic roles of mTOR complex I: integration of nutrient and hormone signals to regulate energy homeostasis

Liu

2016

American Journal of Physiology-Endocrinology and Metabolism

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-Mammalian or mechanistic target of rapamycin (mTOR) senses nutrient, energy, and hormone signals to regulate metabolism and energy homeostasis. mTOR activity in the hypothalamus, which is associated with changes in energy status, plays a critical role in the regulation of food intake and body weight. mTOR integrates signals from a variety of "energy balancing" hormones such as leptin, insulin, and ghrelin, although its action varies in response to these distinct hormonal stimuli as well as across different neuronal populations. In this review, we summarize and highlight recent findings regarding the functional roles of mTOR complex 1 (mTORC1) in the hypothalamus specifically in its regulation of body weight, energy expenditure, and glucose/lipid homeostasis. Understanding the role and underlying mechanisms behind mTOR-related signaling in the brain will undoubtedly pave new avenues for future therapeutics and interventions that can combat obesity, insulin resistance, and diabetes. mTOR; hypothalamus; hormones; nutrients; energy homeostasis BALANCED FOOD INTAKE and energy expenditure are key to maintaining energy homeostasis, whereas impaired regulation of this balance leads to excessive weight gain and obesity. Food intake and energy expenditure are primarily controlled by the central nervous system (CNS), especially the hypothalamus, which acts as a key signaling hub linking CNS action to peripheral organ metabolism. Along with other nutrient sensors in different brain areas, the hypothalamus senses and integrates changes in circulating hormone and nutrient levels by relaying these peripheral signals to neuroendocrine cells, which signal behavioral and metabolic effectors to regulate whole body energy homeostasis (6,53,57,82).Extensive studies have been performed to explore the unique roles and distinct actions of several anatomically well-defined hypothalamic areas in the regulation of energy balance, including the arcuate nucleus (ARC) and ventromedial (VMH), dorsomedial (DMH), paraventricular (PVH), and lateral (LH) hypothalamus (74, 99). In the ARC, hormone and nutrient signals from the periphery induce activity changes of two subpopulations of neurons: an orexigenic population coexpressing the neurotransmitters neuropeptide Y (NPY) and agouti-related peptide (AgRP) and an anorexigenic population coexpressing proopiomelanocortin (POMC) and cocaine-and amphetamine-regulated transcript (CART). Numerous studies have demonstrated that POMC/CART and AgRP/NPY neurons have direct synaptic connections with some neuronal populations located in the VMH, DMH, PVH, and LH, all of which have profound effects on feeding behavior, energy expenditure, and glucose homeostasis (82).Leptin and insulin are two important hormonal regulators of peripheral energy homeostasis, which play critical roles in mediating CNS-controlled glucose, lipid, and energy metabolism by acting on the hypothalamus. Both the insulin and leptin receptors are widely expressed in the ARC, VMH, DMH, LH, and PVH, and together or independently these two ...

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“…Notably, although it is present throughout the central nervous system, the hypothalamus contains the highest density the insulin receptor. This was demonstrated by in situ hybridization for insulin receptor messenger (13), binding assay with isotope-labeling insulin (11;12), and immunohistochemical labeling of the β- (10) or α-subunit (62) of the insulin receptor. Notably, among the hypothalamic nuclei the ARC displayed the highest expression of the insulin receptor (62).…”

Section: Insulin Acts In the Arc To Increase Sympathetic Outflowmentioning

confidence: 99%

Cardiovascular Regulation by the Arcuate Nucleus of the Hypothalamus

Rahmouni

2016

Hypertension

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The Role of Hypothalamic mTORC1 Signaling in Insulin Regulation of Food Intake, Body Weight, and Sympathetic Nerve Activity in Male Mice

Cited by 42 publications

References 55 publications

DEPTOR in POMC neurons affects liver metabolism but is dispensable for the regulation of energy balance

DEPTOR in POMC neurons affects liver metabolism but is dispensable for the regulation of energy balance

Hypothalamic roles of mTOR complex I: integration of nutrient and hormone signals to regulate energy homeostasis

Cardiovascular Regulation by the Arcuate Nucleus of the Hypothalamus

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