S6K1 in the Central Nervous System Regulates Energy Expenditure via MC4R/CRH Pathways in Response to Deprivation of an Essential Amino Acid

Xia, Tingting; Cheng, Ying; Zhang, Qian; Xiao, Fei; Liu, Bin; Chen, Shanghai; Guo, Feifan

doi:10.2337/db11-1278

Cited by 42 publications

(51 citation statements)

References 49 publications

(101 reference statements)

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“…Our previous study has shown that S6K1 activity is decreased in the hypothalamus and acts as a major regulator of increased thermogenesis and fat loss during leucine deprivation (31). By contrast, S6K1 activity is not decreased in the hypothalamus of leucine-deprived db/db and Y3F mice compared with control groups.…”

Section: Discussionmentioning

confidence: 90%

“…To investigate the effects of leucine deprivation on leptin signaling, C57BL/6J wild-type (WT) mice were maintained on a leucinedeficient diet or control diet for 7 days, as described in our previous studies (24,30,31). Leucine deprivation significantly decreased serum leptin levels compared with mice fed a control diet (Fig.…”

Section: Leucine Deprivation Increases Leptin Signaling In Mice-mentioning

confidence: 99%

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Leptin Signaling Is Required for Leucine Deprivation-enhanced Energy Expenditure

Zhang

Liu

Cheng

et al. 2014

Journal of Biological Chemistry

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Background: Leucine deprivation decreases fat mass via enhancing energy expenditure; the involvement of leptin signaling is unknown. Results: Leucine deprivation promoted leptin signaling, and the increased energy expenditure was blocked in leptin signalingdisrupted mice. Conclusion: Leptin signaling is required for leucine deprivation-increased energy expenditure. Significance: Our studies reveal a physiological mechanism linking leptin signaling with leucine deprivation-enhanced energy expenditure.

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Section: Discussionmentioning

confidence: 90%

Section: Leucine Deprivation Increases Leptin Signaling In Mice-mentioning

confidence: 99%

Leptin Signaling Is Required for Leucine Deprivation-enhanced Energy Expenditure

Zhang

Liu

Cheng

et al. 2014

Journal of Biological Chemistry

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“…Interestingly, mice pretreated with rapamycin have no response to icv injection of MTII, an activator of the MC3/4Rs that increases renal SNA or arterial pressure, indicating that mTORC1 may mediate the sympathetic and cardiovascular effects of leptin on the melanocortin system (21). 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.…”

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

confidence: 99%

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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“…Constitutively active S6K1 was constructed following methods described previously by converting Thr 390 to glutamic acid (36). The CAS6K1 vector and package vectors were transfected into HEK 293T/17 cells to generate a lentivirus expressing FLAG-CAS6K1(Lenti-CAS6K1), and a lentivirus expressing green fluorescent protein (Lenti-GFP) was used as control.…”

Section: Mtorc1 Regulates Osteoclast Differentiationmentioning

confidence: 99%

Inactivation of Regulatory-associated Protein of mTOR (Raptor)/Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling in Osteoclasts Increases Bone Mass by Inhibiting Osteoclast Differentiation in Mice

Dai

Xie²,

Han³

et al. 2017

Journal of Biological Chemistry

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Edited by Xiao-Fan WangMammalian target of rapamycin complex 1 (mTORC1) is involved in anabolic metabolism in both osteoblasts and chondrocytes, but the role of mTORC1 in osteoclast biology in vivo remains to be elucidated. In this study, we showed that deletion of regulatory-associated protein of mTOR (Raptor) in osteoclasts led to an increase in bone mass with decreased bone resorption. Raptordeficient bone marrow-derived macrophages exhibited lower mTORC1-S6K1 signaling and retarded osteoclast differentiation, as determined by the number of osteoclasts, tartrate-resistant acid phosphatase activity, and expression of osteoclast-specific genes. Enforced expression of constitutively active S6K1 rescued the impaired osteoclast differentiation in Raptor-deficient bone marrow-derived macrophages. Furthermore, pharmacological inhibition of mTORC1 signaling by rapamycin could also inhibit osteoclast differentiation and osteoclast-specific gene expression. Taken together, our findings demonstrate that mTORC1 plays a key role in the network of catabolic bone resorption in osteoclasts and may serve as a potential pharmacological target for the regulation of osteoclast activity in bone metabolic disorders.Bone is a rigid yet metabolically active organ that is molded, shaped, and repaired continuously (1). After bone is formed, bone undergoes a process known as remodeling by which bone is turned over throughout life (2). Bone remodeling acts as the predominant metabolic regulator of both the physical structure and physiological function of bone. Remodeling is a complex process involving osteoclasts, which are responsible for removing old mineralized matrix, and osteoblasts, which synthesize and secrete new bone matrix (1, 3). An imbalance in bone remodeling can induce perturbation of bone structure and function and potentially result in disease (1). In adults, most bone diseases, such as osteoporosis, rheumatoid arthritis, and periodontal disease, are the result of bone loss secondary to excess osteoclast activity (4). Prevention and treatment of these pathological disorders highlight the study of the underlying mechanisms by which osteoclasts differentiate from their precursors.Osteoclasts are tissue-specific giant multinucleated cells that differentiate from monocyte/macrophage precursor cells at or near the bone surface (1). It is known that the differentiation of osteoclasts is under the control of two important cytokines, receptor activator of nuclear factor B ligand (RANKL) 5 and M-CSF (3). RANKL and macrophage colony-stimulating factor (M-CSF) may activate a set of signaling pathways, including AKT and NF-B, that promote the differentiation, multinucleation, activation, and survival of osteoclasts (5). However, the * This work was supported in part by grants from the 973 Program from the Chinese Ministry of Science and Technology (2014CB964704 and 2015CB964503), the Science and Technology Commission of Shanghai (124119b0101), the National Natural Science Foundation of China (31371463, 81371121, and 81570950), Shan...

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S6K1 in the Central Nervous System Regulates Energy Expenditure via MC4R/CRH Pathways in Response to Deprivation of an Essential Amino Acid

Cited by 42 publications

References 49 publications

Leptin Signaling Is Required for Leucine Deprivation-enhanced Energy Expenditure

Leptin Signaling Is Required for Leucine Deprivation-enhanced Energy Expenditure

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

Inactivation of Regulatory-associated Protein of mTOR (Raptor)/Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling in Osteoclasts Increases Bone Mass by Inhibiting Osteoclast Differentiation in Mice

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