Rapamycin Ameliorates Age-Dependent Obesity Associated with Increased mTOR Signaling in Hypothalamic POMC Neurons

Yang, Sheng‐Ming; Tien, An-Chi; Boddupalli, Gayatri; Xu, Allison; Jan, Yuh Nung

doi:10.1016/j.neuron.2012.03.043

Cited by 196 publications

(177 citation statements)

References 67 publications

Supporting

Mentioning

160

Contrasting

Unclassified

Order By: Relevance

“…Consistently, overactivation of mTORC1 in hypothalamic neurons induces aging-associated feeding behavior and obesity (44,83). Mori et al (44) found that POMC neuron-specific deletion of the Tsc1 gene, a major negative regulator of mTORC1, leads to long-term elevation of mTORC1 signaling associated not only with cellular hypertrophy but also with reduced axonal projections to the hypothalamic PVN, which are linked with hyperphagic obesity.…”

Section: Mtorc1 Signaling In the Hypothalamusmentioning

confidence: 95%

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

View full text Add to dashboard Cite

-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 ...

show abstract

Section: Mtorc1 Signaling In the Hypothalamusmentioning

confidence: 95%

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

View full text Add to dashboard Cite

show abstract

“…The question of what happens to mTORC1 signaling during normal aging has therefore received significant attention. As reported in Table 1, numerous studies have reported increased mTORC1 signaling with age in HSCs (hematopoietic stem cells), hypothalamic POMC neurons, and in the liver and lung of mice (Chen et al ., 2009; Sengupta et al ., 2010; Yang et al ., 2012; Leontieva et al ., 2014; Calhoun et al ., 2015). …”

Section: Introductionmentioning

confidence: 99%

Sex‐ and tissue‐specific changes in mTOR signaling with age in C57 BL /6J mice

et al. 2015

View full text Add to dashboard Cite

SummaryInhibition of the mTOR (mechanistic Target Of Rapamycin) signaling pathway robustly extends the lifespan of model organisms including mice. The precise molecular mechanisms and physiological effects that underlie the beneficial effects of rapamycin are an exciting area of research. Surprisingly, while some data suggest that mTOR signaling normally increases with age in mice, the effect of age on mTOR signaling has never been comprehensively assessed. Here, we determine the age‐associated changes in mTORC1 (mTOR complex 1) and mTORC2 (mTOR complex 2) signaling in the liver, muscle, adipose, and heart of C57BL/6J.Nia mice, the lifespan of which can be extended by rapamycin treatment. We find that the effect of age on several different readouts of mTORC1 and mTORC2 activity varies by tissue and sex in C57BL/6J.Nia mice. Intriguingly, we observed increased mTORC1 activity in the liver and heart tissue of young female mice compared to male mice of the same age. Tissue and substrate‐specific results were observed in the livers of HET3 and DBA/2 mouse strains, and in liver, muscle and adipose tissue of F344 rats. Our results demonstrate that aging does not result in increased mTOR signaling in most tissues and suggest that rapamycin does not promote lifespan by reversing or blunting such an effect.

show abstract

“…On the other hand, the combined systemic disruption of 4ebp1 and 4ebp2 in mice increases the animal's sensitivity to diet-induced obesity, due to increased adipogenesis, reduced lipolysis, and enhanced fatty acid reesterifi cation in the adipose tissue ( 19 ). While these studies provide genetic evidence indicating a positive role for mTORC1 signaling in adipogenesis, they may be confounded by systemic effects of the gene deletions, as mTORC1 is known to also function in the central nervous system to regulate energy balance (20)(21)(22). The adipose-specifi c knockout of raptor , resulting in reduced fat accumulation in mice ( 23 ), confi rms an autonomous, and indispensable, function of mTORC1 in adipogenesis.…”

Section: Discussionmentioning

confidence: 99%