Recent Advances in Adipose mTOR Signaling and Function: Therapeutic Prospects

Cai, Huan; Dong, Lily Q.; Liu, Feng

doi:10.1016/j.tips.2015.11.011

Cited by 113 publications

(93 citation statements)

References 116 publications

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“…Consistent with previous findings that the p38 MAPK/ATF2 axis is indispensable for thermogenesis and the Akt/mTOR pathway is deactivated during browning [11], the p38 MAPK/ATF2 axis was activated and the Akt/mTOR pathway deactivated during browning of C3H10T1/2 cells induced by ATM or DHA ( Figure 1Q-1T). This suggests that artemisinin derivatives may prevent obesity by inducing browning during adipogenesis through regulating these two pathways.…”

Section: Dear Editorsupporting

confidence: 92%

Artemisinin derivatives prevent obesity by inducing browning of WAT and enhancing BAT function

et al. 2016

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Section: Dear Editorsupporting

confidence: 92%

Artemisinin derivatives prevent obesity by inducing browning of WAT and enhancing BAT function

et al. 2016

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“…Alternatively, rapamycin could act directly on adipose tissue by inhibiting mTOR signaling in these cells. mTOR signaling plays a major role in regulating a variety of adipose tissue functions, including adipogenesis (for review see Cai et al, 2015). Notably, the pronounced ability of rapamycin to block weight gain following SE raises the possibility that the drug’s anti-epileptogenic effects may be mediated by tissues outside the CNS.…”

Section: Discussionmentioning

confidence: 99%

Impact of rapamycin on status epilepticus induced hippocampal pathology and weight gain

Hester

Hosford

Santos

et al. 2016

Experimental Neurology

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Growing evidence implicates the dentate gyrus in temporal lobe epilepsy (TLE). Dentate granule cells limit the amount of excitatory signaling through the hippocampus and exhibit striking neuroplastic changes that may impair this function during epileptogenesis. Furthermore, aberrant integration of newly-generated granule cells underlies the majority of dentate restructuring. Recently, attention has focused on the mammalian target of rapamycin (mTOR) signaling pathway as a potential mediator of epileptogenic change. Systemic administration of the mTOR inhibitor rapamycin has promising therapeutic potential, as it has been shown to reduce seizure frequency and seizure severity in rodent models. Here, we tested whether mTOR signaling facilitates abnormal development of granule cells during epileptogenesis. We also examined dentate inflammation and mossy cell death in the dentate hilus. To determine if mTOR activation is necessary for abnormal granule cell development, transgenic mice that harbored fluorescently-labeled adult-born granule cells were treated with rapamycin following pilocarpine-induced status epilepticus. Systemic rapamycin effectively blocked phosphorylation of S6 protein (a readout of mTOR activity) and reduced granule cell mossy fiber axon sprouting. However, the accumulation of ectopic granule cells and granule cells with aberrant basal dendrites was not significantly reduced. Mossy cell death and reactive astrocytosis were also unaffected. These data suggest that anti-epileptogenic effects of mTOR inhibition may be mediated by mechanisms other than inhibition of these common dentate pathologies. Consistent with this conclusion, rapamycin prevented pathological weight gain in epileptic mice, suggesting that rapamycin might act on central circuits or even peripheral tissues controlling weight gain in epilepsy.

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“…The Ser/Thr protein kinase mTOR integrates various internal and external signals to regulate many cellular activities, including mRNA translation, protein synthesis, cell proliferation and growth, autophagy, lipogenesis, and thermogenesis (8,79,89). mTOR exerts its biological activities in mammalian cells by forming two distinct complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), which differ in their components, regulation, function, and sensitivity to rapamycin.…”

Section: Mtor Signaling and Energy Homeostasismentioning

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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Recent Advances in Adipose mTOR Signaling and Function: Therapeutic Prospects

Cited by 113 publications

References 116 publications

Artemisinin derivatives prevent obesity by inducing browning of WAT and enhancing BAT function

Artemisinin derivatives prevent obesity by inducing browning of WAT and enhancing BAT function

Impact of rapamycin on status epilepticus induced hippocampal pathology and weight gain

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

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