DEPTOR Cell-Autonomously Promotes Adipogenesis, and Its Expression Is Associated with Obesity

Laplante, Mathieu; Horvat, Simon; Festuccia, William T.; Birsoy, Kıvanç; Prevoršek, Zala; Efeyan, Alejo; Sabatini, David M.

doi:10.1016/j.cmet.2012.07.008

Cited by 102 publications

(170 citation statements)

References 43 publications

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“…A recent study showed that POMC-specific ablation of p70 S6 kinase 1 (S6K1), a downstream substrate of mTORC1, affects hepatic glucose production and peripheral lipid metabolism without affecting energy balance (35). It was reported that reducing S6K1 activity, an effect observed in response to DEPTOR overexpression (6,19,31), increases hepatic glucose output (35). Supporting these results, we observed that hepatic glucose production was significantly increased in POMC-Deptor O/E mice.…”

Section: Discussionsupporting

confidence: 77%

“…Further investigations are needed to determine whether the inhibition of S6K1 in POMC neurons plays an important role in mediating the effect of DEPTOR on liver metabolism. Over the years, it was shown several times that DEPTOR promotes insulin signaling by dampening the feedback inhibition from mTORC1 to phosphoinositide-3-kinase (PI3K), which leads to an activation of protein kinase B (Akt/PKB) (6,19,22,23,31). Defining whether changes in insulin signaling contribute to modulate the brain-liver connection that we report here represents another key question that will require additional experiments.…”

Section: Discussionmentioning

confidence: 99%

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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: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

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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“…Laplante et al recently reported that overexpression of the mTOR inhibitor DEPTOR promotes adipogenesis in vivo ( 42 ), which corroborates our main conclusion in this study. Overexpression of DEPTOR is found to suppress Ser636/639 phosphorylation of IRS1 and enhance Akt phosphorylation in adipocytes ( 42 ).…”

Section: Downloaded Fromsupporting

confidence: 82%

“…Overexpression of DEPTOR is found to suppress Ser636/639 phosphorylation of IRS1 and enhance Akt phosphorylation in adipocytes ( 42 ). DEPTOR is capable of inhibiting both mTORC1 and mTORC2 kinase activity ( 43 ); hence, the differential effects of DEPTOR overexpression on mTORC1 inhibition of Akt and mTORC2 activation of Akt mirror those of mTOR depletion.…”

Section: Downloaded Frommentioning

confidence: 99%

Mechanistic target of rapamycin controls homeostasis of adipogenesis

Yoon¹,

Zhang²,

Sun

et al. 2013

Journal of Lipid Research

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“…Whether LMO3 and Dexras1 interface in regulating adipogenesis is unclear. DEPTOR, a component of the mTOR system (25), may also interface with the Dexras1 system, because DEPTOR is induced by glucocorticoids and promotes adipogenesis (26). Our findings may be relevant to clinical instances of glucocorticoid-associated adiposity.…”

Section: Discussionmentioning

confidence: 79%

Dexras1 mediates glucocorticoid-associated adipogenesis and diet-induced obesity

Jiyoung

Kim

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Adipogenesis, the conversion of precursor cells into adipocytes, is associated with obesity and is mediated by glucocorticoids acting via hitherto poorly characterized mechanisms. Dexras1 is a small G protein of the Ras family discovered on the basis of its marked induction by the synthetic glucocorticoid dexamethasone. We show that Dexras1 mediates adipogenesis and diet-induced obesity. Adipogenic differentiation of 3T3-L1 cells is abolished with Dexras1 depletion, whereas overexpression of Dexras1 elicits adipogenesis. Adipogenesis is markedly reduced in mouse embryonic fibroblasts from Dexras1-deleted mice, whereas adiposity and dietinduced weight gain are diminished in the mutant mice.insulin | cyclic AMP | nitric oxide | Cushing disease

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DEPTOR Cell-Autonomously Promotes Adipogenesis, and Its Expression Is Associated with Obesity

Cited by 102 publications

References 43 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

Mechanistic target of rapamycin controls homeostasis of adipogenesis

Dexras1 mediates glucocorticoid-associated adipogenesis and diet-induced obesity

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