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Mol Metab. 2015 Dec 8;5(2):102-112. doi: 10.1016/j.molmet.2015.11.005. eCollection 2016 Feb.

Mediobasal hypothalamic overexpression of DEPTOR protects against high-fat diet-induced obesity.

Author information

1
Institut universitaire de cardiologie et de pneumologie de Québec, 2725 chemin Sainte-Foy, Québec, Québec, G1V 4G5, Canada; Département de Médecine, Faculté de Médecine, Université Laval, Québec, Québec, Canada.
2
Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA, 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA; David H. Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA, 02139, USA; Broad Institute, Seven Cambridge Center, Cambridge, MA, 02142, USA; Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
3
Institut universitaire de cardiologie et de pneumologie de Québec, 2725 chemin Sainte-Foy, Québec, Québec, G1V 4G5, Canada; Département de Médecine, Faculté de Médecine, Université Laval, Québec, Québec, Canada. Electronic address: denis.richard@criucpq.ulaval.ca.
4
Institut universitaire de cardiologie et de pneumologie de Québec, 2725 chemin Sainte-Foy, Québec, Québec, G1V 4G5, Canada; Département de Médecine, Faculté de Médecine, Université Laval, Québec, Québec, Canada. Electronic address: mathieu.laplante@criucpq.ulaval.ca.

Abstract

BACKGROUND/OBJECTIVE:

The mechanistic target of rapamycin (mTOR) is a serine-threonine kinase that functions into distinct protein complexes (mTORC1 and mTORC2) that regulate energy homeostasis. DEP-domain containing mTOR-interacting protein (DEPTOR) is part of these complexes and is known to dampen mTORC1 function, consequently reducing mTORC1 negative feedbacks and promoting insulin signaling and Akt/PKB activation in several models. Recently, we observed that DEPTOR is expressed in several structures of the brain including the mediobasal hypothalamus (MBH), a region that regulates energy balance. Whether DEPTOR in the MBH plays a functional role in regulating energy balance and hypothalamic insulin signaling has never been tested.

METHODS:

We have generated a novel conditional transgenic mouse model based on the Cre-LoxP system allowing targeted overexpression of DEPTOR. Mice overexpressing DEPTOR in the MBH were subjected to a metabolic phenotyping and MBH insulin signaling was evaluated.

RESULTS:

We first report that systemic (brain and periphery) overexpression of DEPTOR prevents high-fat diet-induced obesity, improves glucose metabolism and protects against hepatic steatosis. These phenotypes were associated with a reduction in food intake and feed efficiency and an elevation in oxygen consumption. Strikingly, specific overexpression of DEPTOR in the MBH completely recapitulated these phenotypes. DEPTOR overexpression was associated with an increase in hypothalamic insulin signaling, as illustrated by elevated Akt/PKB activation.

CONCLUSION:

Altogether, these results support a role for MBH DEPTOR in the regulation of energy balance and metabolism.

KEYWORDS:

DEPTOR; Energy balance; Glucose metabolism; Hypothalamus; mTOR

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