title: Mediobasal hypothalamic overexpression of DEPTOR protects against high-fat diet-induced obesity.
abstract: 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.
  
  
  CONCLUSIONS
  Altogether, these results support a role for MBH DEPTOR in the regulation of energy balance and metabolism.
authors.affiliation: 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.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Caron
authors.affiliation: 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.
authors.forename: Sébastien M
authors.initials: SM
authors.lastname: Labbé
authors.affiliation: 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.
authors.forename: Damien
authors.initials: D
authors.lastname: Lanfray
authors.affiliation: 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.
authors.forename: Pierre-Gilles
authors.initials: PG
authors.lastname: Blanchard
authors.affiliation: 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.
authors.forename: Romain
authors.initials: R
authors.lastname: Villot
authors.affiliation: 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.
authors.forename: Christian
authors.initials: C
authors.lastname: Roy
authors.affiliation: 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.
authors.forename: David M
authors.initials: DM
authors.lastname: Sabatini
authors.affiliation: 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.
authors.forename: Denis
authors.initials: D
authors.lastname: Richard
authors.affiliation: 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.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Laplante
keywords: DEPTOR; Energy balance; Glucose metabolism; Hypothalamus; mTOR