PMID- 26909318
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20160224
LR  - 20210208
IS  - 2212-8778 (Print)
IS  - 2212-8778 (Electronic)
IS  - 2212-8778 (Linking)
VI  - 5
IP  - 2
DP  - 2016 Feb
TI  - Mediobasal hypothalamic overexpression of DEPTOR protects against high-fat 
      diet-induced obesity.
PG  - 102-112
LID - S2212-8778(15)00217-3 [pii]
LID - 10.1016/j.molmet.2015.11.005 [doi]
AB  - 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.
FAU - Caron, Alexandre
AU  - Caron A
AD  - Institut universitaire de cardiologie et de pneumologie de Quebec, 2725 chemin 
      Sainte-Foy, Quebec, Quebec, G1V 4G5, Canada; Departement de Medecine, Faculte de 
      Medecine, Universite Laval, Quebec, Quebec, Canada.
FAU - Labbe, Sebastien M
AU  - Labbe SM
AD  - Institut universitaire de cardiologie et de pneumologie de Quebec, 2725 chemin 
      Sainte-Foy, Quebec, Quebec, G1V 4G5, Canada; Departement de Medecine, Faculte de 
      Medecine, Universite Laval, Quebec, Quebec, Canada.
FAU - Lanfray, Damien
AU  - Lanfray D
AD  - Institut universitaire de cardiologie et de pneumologie de Quebec, 2725 chemin 
      Sainte-Foy, Quebec, Quebec, G1V 4G5, Canada; Departement de Medecine, Faculte de 
      Medecine, Universite Laval, Quebec, Quebec, Canada.
FAU - Blanchard, Pierre-Gilles
AU  - Blanchard PG
AD  - Institut universitaire de cardiologie et de pneumologie de Quebec, 2725 chemin 
      Sainte-Foy, Quebec, Quebec, G1V 4G5, Canada; Departement de Medecine, Faculte de 
      Medecine, Universite Laval, Quebec, Quebec, Canada.
FAU - Villot, Romain
AU  - Villot R
AD  - Institut universitaire de cardiologie et de pneumologie de Quebec, 2725 chemin 
      Sainte-Foy, Quebec, Quebec, G1V 4G5, Canada; Departement de Medecine, Faculte de 
      Medecine, Universite Laval, Quebec, Quebec, Canada.
FAU - Roy, Christian
AU  - Roy C
AD  - Institut universitaire de cardiologie et de pneumologie de Quebec, 2725 chemin 
      Sainte-Foy, Quebec, Quebec, G1V 4G5, Canada; Departement de Medecine, Faculte de 
      Medecine, Universite Laval, Quebec, Quebec, Canada.
FAU - Sabatini, David M
AU  - Sabatini DM
AD  - 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.
FAU - Richard, Denis
AU  - Richard D
AD  - Institut universitaire de cardiologie et de pneumologie de Quebec, 2725 chemin 
      Sainte-Foy, Quebec, Quebec, G1V 4G5, Canada; Departement de Medecine, Faculte de 
      Medecine, Universite Laval, Quebec, Quebec, Canada. Electronic address: 
      denis.richard@criucpq.ulaval.ca.
FAU - Laplante, Mathieu
AU  - Laplante M
AD  - Institut universitaire de cardiologie et de pneumologie de Quebec, 2725 chemin 
      Sainte-Foy, Quebec, Quebec, G1V 4G5, Canada; Departement de Medecine, Faculte de 
      Medecine, Universite Laval, Quebec, Quebec, Canada. Electronic address: 
      mathieu.laplante@criucpq.ulaval.ca.
LA  - eng
GR  - R01 CA103866/CA/NCI NIH HHS/United States
GR  - R01 CA129105/CA/NCI NIH HHS/United States
GR  - R37 AI047389/AI/NIAID NIH HHS/United States
PT  - Journal Article
DEP - 20151208
PL  - Germany
TA  - Mol Metab
JT  - Molecular metabolism
JID - 101605730
PMC - PMC4735664
OTO - NOTNLM
OT  - DEPTOR
OT  - Energy balance
OT  - Glucose metabolism
OT  - Hypothalamus
OT  - mTOR
EDAT- 2016/02/26 06:00
MHDA- 2016/02/26 06:01
PMCR- 2015/12/08
CRDT- 2016/02/25 06:00
PHST- 2015/11/02 00:00 [received]
PHST- 2015/11/18 00:00 [revised]
PHST- 2015/11/25 00:00 [accepted]
PHST- 2016/02/25 06:00 [entrez]
PHST- 2016/02/26 06:00 [pubmed]
PHST- 2016/02/26 06:01 [medline]
PHST- 2015/12/08 00:00 [pmc-release]
AID - S2212-8778(15)00217-3 [pii]
AID - 10.1016/j.molmet.2015.11.005 [doi]
PST - epublish
SO  - Mol Metab. 2015 Dec 8;5(2):102-112. doi: 10.1016/j.molmet.2015.11.005. 
      eCollection 2016 Feb.