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

Alexandre Caron, Sébastien M. Labbé, Damien Lanfray, Pierre Gilles Blanchard, Romain Villot, Christian Roy, David M. Sabatini, Denis Richard, Mathieu Laplante

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)102-112
Number of pages11
JournalMolecular Metabolism
Volume5
Issue number2
DOIs
StatePublished - Feb 1 2016
Externally publishedYes

Fingerprint

High Fat Diet
Hypothalamus
Obesity
Insulin
TOR Serine-Threonine Kinases
Phenotype
Protein-Serine-Threonine Kinases
Brain
Sirolimus
Oxygen Consumption
Energy Metabolism
Transgenic Mice
Homeostasis
Eating
Glucose
Liver
mechanistic target of rapamycin complex 1
Proteins

Keywords

  • DEPTOR
  • Energy balance
  • Glucose metabolism
  • Hypothalamus
  • MTOR

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Caron, A., Labbé, S. M., Lanfray, D., Blanchard, P. G., Villot, R., Roy, C., ... Laplante, M. (2016). Mediobasal hypothalamic overexpression of DEPTOR protects against high-fat diet-induced obesity. Molecular Metabolism, 5(2), 102-112. https://doi.org/10.1016/j.molmet.2015.11.005

Mediobasal hypothalamic overexpression of DEPTOR protects against high-fat diet-induced obesity. / Caron, Alexandre; Labbé, Sébastien M.; Lanfray, Damien; Blanchard, Pierre Gilles; Villot, Romain; Roy, Christian; Sabatini, David M.; Richard, Denis; Laplante, Mathieu.

In: Molecular Metabolism, Vol. 5, No. 2, 01.02.2016, p. 102-112.

Research output: Contribution to journalArticle

Caron, A, Labbé, SM, Lanfray, D, Blanchard, PG, Villot, R, Roy, C, Sabatini, DM, Richard, D & Laplante, M 2016, 'Mediobasal hypothalamic overexpression of DEPTOR protects against high-fat diet-induced obesity', Molecular Metabolism, vol. 5, no. 2, pp. 102-112. https://doi.org/10.1016/j.molmet.2015.11.005
Caron, Alexandre ; Labbé, Sébastien M. ; Lanfray, Damien ; Blanchard, Pierre Gilles ; Villot, Romain ; Roy, Christian ; Sabatini, David M. ; Richard, Denis ; Laplante, Mathieu. / Mediobasal hypothalamic overexpression of DEPTOR protects against high-fat diet-induced obesity. In: Molecular Metabolism. 2016 ; Vol. 5, No. 2. pp. 102-112.
@article{3437e168e3b24085bcf59e4ea0112d47,
title = "Mediobasal hypothalamic overexpression of DEPTOR protects against high-fat diet-induced obesity",
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",
author = "Alexandre Caron and Labb{\'e}, {S{\'e}bastien M.} and Damien Lanfray and Blanchard, {Pierre Gilles} and Romain Villot and Christian Roy and Sabatini, {David M.} and Denis Richard and Mathieu Laplante",
year = "2016",
month = "2",
day = "1",
doi = "10.1016/j.molmet.2015.11.005",
language = "English (US)",
volume = "5",
pages = "102--112",
journal = "Molecular Metabolism",
issn = "2212-8778",
publisher = "Elsevier GmbH",
number = "2",

}

TY - JOUR

T1 - Mediobasal hypothalamic overexpression of DEPTOR protects against high-fat diet-induced obesity

AU - Caron, Alexandre

AU - Labbé, Sébastien M.

AU - Lanfray, Damien

AU - Blanchard, Pierre Gilles

AU - Villot, Romain

AU - Roy, Christian

AU - Sabatini, David M.

AU - Richard, Denis

AU - Laplante, Mathieu

PY - 2016/2/1

Y1 - 2016/2/1

N2 - 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.

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.

KW - DEPTOR

KW - Energy balance

KW - Glucose metabolism

KW - Hypothalamus

KW - MTOR

UR - http://www.scopus.com/inward/record.url?scp=84958047525&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84958047525&partnerID=8YFLogxK

U2 - 10.1016/j.molmet.2015.11.005

DO - 10.1016/j.molmet.2015.11.005

M3 - Article

C2 - 26909318

AN - SCOPUS:84958047525

VL - 5

SP - 102

EP - 112

JO - Molecular Metabolism

JF - Molecular Metabolism

SN - 2212-8778

IS - 2

ER -