PMID- 28462079
OWN - NLM
STAT- MEDLINE
DCOM- 20181115
LR  - 20181115
IS  - 2212-8778 (Electronic)
IS  - 2212-8778 (Linking)
VI  - 6
IP  - 5
DP  - 2017 May
TI  - Loss of hepatic DEPTOR alters the metabolic transition to fasting.
PG  - 447-458
LID - S2212-8778(16)30336-2 [pii]
LID - 10.1016/j.molmet.2017.02.005 [doi]
AB  - OBJECTIVE: The mechanistic target of rapamycin (mTOR) is a serine/threonine 
      kinase that functions into distinct protein complexes (mTORC1 and mTORC2) that 
      regulates growth and metabolism. DEP-domain containing mTOR-interacting protein 
      (DEPTOR) is part of these complexes and is known to reduce their activity. 
      Whether DEPTOR loss affects metabolism and organismal growth in vivo has never 
      been tested. METHODS: We have generated a conditional transgenic mouse allowing 
      the tissue-specific deletion of DEPTOR. This model was crossed with CMV-cre mice 
      or Albumin-cre mice to generate either whole-body or liver-specific DEPTOR 
      knockout (KO) mice. RESULTS: Whole-body DEPTOR KO mice are viable, fertile, 
      normal in size, and do not display any gross physical and metabolic 
      abnormalities. To circumvent possible compensatory mechanisms linked to the early 
      and systemic loss of DEPTOR, we have deleted DEPTOR specifically in the liver, a 
      tissue in which DEPTOR protein is expressed and affected in response to mTOR 
      activation. Liver-specific DEPTOR null mice showed a reduction in circulating 
      glucose upon fasting versus control mice. This effect was not associated with 
      change in hepatic gluconeogenesis potential but was linked to a sustained 
      reduction in circulating glucose during insulin tolerance tests. In addition to 
      the reduction in glycemia, liver-specific DEPTOR KO mice had reduced hepatic 
      glycogen content when fasted. We showed that loss of DEPTOR cell-autonomously 
      increased oxidative metabolism in hepatocytes, an effect associated with 
      increased cytochrome c expression but independent of changes in mitochondrial 
      content or in the expression of genes controlling oxidative metabolism. We found 
      that liver-specific DEPTOR KO mice showed sustained mTORC1 activation upon 
      fasting, and that acute treatment with rapamycin was sufficient to normalize 
      glycemia in these mice. CONCLUSION: We propose a model in which hepatic DEPTOR 
      accelerates the inhibition of mTORC1 during the transition to fasting to adjust 
      metabolism to the nutritional status.
FAU - Caron, Alexandre
AU  - Caron A
AD  - Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie 
      de Quebec (CRIUCPQ), Faculte de Medecine, Universite Laval, 2725 Chemin Ste-Foy, 
      Quebec, Qc, G1V 4G5, Canada.
FAU - Mouchiroud, Mathilde
AU  - Mouchiroud M
AD  - Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie 
      de Quebec (CRIUCPQ), Faculte de Medecine, Universite Laval, 2725 Chemin Ste-Foy, 
      Quebec, Qc, G1V 4G5, Canada.
FAU - Gautier, Nicolas
AU  - Gautier N
AD  - Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie 
      de Quebec (CRIUCPQ), Faculte de Medecine, Universite Laval, 2725 Chemin Ste-Foy, 
      Quebec, Qc, G1V 4G5, Canada.
FAU - Labbe, Sebastien M
AU  - Labbe SM
AD  - Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie 
      de Quebec (CRIUCPQ), Faculte de Medecine, Universite Laval, 2725 Chemin Ste-Foy, 
      Quebec, Qc, G1V 4G5, Canada.
FAU - Villot, Romain
AU  - Villot R
AD  - Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie 
      de Quebec (CRIUCPQ), Faculte de Medecine, Universite Laval, 2725 Chemin Ste-Foy, 
      Quebec, Qc, G1V 4G5, Canada.
FAU - Turcotte, Laurie
AU  - Turcotte L
AD  - Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie 
      de Quebec (CRIUCPQ), Faculte de Medecine, Universite Laval, 2725 Chemin Ste-Foy, 
      Quebec, Qc, G1V 4G5, Canada.
FAU - Secco, Blandine
AU  - Secco B
AD  - Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie 
      de Quebec (CRIUCPQ), Faculte de Medecine, Universite Laval, 2725 Chemin Ste-Foy, 
      Quebec, Qc, G1V 4G5, Canada.
FAU - Lamoureux, Guillaume
AU  - Lamoureux G
AD  - Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie 
      de Quebec (CRIUCPQ), Faculte de Medecine, Universite Laval, 2725 Chemin Ste-Foy, 
      Quebec, Qc, G1V 4G5, Canada.
FAU - Shum, Michael
AU  - Shum M
AD  - Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie 
      de Quebec (CRIUCPQ), Faculte de Medecine, Universite Laval, 2725 Chemin Ste-Foy, 
      Quebec, Qc, G1V 4G5, Canada.
FAU - Gelinas, Yves
AU  - Gelinas Y
AD  - Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie 
      de Quebec (CRIUCPQ), Faculte de Medecine, Universite Laval, 2725 Chemin Ste-Foy, 
      Quebec, Qc, G1V 4G5, Canada.
FAU - Marette, Andre
AU  - Marette A
AD  - Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie 
      de Quebec (CRIUCPQ), Faculte de Medecine, Universite Laval, 2725 Chemin Ste-Foy, 
      Quebec, Qc, G1V 4G5, Canada.
FAU - Richard, Denis
AU  - Richard D
AD  - Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie 
      de Quebec (CRIUCPQ), Faculte de Medecine, Universite Laval, 2725 Chemin Ste-Foy, 
      Quebec, Qc, G1V 4G5, Canada.
FAU - Sabatini, David M
AU  - Sabatini DM
AD  - Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, 
      MA, 02142, USA; Howard Hughes Medical Institute, Department of Biology, 
      Massachusetts Institute of Technology, Cambridge, MA, 02139, USA; Koch Center for 
      Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, MA, 
      02139, USA.
FAU - Laplante, Mathieu
AU  - Laplante M
AD  - Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie 
      de Quebec (CRIUCPQ), Faculte de Medecine, Universite Laval, 2725 Chemin Ste-Foy, 
      Quebec, Qc, G1V 4G5, Canada. Electronic address: 
      Mathieu.laplante@criucpq.ulaval.ca.
LA  - eng
GR  - R01 AI047389/AI/NIAID NIH HHS/United States
GR  - R01 CA103866/CA/NCI NIH HHS/United States
GR  - R37 AI047389/AI/NIAID NIH HHS/United States
GR  - MOP123387/CIHR/Canada
GR  - HHMI/Howard Hughes Medical Institute/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20170217
PL  - Germany
TA  - Mol Metab
JT  - Molecular metabolism
JID - 101605730
RN  - 0 (Blood Glucose)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (deptor protein, mouse)
RN  - 9005-79-2 (Glycogen)
RN  - 9007-43-6 (Cytochromes c)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
SB  - IM
MH  - Animals
MH  - Blood Glucose/*metabolism
MH  - Cytochromes c/metabolism
MH  - Fasting/*metabolism
MH  - Glycogen/metabolism
MH  - Intracellular Signaling Peptides and Proteins/*genetics/metabolism
MH  - Liver/*metabolism
MH  - Male
MH  - Mechanistic Target of Rapamycin Complex 1/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
PMC - PMC5404102
OTO - NOTNLM
OT  - DEPTOR
OT  - Fasting
OT  - Glucose
OT  - Liver
OT  - mTOR
EDAT- 2017/05/04 06:00
MHDA- 2018/11/16 06:00
PMCR- 2017/02/17
CRDT- 2017/05/03 06:00
PHST- 2016/12/15 00:00 [received]
PHST- 2017/01/30 00:00 [revised]
PHST- 2017/02/13 00:00 [accepted]
PHST- 2017/05/03 06:00 [entrez]
PHST- 2017/05/04 06:00 [pubmed]
PHST- 2018/11/16 06:00 [medline]
PHST- 2017/02/17 00:00 [pmc-release]
AID - S2212-8778(16)30336-2 [pii]
AID - 10.1016/j.molmet.2017.02.005 [doi]
PST - epublish
SO  - Mol Metab. 2017 Feb 17;6(5):447-458. doi: 10.1016/j.molmet.2017.02.005. 
      eCollection 2017 May.