PMID- 25082895
OWN - NLM
STAT- MEDLINE
DCOM- 20141020
LR  - 20211203
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 111
IP  - 32
DP  - 2014 Aug 12
TI  - Hepatic mTORC1 controls locomotor activity, body temperature, and lipid 
      metabolism through FGF21.
PG  - 11592-9
LID - 10.1073/pnas.1412047111 [doi]
AB  - The liver is a key metabolic organ that controls whole-body physiology in 
      response to nutrient availability. Mammalian target of rapamycin (mTOR) is a 
      nutrient-activated kinase and central controller of growth and metabolism that is 
      negatively regulated by the tumor suppressor tuberous sclerosis complex 1 (TSC1). 
      To investigate the role of hepatic mTOR complex 1 (mTORC1) in whole-body 
      physiology, we generated liver-specific Tsc1 (L-Tsc1 KO) knockout mice. L-Tsc1 KO 
      mice displayed reduced locomotor activity, body temperature, and hepatic 
      triglyceride content in a rapamycin-sensitive manner. Ectopic activation of 
      mTORC1 also caused depletion of hepatic and plasma glutamine, leading to 
      peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha)-dependent 
      fibroblast growth factor 21 (FGF21) expression in the liver. Injection of 
      glutamine or knockdown of PGC-1alpha or FGF21 in the liver suppressed the behavioral 
      and metabolic defects due to mTORC1 activation. Thus, mTORC1 in the liver 
      controls whole-body physiology through PGC-1alpha and FGF21. Finally, mTORC1 
      signaling correlated with FGF21 expression in human liver tumors, suggesting that 
      treatment of glutamine-addicted cancers with mTOR inhibitors might have 
      beneficial effects at both the tumor and whole-body level.
FAU - Cornu, Marion
AU  - Cornu M
AD  - Biozentrum, University of Basel, CH-4056 Basel, Switzerland;
FAU - Oppliger, Wolfgang
AU  - Oppliger W
AD  - Biozentrum, University of Basel, CH-4056 Basel, Switzerland;
FAU - Albert, Verena
AU  - Albert V
AD  - Biozentrum, University of Basel, CH-4056 Basel, Switzerland;
FAU - Robitaille, Aaron M
AU  - Robitaille AM
AD  - Biozentrum, University of Basel, CH-4056 Basel, Switzerland;
FAU - Trapani, Francesca
AU  - Trapani F
AD  - Institute of Pathology, Molecular Pathology Division, University Hospital of 
      Basel, CH-4003 Basel, Switzerland; and.
FAU - Quagliata, Luca
AU  - Quagliata L
AD  - Institute of Pathology, Molecular Pathology Division, University Hospital of 
      Basel, CH-4003 Basel, Switzerland; and.
FAU - Fuhrer, Tobias
AU  - Fuhrer T
AD  - Institute of Molecular Systems Biology, Swiss Federal Institute of Technology 
      (ETH) Zurich, CH-8093 Zurich, Switzerland.
FAU - Sauer, Uwe
AU  - Sauer U
AD  - Institute of Molecular Systems Biology, Swiss Federal Institute of Technology 
      (ETH) Zurich, CH-8093 Zurich, Switzerland.
FAU - Terracciano, Luigi
AU  - Terracciano L
AD  - Institute of Pathology, Molecular Pathology Division, University Hospital of 
      Basel, CH-4003 Basel, Switzerland; and.
FAU - Hall, Michael N
AU  - Hall MN
AD  - Biozentrum, University of Basel, CH-4056 Basel, Switzerland; M.Hall@unibas.ch.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140731
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha)
RN  - 0 (Ppargc1a protein, mouse)
RN  - 0 (RNA, Messenger)
RN  - 0 (TSC1 protein, human)
RN  - 0 (Transcription Factors)
RN  - 0 (Tsc1 protein, mouse)
RN  - 0 (Tuberous Sclerosis Complex 1 Protein)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 0 (fibroblast growth factor 21)
RN  - 0RH81L854J (Glutamine)
RN  - 62031-54-3 (Fibroblast Growth Factors)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Body Temperature/*physiology
MH  - Carcinoma, Hepatocellular/metabolism
MH  - Fibroblast Growth Factors/antagonists & inhibitors/genetics/*metabolism
MH  - Gene Knockdown Techniques
MH  - Glutamine/metabolism
MH  - Humans
MH  - *Lipid Metabolism
MH  - Liver/*metabolism
MH  - Liver Neoplasms/metabolism
MH  - Male
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mice
MH  - Mice, 129 Strain
MH  - Mice, Inbred BALB C
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Motor Activity/*physiology
MH  - Multiprotein Complexes/*metabolism
MH  - Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
MH  - RNA, Messenger/genetics/metabolism
MH  - Signal Transduction
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Transcription Factors/antagonists & inhibitors/genetics/metabolism
MH  - Tuberous Sclerosis Complex 1 Protein
MH  - Tumor Suppressor Proteins/deficiency/genetics/metabolism
PMC - PMC4136616
OTO - NOTNLM
OT  - TSC
OT  - behavior
OT  - hepatocellular carcinoma
OT  - metabolic stress
COIS- The authors declare no conflict of interest.
EDAT- 2014/08/02 06:00
MHDA- 2014/10/21 06:00
PMCR- 2015/02/12
CRDT- 2014/08/02 06:00
PHST- 2014/08/02 06:00 [entrez]
PHST- 2014/08/02 06:00 [pubmed]
PHST- 2014/10/21 06:00 [medline]
PHST- 2015/02/12 00:00 [pmc-release]
AID - 1412047111 [pii]
AID - 201412047 [pii]
AID - 10.1073/pnas.1412047111 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2014 Aug 12;111(32):11592-9. doi: 
      10.1073/pnas.1412047111. Epub 2014 Jul 31.