title: Hepatic mTORC1 controls locomotor activity, body temperature, and lipid metabolism through FGF21.
abstract: 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 γ coactivator-1α (PGC-1α)-dependent fibroblast growth factor 21 (FGF21) expression in the liver. Injection of glutamine or knockdown of PGC-1α 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-1α 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.
authors.affiliation: Biozentrum, University of Basel, CH-4056 Basel, Switzerland;
authors.forename: Marion
authors.initials: M
authors.lastname: Cornu
authors.affiliation: Biozentrum, University of Basel, CH-4056 Basel, Switzerland;
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Oppliger
authors.affiliation: Biozentrum, University of Basel, CH-4056 Basel, Switzerland;
authors.forename: Verena
authors.initials: V
authors.lastname: Albert
authors.affiliation: Biozentrum, University of Basel, CH-4056 Basel, Switzerland;
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Robitaille
authors.affiliation: Institute of Pathology, Molecular Pathology Division, University Hospital of Basel, CH-4003 Basel, Switzerland; and.
authors.forename: Francesca
authors.initials: F
authors.lastname: Trapani
authors.affiliation: Institute of Pathology, Molecular Pathology Division, University Hospital of Basel, CH-4003 Basel, Switzerland; and.
authors.forename: Luca
authors.initials: L
authors.lastname: Quagliata
authors.affiliation: Institute of Molecular Systems Biology, Swiss Federal Institute of Technology (ETH) Zürich, CH-8093 Zurich, Switzerland.
authors.forename: Tobias
authors.initials: T
authors.lastname: Fuhrer
authors.affiliation: Institute of Molecular Systems Biology, Swiss Federal Institute of Technology (ETH) Zürich, CH-8093 Zurich, Switzerland.
authors.forename: Uwe
authors.initials: U
authors.lastname: Sauer
authors.affiliation: Institute of Pathology, Molecular Pathology Division, University Hospital of Basel, CH-4003 Basel, Switzerland; and.
authors.forename: Luigi
authors.initials: L
authors.lastname: Terracciano
authors.affiliation: Biozentrum, University of Basel, CH-4056 Basel, Switzerland; M.Hall@unibas.ch.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Hall
mesh_terms: D000818:Animals; D001831:Body Temperature / Q000502:physiology*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D005973:Glutamine / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology*; D046912:Multiprotein Complexes / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: D046912:Multiprotein Complexes; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D012333:RNA, Messenger; C000624650:TSC1 protein, human; D014157:Transcription Factors; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; C414620:fibroblast growth factor 21; D005973:Glutamine; D005346:Fibroblast Growth Factors; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
keywords: TSC; behavior; hepatocellular carcinoma; metabolic stress
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