Hepatic mTORC1 controls locomotor activity, body temperature, and lipid metabolism through FGF21

Proc Natl Acad Sci U S A. 2014 Aug 12;111(32):11592-9. doi: 10.1073/pnas.1412047111. Epub 2014 Jul 31.

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.

Keywords: TSC; behavior; hepatocellular carcinoma; metabolic stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Temperature / physiology*
  • Carcinoma, Hepatocellular / metabolism
  • Fibroblast Growth Factors / antagonists & inhibitors
  • Fibroblast Growth Factors / genetics
  • Fibroblast Growth Factors / metabolism*
  • Gene Knockdown Techniques
  • Glutamine / metabolism
  • Humans
  • Lipid Metabolism*
  • Liver / metabolism*
  • Liver Neoplasms / metabolism
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Motor Activity / physiology*
  • Multiprotein Complexes / metabolism*
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Signal Transduction
  • TOR Serine-Threonine Kinases / metabolism*
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Tuberous Sclerosis Complex 1 Protein
  • Tumor Suppressor Proteins / deficiency
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism

Substances

  • Multiprotein Complexes
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • RNA, Messenger
  • TSC1 protein, human
  • Transcription Factors
  • Tsc1 protein, mouse
  • Tuberous Sclerosis Complex 1 Protein
  • Tumor Suppressor Proteins
  • fibroblast growth factor 21
  • Glutamine
  • Fibroblast Growth Factors
  • Mechanistic Target of Rapamycin Complex 1
  • TOR Serine-Threonine Kinases