Editors' ChoiceMetabolism

Synchronizing Metabolism, Physiology, and Behavior Through mTORC1 and FGF21

Sci. Signal.  19 Aug 2014:
Vol. 7, Issue 339, pp. ec218
DOI: 10.1126/scisignal.2005809

Physiology (body temperature and hormone metabolism) and behavior (feeding and locomotion) exhibit a coordinated circadian rhythm. A protein complex containing the kinase mTOR (mTORC1) translates changes in nutrient availability to changes in cellular metabolism of proteins, lipids, and nucleic acids. The tuberous sclerosis complex (TSC) composed of TSC1 and TSC2 inhibits mTORC1. The transcription factor PGC-1α, which is activated by mTORC1, affects metabolism by targeting genes involved in multiple biochemical and regulatory pathways, including increasing the expression of Fgf21, which encodes a secreted growth factor that is expressed in a circadian manner primarily in the liver. In mice, Fgf21 expression typically peaks at night when they are most active. Cornu et al. explored the connection between hepatic mTORC1 signaling and organismal physiology and behavior in mice with liver-specific knockout of Tsc1 (LKO-Tsc1). Compared with fasted control mice, fasted LKO-Tsc1 mice had constitutively active mTORC1 signaling, increased blood glucose, increased fatty acid oxidation associated with reduced hepatic triglycerides, reduced nocturnal body temperature and locomotor activity, and increased nocturnal expression of Pgc-1α and Fgf21 in the liver. Injection with the mTORC1 inhibitor rapamycin or genetic inhibition of Pgc-1α or Fgf21 decreased the amount of circulating FGF21 and reversed the metabolic and behavioral defects in LKO-Tsc1 mice. Fasted LKO-Tsc1 mice had decreased circulating and hepatic glutamine at night, consistent with the ability of mTORC1 to promote glutaminolysis, and injection of glutamine in LKO-Tsc1 mice reduced Fgf21 and Pgc-1α expression in the liver, reduced FGF21 concentration in circulation, and increased nocturnal body temperature. Thus, hepatic mTORC1 signaling activates glutaminolysis leading to carbon-depletion stress that promotes PGC-1α–dependent production of FGF21 that affects whole-body physiology.

M. Cornu, W. Oppliger, V. Albert, A. M. Robitaille, F. Trapani, L. Quagliata, T. Fuhrer, U. Sauer, L. Terracciano, M. N. Hall, Hepatic mTORC1 controls locomotor activity, body temperature, and lipid metabolism through FGF21. Proc. Natl. Acad. Sci. U.S.A. 111, 11592–11599 (2014). [Abstract] [Full Text]