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

Significance The mammalian target of rapamycin complex 1 (mTORC1) controls cell growth and metabolism in response to nutrients, growth factors, and cellular energy. Aberrant mTORC1 signaling is implicated in human diseases such as diabetes, obesity, and cancer. Our results reveal that ectopic mTORC1 activation in the liver controls the stress hormone fibroblast growth factor 21 (FGF21) in a peroxisome proliferator–activated receptor γ coactivator-1α (PGC-1α)–dependent manner via glutamine depletion, which in turn affects whole-body behavior and metabolism. mTORC1 signaling correlates with FGF21 expression in human liver tumors, suggesting that our findings in mice may have physiological relevance in glutamine-addicted human cancers. Thus, treatment with the anticancer drug rapamycin may have beneficial effects by blocking tumor growth and by preventing deregulation of whole-body physiology due to FGF21 expression. 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.

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