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Nat Commun. 2015 Aug 13;6:7940. doi: 10.1038/ncomms8940.

A hepatic amino acid/mTOR/S6K-dependent signalling pathway modulates systemic lipid metabolism via neuronal signals.

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Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
Division of Diabetes and Metabolism, Iwate Medical University, Morioka 020-8505, Japan.
The Fourth Department of Internal Medicine, Saitama Medical University, Saitama 350-0495, Japan.
Department of Medical Science, Graduate School of Medicine, University of Hiroshima, Hiroshima 734-8553, Japan.
Japan Science and Technology Agency, CREST, Sendai 980-8575, Japan.


Metabolism is coordinated among tissues and organs via neuronal signals. Levels of circulating amino acids (AAs), which are elevated in obesity, activate the intracellular target of rapamycin complex-1 (mTORC1)/S6kinase (S6K) pathway in the liver. Here we demonstrate that hepatic AA/mTORC1/S6K signalling modulates systemic lipid metabolism via a mechanism involving neuronal inter-tissue communication. Hepatic expression of an AA transporter, SNAT2, activates the mTORC1/S6K pathway, and markedly elevates serum triglycerides (TGs), while downregulating adipose lipoprotein lipase (LPL). Hepatic Rheb or active-S6K expression have similar metabolic effects, whereas hepatic expression of dominant-negative-S6K inhibits TG elevation in SNAT2 mice. Denervation, pharmacological deafferentation and β-blocker administration suppress obesity-related hypertriglyceridemia with adipose LPL upregulation, suggesting that signals are transduced between liver and adipose tissue via a neuronal pathway consisting of afferent vagal and efferent sympathetic nerves. Thus, the neuronal mechanism uncovered here serves to coordinate amino acid and lipid levels and contributes to the development of obesity-related hypertriglyceridemia.

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