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

Kenji Uno, Tetsuya Yamada, Yasushi Ishigaki, Junta Imai, Yutaka Hasegawa, Shojiro Sawada, Keizo Kaneko, Hiraku Ono, Tomoichiro Asano, Yoshitomo Oka and Hideki Katagiri ()
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Kenji Uno: Tohoku University Graduate School of Medicine
Tetsuya Yamada: Tohoku University Graduate School of Medicine
Yasushi Ishigaki: Iwate Medical University
Junta Imai: Tohoku University Graduate School of Medicine
Yutaka Hasegawa: Tohoku University Graduate School of Medicine
Shojiro Sawada: Tohoku University Graduate School of Medicine
Keizo Kaneko: Tohoku University Graduate School of Medicine
Hiraku Ono: Saitama Medical University
Tomoichiro Asano: Graduate School of Medicine, University of Hiroshima
Yoshitomo Oka: Tohoku University Graduate School of Medicine
Hideki Katagiri: Tohoku University Graduate School of Medicine

Nature Communications, 2015, vol. 6, issue 1, 1-15

Abstract: Abstract 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.

Date: 2015
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DOI: 10.1038/ncomms8940

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