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

• Published in: Nature communications 2015-08, Vol.6 (1), p.7940-7940, Article 7940
• Main Authors: Uno, Kenji, Yamada, Tetsuya, Ishigaki, Yasushi, Imai, Junta, Hasegawa, Yutaka, Sawada, Shojiro, Kaneko, Keizo, Ono, Hiraku, Asano, Tomoichiro, Oka, Yoshitomo, Katagiri, Hideki
• Format: Article
• Language: English
• Subjects: 38/77; 38/90; 42/41; 42/44; 631/443/319; 631/443/319/1642; 631/80/86; 64/60; 692/308; 82/51; 82/80; 96/1; Adenoviridae; Adipose tissue; Amino Acid Transport System A - genetics; Amino Acid Transport System A - metabolism; Amino acids; Amino Acids - metabolism; Animals; Denervation; Dietary Fats; Gene Expression Regulation, Enzymologic; Humanities and Social Sciences; Hypertriglyceridemia; Hypertriglyceridemia - metabolism; Lipase; Lipid metabolism; Lipid Metabolism - physiology; Lipids; Lipoprotein lipase; Liver; Liver - metabolism; Male; Metabolism; Mice; Mice, Inbred Strains; multidisciplinary; Nerves; Neurons - physiology; Obesity; Organs; Pharmacology; Rapamycin; Ribosomal Protein S6 Kinases - genetics; Ribosomal Protein S6 Kinases - metabolism; Science; Science (multidisciplinary); Sensory neurons; Signal Transduction; Signaling; Sympathetic nerves; TOR protein; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Triglycerides; Triglycerides - metabolism; Vagus nerve
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms8940

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. Neuronal signals can coordinate metabolic processes across tissues. Here, the authors show that plasma amino acid and triglyceride levels are linked by a neuronal mechanism that couples amino acid sensing in the liver with the expression of lipoprotein lipase in adipose tissue.