A hepatic amino acid/mTOR/S6K-dependent signalling pathway modulates systemic lipid metabolism via neuronal signals.
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.
Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
Kenji
K
Uno
Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
Tetsuya
T
Yamada
Division of Diabetes and Metabolism, Iwate Medical University, Morioka 020-8505, Japan.
Yasushi
Y
Ishigaki
Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
Junta
J
Imai
Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
Yutaka
Y
Hasegawa
Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
Shojiro
S
Sawada
Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
Keizo
K
Kaneko
The Fourth Department of Internal Medicine, Saitama Medical University, Saitama 350-0495, Japan.
Hiraku
H
Ono
Department of Medical Science, Graduate School of Medicine, University of Hiroshima, Hiroshima 734-8553, Japan.
Tomoichiro
T
Asano
Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
Yoshitomo
Y
Oka
Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.|Japan Science and Technology Agency, CREST, Sendai 980-8575, Japan.
Hideki
H
Katagiri
D000256:Adenoviridae; D026924:Amino Acid Transport System A / Q000235:genetics / Q000378:metabolism*; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D004041:Dietary Fats; D015971:Gene Expression Regulation, Enzymologic; D015228:Hypertriglyceridemia / Q000378:metabolism; D050356:Lipid Metabolism / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009474:Neurons / Q000502:physiology*; D019893:Ribosomal Protein S6 Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism
D026924:Amino Acid Transport System A; D000596:Amino Acids; D004041:Dietary Fats; C498798:Slc38a2 protein, mouse; D014280:Triglycerides; C546843:mTOR protein, mouse; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases