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

Uno K, Yamada T, Ishigaki Y, Imai J, Hasegawa Y, Sawada S, Kaneko K, Ono H, Asano T, Oka Y, Katagiri H - Nat Commun (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.

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.

No MeSH data available.


Related in: MedlinePlus

Blockage of SNAT2-induced hepatic mTORC1/S6K activation improves hypertriglyceridemia.(a–d) Mixed adenoviruses, that is, double-dose LacZ-adenovirus (ZZ), LacZ plus SNAT2 (ZS) and SNAT2 plus DN-S6K (SDN) adenoviruses, were administered to C57BL/6 mice. (a) Immunoblotting of liver extracts with anti-SNAT2 or p70-S6K antibodies. (b) SNAT2 mRNA expressions in the liver were analysed by RT–PCR (n=5–6). (c) Immunoblotting of liver extracts with anti-phospho-S6 or S6 antibodies. (d) Serum TG levels were measured on day 5 after adenovirus administration (n=4–6). The representative images derived from at least two experiments were displayed (a and c). Data are presented as means±s.d. **P<0.01 by the unpaired t-test. NS, not significant.
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f5: Blockage of SNAT2-induced hepatic mTORC1/S6K activation improves hypertriglyceridemia.(a–d) Mixed adenoviruses, that is, double-dose LacZ-adenovirus (ZZ), LacZ plus SNAT2 (ZS) and SNAT2 plus DN-S6K (SDN) adenoviruses, were administered to C57BL/6 mice. (a) Immunoblotting of liver extracts with anti-SNAT2 or p70-S6K antibodies. (b) SNAT2 mRNA expressions in the liver were analysed by RT–PCR (n=5–6). (c) Immunoblotting of liver extracts with anti-phospho-S6 or S6 antibodies. (d) Serum TG levels were measured on day 5 after adenovirus administration (n=4–6). The representative images derived from at least two experiments were displayed (a and c). Data are presented as means±s.d. **P<0.01 by the unpaired t-test. NS, not significant.

Mentions: Next, to determine whether the hepatic mTORC1/S6K pathway is actually involved in the hypertriglyceridemia induced by hepatic SNAT2 expression, we blocked this pathway in SNAT2 mice by expressing the dominant-negative form of p70-S6kinase (DN-S6K)32 in the liver. Mixed recombinant adenoviruses, SNAT2 plus DN-S6K (SDN mice), LacZ plus SNAT2 (ZS mice) and double-dose LacZ (ZZ mice), were administered to C57BL/6 mice fed standard chow. Hepatic SNAT2 expression was similarly increased in ZS mice and SDN mice (Fig. 5a,b). Although S6 phosphorylation was enhanced in ZS mice, it was markedly suppressed in SDN mice (Fig. 5c). Under these conditions, SNAT2-induced hypertriglyceridemia was markedly inhibited by DN-S6K expression (Fig. 5d). Thus, hepatic mTORC1/S6K activation is responsible for alterations in systemic lipid metabolism induced by increased AA entry into the liver.


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

Uno K, Yamada T, Ishigaki Y, Imai J, Hasegawa Y, Sawada S, Kaneko K, Ono H, Asano T, Oka Y, Katagiri H - Nat Commun (2015)

Blockage of SNAT2-induced hepatic mTORC1/S6K activation improves hypertriglyceridemia.(a–d) Mixed adenoviruses, that is, double-dose LacZ-adenovirus (ZZ), LacZ plus SNAT2 (ZS) and SNAT2 plus DN-S6K (SDN) adenoviruses, were administered to C57BL/6 mice. (a) Immunoblotting of liver extracts with anti-SNAT2 or p70-S6K antibodies. (b) SNAT2 mRNA expressions in the liver were analysed by RT–PCR (n=5–6). (c) Immunoblotting of liver extracts with anti-phospho-S6 or S6 antibodies. (d) Serum TG levels were measured on day 5 after adenovirus administration (n=4–6). The representative images derived from at least two experiments were displayed (a and c). Data are presented as means±s.d. **P<0.01 by the unpaired t-test. NS, not significant.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4557134&req=5

f5: Blockage of SNAT2-induced hepatic mTORC1/S6K activation improves hypertriglyceridemia.(a–d) Mixed adenoviruses, that is, double-dose LacZ-adenovirus (ZZ), LacZ plus SNAT2 (ZS) and SNAT2 plus DN-S6K (SDN) adenoviruses, were administered to C57BL/6 mice. (a) Immunoblotting of liver extracts with anti-SNAT2 or p70-S6K antibodies. (b) SNAT2 mRNA expressions in the liver were analysed by RT–PCR (n=5–6). (c) Immunoblotting of liver extracts with anti-phospho-S6 or S6 antibodies. (d) Serum TG levels were measured on day 5 after adenovirus administration (n=4–6). The representative images derived from at least two experiments were displayed (a and c). Data are presented as means±s.d. **P<0.01 by the unpaired t-test. NS, not significant.
Mentions: Next, to determine whether the hepatic mTORC1/S6K pathway is actually involved in the hypertriglyceridemia induced by hepatic SNAT2 expression, we blocked this pathway in SNAT2 mice by expressing the dominant-negative form of p70-S6kinase (DN-S6K)32 in the liver. Mixed recombinant adenoviruses, SNAT2 plus DN-S6K (SDN mice), LacZ plus SNAT2 (ZS mice) and double-dose LacZ (ZZ mice), were administered to C57BL/6 mice fed standard chow. Hepatic SNAT2 expression was similarly increased in ZS mice and SDN mice (Fig. 5a,b). Although S6 phosphorylation was enhanced in ZS mice, it was markedly suppressed in SDN mice (Fig. 5c). Under these conditions, SNAT2-induced hypertriglyceridemia was markedly inhibited by DN-S6K expression (Fig. 5d). Thus, hepatic mTORC1/S6K activation is responsible for alterations in systemic lipid metabolism induced by increased AA entry into the liver.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.

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.

No MeSH data available.


Related in: MedlinePlus