Hepatic mTORC2 activates glycolysis and lipogenesis through Akt, glucokinase, and SREBP1c

Asami Hagiwara; Marion Cornu; Nadine Cybulski; Pazit Polak; Charles Betz; Francesca Trapani; Luigi Terracciano; Markus H. Heim; Markus A. Rüegg; Michael N. Hall

doi:10.1016/j.cmet.2012.03.015

Hepatic mTORC2 activates glycolysis and lipogenesis through Akt, glucokinase, and SREBP1c

Asami Hagiwara, Marion Cornu, Nadine Cybulski, Pazit Polak, Charles Betz, Francesca Trapani, Luigi Terracciano, Markus H. Heim, Markus A. Rüegg, Michael N. Hall

University of Basel

Research output: Contribution to journal › Article › peer-review

443 Scopus citations

Abstract

Mammalian target of rapamycin complex 2 (mTORC2) phosphorylates and activates AGC kinase family members, including Akt, SGK1, and PKC, in response to insulin/IGF1. The liver is a key organ in insulin-mediated regulation of metabolism. To assess the role of hepatic mTORC2, we generated liver-specific rictor knockout (LiRiKO) mice. Fed LiRiKO mice displayed loss of Akt Ser473 phosphorylation and reduced glucokinase and SREBP1c activity in the liver, leading to constitutive gluconeogenesis, and impaired glycolysis and lipogenesis, suggesting that the mTORC2-deficient liver is unable to sense satiety. These liver-specific defects resulted in systemic hyperglycemia, hyperinsulinemia, and hypolipidemia. Expression of constitutively active Akt2 in mTORC2-deficient hepatocytes restored both glucose flux and lipogenesis, whereas glucokinase overexpression rescued glucose flux but not lipogenesis. Thus, mTORC2 regulates hepatic glucose and lipid metabolism via insulin-induced Akt signaling to control whole-body metabolic homeostasis. These findings have implications for emerging drug therapies that target mTORC2.

Original language	English
Pages (from-to)	725-738
Number of pages	14
Journal	Cell Metabolism
Volume	15
Issue number	5
DOIs	https://doi.org/10.1016/j.cmet.2012.03.015
State	Published - 2 May 2012
Externally published	Yes

Bibliographical note

Funding Information:
We thank Andrea Loeschmann for expert technical support; Christoph Handschin (University of Basel, Switzerland) for use of the EchoMRI-100 qNMR and cobas c; and Brian A. Hemmings (FMI, Switzerland), Wataru Ogawa (Kobe University, Japan), and Bernard Thorens (University of Lausanne, Switzerland) for reagents. We acknowledge support from Ajinomoto Co., Inc. (A.H.), the SFD-ALFEDIAM (M.C.), the Misrock Foundation (C.B.), the Louis Jeantet Foundation (M.N.H.), the Canton of Basel, and the Swiss National Science Foundation.

Funding

We thank Andrea Loeschmann for expert technical support; Christoph Handschin (University of Basel, Switzerland) for use of the EchoMRI-100 qNMR and cobas c; and Brian A. Hemmings (FMI, Switzerland), Wataru Ogawa (Kobe University, Japan), and Bernard Thorens (University of Lausanne, Switzerland) for reagents. We acknowledge support from Ajinomoto Co., Inc. (A.H.), the SFD-ALFEDIAM (M.C.), the Misrock Foundation (C.B.), the Louis Jeantet Foundation (M.N.H.), the Canton of Basel, and the Swiss National Science Foundation.

Funders	Funder number
Ajinomoto Co., Inc.
Canton of Basel
Louis Jeantet Foundation
Misrock Foundation
SFD-ALFEDIAM
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung	130243, 133133, 125348, 139228, 141184

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10.1016/j.cmet.2012.03.015

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title = "Hepatic mTORC2 activates glycolysis and lipogenesis through Akt, glucokinase, and SREBP1c",

abstract = "Mammalian target of rapamycin complex 2 (mTORC2) phosphorylates and activates AGC kinase family members, including Akt, SGK1, and PKC, in response to insulin/IGF1. The liver is a key organ in insulin-mediated regulation of metabolism. To assess the role of hepatic mTORC2, we generated liver-specific rictor knockout (LiRiKO) mice. Fed LiRiKO mice displayed loss of Akt Ser473 phosphorylation and reduced glucokinase and SREBP1c activity in the liver, leading to constitutive gluconeogenesis, and impaired glycolysis and lipogenesis, suggesting that the mTORC2-deficient liver is unable to sense satiety. These liver-specific defects resulted in systemic hyperglycemia, hyperinsulinemia, and hypolipidemia. Expression of constitutively active Akt2 in mTORC2-deficient hepatocytes restored both glucose flux and lipogenesis, whereas glucokinase overexpression rescued glucose flux but not lipogenesis. Thus, mTORC2 regulates hepatic glucose and lipid metabolism via insulin-induced Akt signaling to control whole-body metabolic homeostasis. These findings have implications for emerging drug therapies that target mTORC2.",

author = "Asami Hagiwara and Marion Cornu and Nadine Cybulski and Pazit Polak and Charles Betz and Francesca Trapani and Luigi Terracciano and Heim, {Markus H.} and R{\"u}egg, {Markus A.} and Hall, {Michael N.}",

note = "Funding Information: We thank Andrea Loeschmann for expert technical support; Christoph Handschin (University of Basel, Switzerland) for use of the EchoMRI-100 qNMR and cobas c; and Brian A. Hemmings (FMI, Switzerland), Wataru Ogawa (Kobe University, Japan), and Bernard Thorens (University of Lausanne, Switzerland) for reagents. We acknowledge support from Ajinomoto Co., Inc. (A.H.), the SFD-ALFEDIAM (M.C.), the Misrock Foundation (C.B.), the Louis Jeantet Foundation (M.N.H.), the Canton of Basel, and the Swiss National Science Foundation. ",

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doi = "10.1016/j.cmet.2012.03.015",

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AU - Hagiwara, Asami

AU - Cornu, Marion

AU - Cybulski, Nadine

AU - Polak, Pazit

AU - Betz, Charles

AU - Trapani, Francesca

AU - Terracciano, Luigi

AU - Heim, Markus H.

AU - Rüegg, Markus A.

AU - Hall, Michael N.

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PY - 2012/5/2

Y1 - 2012/5/2

N2 - Mammalian target of rapamycin complex 2 (mTORC2) phosphorylates and activates AGC kinase family members, including Akt, SGK1, and PKC, in response to insulin/IGF1. The liver is a key organ in insulin-mediated regulation of metabolism. To assess the role of hepatic mTORC2, we generated liver-specific rictor knockout (LiRiKO) mice. Fed LiRiKO mice displayed loss of Akt Ser473 phosphorylation and reduced glucokinase and SREBP1c activity in the liver, leading to constitutive gluconeogenesis, and impaired glycolysis and lipogenesis, suggesting that the mTORC2-deficient liver is unable to sense satiety. These liver-specific defects resulted in systemic hyperglycemia, hyperinsulinemia, and hypolipidemia. Expression of constitutively active Akt2 in mTORC2-deficient hepatocytes restored both glucose flux and lipogenesis, whereas glucokinase overexpression rescued glucose flux but not lipogenesis. Thus, mTORC2 regulates hepatic glucose and lipid metabolism via insulin-induced Akt signaling to control whole-body metabolic homeostasis. These findings have implications for emerging drug therapies that target mTORC2.

AB - Mammalian target of rapamycin complex 2 (mTORC2) phosphorylates and activates AGC kinase family members, including Akt, SGK1, and PKC, in response to insulin/IGF1. The liver is a key organ in insulin-mediated regulation of metabolism. To assess the role of hepatic mTORC2, we generated liver-specific rictor knockout (LiRiKO) mice. Fed LiRiKO mice displayed loss of Akt Ser473 phosphorylation and reduced glucokinase and SREBP1c activity in the liver, leading to constitutive gluconeogenesis, and impaired glycolysis and lipogenesis, suggesting that the mTORC2-deficient liver is unable to sense satiety. These liver-specific defects resulted in systemic hyperglycemia, hyperinsulinemia, and hypolipidemia. Expression of constitutively active Akt2 in mTORC2-deficient hepatocytes restored both glucose flux and lipogenesis, whereas glucokinase overexpression rescued glucose flux but not lipogenesis. Thus, mTORC2 regulates hepatic glucose and lipid metabolism via insulin-induced Akt signaling to control whole-body metabolic homeostasis. These findings have implications for emerging drug therapies that target mTORC2.

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Hepatic mTORC2 activates glycolysis and lipogenesis through Akt, glucokinase, and SREBP1c

Abstract

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