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

Cell Metab. 2012 May 2;15(5):725-38. doi: 10.1016/j.cmet.2012.03.015. Epub 2012 Apr 19.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Glucokinase / genetics
  • Glucokinase / metabolism*
  • Gluconeogenesis
  • Glucose / genetics
  • Glucose / metabolism
  • Glucose Intolerance / genetics
  • Glucose Intolerance / metabolism
  • Glycogen Synthase Kinase 3 / genetics
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Glycolysis
  • Hepatocytes / metabolism
  • Homeostasis
  • Hyperglycemia / genetics
  • Hyperglycemia / metabolism
  • Hyperinsulinism / genetics
  • Hyperinsulinism / metabolism
  • Insulin / genetics
  • Insulin / metabolism
  • Lipid Metabolism
  • Lipogenesis
  • Liver / enzymology
  • Liver / metabolism*
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2
  • Mice
  • Mice, Knockout
  • Multiprotein Complexes / metabolism*
  • Phosphorylation
  • Proteins / genetics
  • Proteins / metabolism
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction
  • Sterol Regulatory Element Binding Protein 1 / genetics
  • Sterol Regulatory Element Binding Protein 1 / metabolism*
  • TOR Serine-Threonine Kinases / metabolism*
  • Trans-Activators / deficiency
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transcription Factors

Substances

  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Foxo1 protein, mouse
  • Insulin
  • Multiprotein Complexes
  • Proteins
  • Sterol Regulatory Element Binding Protein 1
  • Trans-Activators
  • Transcription Factors
  • TOR Serine-Threonine Kinases
  • Glucokinase
  • Akt2 protein, mouse
  • Glycogen Synthase Kinase 3 beta
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3
  • Glucose