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

Asami Hagiwara1, Marion Cornu, Nadine Cybulski

  • 1Biozentrum, University of Basel, CH-4056 Basel, Switzerland.

Cell Metabolism
|April 24, 2012
PubMed

Insights

Mammalian target of rapamycin complex 2 (mTORC2) regulates liver metabolism by activating Akt signaling. Liver-specific mTORC2 deficiency causes hyperglycemia and hypolipidemia, impacting whole-body metabolic homeostasis.

Area of Science:

  • Biochemistry
  • Metabolic Regulation
  • Cell Signaling

Background:

  • Mammalian target of rapamycin complex 2 (mTORC2) is crucial for cell growth and survival.
  • mTORC2 phosphorylates AGC kinases like Akt, SGK1, and PKC in response to insulin/IGF1.
  • The liver plays a central role in insulin-mediated metabolic control.

Purpose of the Study:

  • To investigate the specific role of hepatic mTORC2 in regulating liver metabolism.
  • To understand the downstream signaling pathways affected by hepatic mTORC2.
  • To determine the impact of liver-specific mTORC2 deficiency on systemic metabolic homeostasis.

Main Methods:

  • Generation of liver-specific rictor knockout (LiRiKO) mice.
  • Analysis of hepatic Akt phosphorylation, glucokinase, and SREBP1c activity.
  • Assessment of glucose and lipid metabolism in LiRiKO mice and hepatocytes.

Main Results:

  • LiRiKO mice exhibited loss of Akt Ser473 phosphorylation in the liver.
  • Hepatic mTORC2 deficiency led to constitutive gluconeogenesis and impaired glycolysis/lipogenesis.
  • Systemic effects included hyperglycemia, hyperinsulinemia, and hypolipidemia.
  • Restoration of Akt2 or glucokinase activity in deficient hepatocytes partially rescued metabolic defects.

Conclusions:

  • Hepatic mTORC2 is essential for regulating glucose and lipid metabolism through insulin-induced Akt signaling.
  • mTORC2-deficient livers are unable to sense satiety, leading to metabolic dysregulation.
  • These findings highlight mTORC2 as a potential therapeutic target for metabolic disorders.

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