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Isolation of Primary Mouse Hepatocytes for Nascent Protein Synthesis Analysis by Non-radioactive L-azidohomoalanine Labeling Method
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TORC2 regulates hepatic insulin signaling via a mammalian phosphatidic acid phosphatase, LIPIN1

Dongryeol Ryu1, Kyoung-Jin Oh, Hee-Yeon Jo

  • 1Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, 300 Chunchun-dong, Jangan-gu, Suwon, Gyeonggi-do 440-746, Korea.

Cell Metabolism
|March 4, 2009
PubMed

Insights

TORC2 hyperactivation worsens insulin resistance by increasing LIPIN1, a key enzyme in lipid synthesis. Reducing LIPIN1 improves glucose metabolism and insulin sensitivity in obesity models, highlighting a new therapeutic target for type 2 diabetes.

Area of Science:

  • Metabolic regulation
  • Hepatology
  • Molecular endocrinology

Background:

  • TORC2 (transducer of regulated CREB activity) is crucial for liver glucose production.
  • Insulin normally inhibits TORC2 activity through SIK2-dependent phosphorylation, preventing excessive glucose output.
  • Dysregulation of this pathway contributes to hyperglycemia and insulin resistance.

Purpose of the Study:

  • To investigate the role of TORC2 in exacerbating insulin resistance.
  • To determine the involvement of LIPIN1 in TORC2-mediated hepatic insulin resistance.
  • To explore LIPIN1 as a potential therapeutic target for type 2 diabetes.

Main Methods:

  • Studied TORC2 activity and LIPIN1 expression in diet-induced and genetic obesity mouse models.
  • Utilized overexpression and knockdown techniques for TORC2 and LIPIN1.
  • Assessed hepatic glucose production, insulin signaling, diacylglycerol (DAG) levels, and PKCε activity.
  • Examined effects in db/db mice to evaluate therapeutic potential.

Main Results:

  • Hyperactivation of TORC2 enhances LIPIN1 expression in the liver, promoting diacylglycerol (DAG) synthesis.
  • Increased LIPIN1 levels disrupt hepatic insulin signaling, contributing to insulin resistance.
  • Knockdown of LIPIN1 ameliorates hyperglycemia and insulin resistance in obese mice by reducing DAG and PKCε activity.
  • Reducing LIPIN1 partially rescues TORC2-mediated insulin resistance.

Conclusions:

  • TORC2 hyperactivation exacerbates insulin resistance and promotes hyperglycemia via LIPIN1.
  • LIPIN1 is a critical mediator of TORC2-induced hepatic insulin resistance.
  • Targeting LIPIN1 may offer a strategy to combat type 2 diabetes associated with TORC2 dysregulation.

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