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Adipose tissue mTORC2 regulates ChREBP-driven de novo lipogenesis and hepatic glucose metabolism

Yuefeng Tang1, Martina Wallace2, Joan Sanchez-Gurmaches1

  • 1Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, Massachusetts 01605, USA.

Nature Communications
|April 22, 2016
PubMed

Insights

Mechanistic target of rapamycin complex 2 (mTORC2) in white adipose tissue controls glucose metabolism and insulin sensitivity by regulating de novo lipogenesis (DNL). This pathway is crucial for managing type 2 diabetes and obesity.

Area of Science:

  • Metabolism and Endocrinology
  • Cellular Signaling
  • Molecular Biology

Background:

  • Adipose tissue de novo lipogenesis (DNL) is vital for insulin sensitivity and impaired in obesity and insulin resistance.
  • Understanding DNL regulation in adipose tissue is key for developing type 2 diabetes therapies.

Purpose of the Study:

  • To investigate the role of mechanistic target of rapamycin complex 2 (mTORC2) in white adipose tissue (WAT) in regulating DNL and insulin sensitivity.
  • To elucidate the molecular mechanisms by which mTORC2 influences lipogenesis and glucose homeostasis.

Main Methods:

  • Conditional deletion of the mTORC2 subunit Rictor in mature adipocytes of mice.
  • Analysis of ChREBPβ expression, DNL rates, glucose uptake, and insulin sensitivity in WAT and liver.
  • Assessment of diet-induced insulin resistance models.

Main Results:

  • Rictor deletion in WAT adipocytes reduced ChREBPβ expression, decreased WAT DNL, and impaired hepatic insulin sensitivity.
  • mTORC2 signaling promotes ChREBPβ expression partly via glucose uptake, without affecting pan-AKT signaling.
  • High-fat diet rapidly decreased adipose tissue ChREBPβ expression and insulin sensitivity, independent of Rictor deletion.

Conclusions:

  • mTORC2 in WAT regulates ChREBPβ expression and DNL, impacting systemic insulin sensitivity.
  • Adipose tissue DNL is an early target in diet-induced insulin resistance.
  • mTORC2 in WAT acts as an extra-hepatic nutrient sensor controlling glucose homeostasis.

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