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Tyk2 and Stat3 regulate brown adipose tissue differentiation and obesity

Marta Derecka1, Agnieszka Gornicka, Sergei B Koralov

  • 1Department of Biochemistry and Molecular Biology and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.

Cell Metabolism
|December 11, 2012
PubMed

Insights

Mice lacking Tyrosine Kinase 2 (Tyk2) develop obesity due to impaired brown fat development. Restoring Tyk2 or Stat3 function improved brown adipose tissue (BAT) development and reduced obesity.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Obesity Research

Background:

  • Tyk2 (Tyrosine Kinase 2) is a JAK tyrosine kinase.
  • Brown adipose tissue (BAT) plays a crucial role in energy expenditure and thermogenesis.
  • Aberrant BAT development is linked to obesity.

Purpose of the Study:

  • To investigate the role of Tyk2 in brown adipose tissue (BAT) development.
  • To explore the relationship between Tyk2, Stat3, and BAT differentiation.
  • To identify potential therapeutic targets for obesity.

Main Methods:

  • Generation and analysis of Tyk2-deficient mice.
  • High-fat diet feeding studies.
  • Analysis of gene expression and protein stability.
  • Studies involving Stat3 activation and PRDM16 interaction.

Main Results:

  • Tyk2 deficiency leads to progressive obesity and impaired Myf5+ BAT development in mice.
  • Tyk2 RNA levels are decreased in BAT and skeletal muscle of mice on high-fat diets and in obese humans.
  • Restoration of Tyk2 or Stat3 (Signal Transducer and Activator of Transcription 3) function in Tyk2(-/-) brown preadipocytes improved differentiation.
  • CAStat3 (constitutively active Stat3) expression in BAT of Tyk2(-/-) mice improved BAT development, insulin levels, and reduced body weight.
  • Stat3 binds to and enhances the stability of PRDM16, a key regulator of BAT differentiation.

Conclusions:

  • Tyk2 and Stat3 are critical determinants of brown fat lineage.
  • Altered Tyk2 levels are associated with obesity in both rodents and humans.
  • Targeting the Tyk2-Stat3-PRDM16 pathway may offer a therapeutic strategy for obesity.

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