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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
Summary
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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