Molecular Regulators of Obesity Control Differentiation of Brown Adipose Tissue

The Jak tyrosine kinase member Tyk2 associates with the cytoplasmic domain of type I and type II cytokine receptors and promulgates cytokine signals by phosphorylating receptor subunits. It is also a component of both the type I and type III interferon signaling pathways.

The Stat protein family regulates many aspects of cell growth, survival, and differentiation. Dysregulation of this signaling pathway is frequently observed in primary tumors and leads to increased angiogenesis and enhanced tumor survival. Knockout studies have provided evidence that Stat proteins are involved in the development and function of the immune system and play a role in maintaining immune tolerance and tumor surveillance. Constitutive Stat3 activation is associated with various human cancers and commonly suggests poor prognosis. It has antiapoptotic as well as proliferative effects.

The expression of Tyk2, which is required for differentiation of brown adipose tissue, is decreased in obese mice and obese humans. To explain this decrease the investigators genetically engineered a line of mice to lack the Tyk2 gene. They found that these mice became progressively obese due to aberrant development of BAT. Increased expression of Tyk2 or constitutively active Stat3 restored BAT differentiation in the genetically engineered mice. Furthermore, the genetically engineered mice with active Stat3 in their BAT progenitor cells showed improved BAT development, normal levels of insulin, and significantly lower body weights.

In other studies they found that Tyk2 RNA levels in BAT and skeletal muscle, which shares a common progenitor with BAT, were dramatically decreased in mice placed on a high-fat diet and in obese humans.

At the mechanistic level, the investigators found that Stat3 bound to the protein PRDM16, a master regulator of BAT differentiation, and enhanced the stability of the PRDM16 protein.

“We discovered that Tyk2 levels in mice are regulated by diet. We then tested tissue samples from humans and found that levels of Tyk2 were more than 50% lower in obese humans,” said senior author Dr. Andrew C. Larner, professor of oncology at Virginia Commonwealth University. “Our findings open new potential avenues for research and development of new pharmacological and nutritional treatments for obesity.”

“We have made some very interesting observations in this study, but there are many questions left unanswered,” said Dr. Larner. “We plan to further investigate the actions of Tyk2 and Stat3 in order to better understand the mechanisms involved in the development of brown adipose tissue. We are hopeful this research will help lead to new targets to treat a variety of obesity-related diseases such as cancer, cardiovascular disease, and diabetes.”

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