Kinase inactive Tyrosine kinase (Tyk2) Supports Differentiation of Brown fat Cells

It has been known for decades that brown adipose tissue (BAT) plays a central role in maintaining body temperature in hibernating animals and human infants. Recently, it has become evident that there are also depots of brown fat in adult humans, and the mass of brown fat is inversely correlated with body weight. There are a variety of transcription factors implicated in the differentiation of classical Myf5+ brown preadipocytes, one of the most important of which is PRDM16. We have recently identified that in addition to PRDM16, the tyrosine kinase Tyk2 and the STAT3 transcription factor are required for the differentiation of Myf5 positive brown preadipocytes both in cell culture and in mice. Tyk2 is a member of the Jak family of tyrosine kinases, which are activated by exposure of cells to different cytokines and growth factors. In this study we report the surprising observation that a mutated form of Tyk2, which lacks tyrosine kinase activity (Tyk2KD) restores differentiation of brown preadipocytes in vitro as well as in Tyk2-/- mice. Furthermore, expression of the Tyk2KD transgene in brown fat reverses the obese phenotype of Tyk2-/- animals. Treatment of cells with Jak-selective inhibitors suggests that the mechanism by which Tyk2KD functions to restore BAT differentiation is by dimerizing with kinase active Jak1 or Jak2. These results indicate that there are redundant mechanisms by which members of the Jak family can contribute to differentiation of BAT.