Mice lacking the Jak tyrosine kinase member Tyk2 become progressively obese due to aberrant development of Myf5+ brown adipose tissue (BAT). Tyk2 RNA levels in BAT and skeletal muscle, which shares a common progenitor with BAT, are dramatically decreased in mice placed on a high fat diet and in obese humans. Expression of Tyk2 or the constitutively active form of the transcription factor Stat3 (CAStat3) restores differentiation in Tyk2−/− brown preadipocytes. Furthermore, Tyk2−/− mice expressing CAStat3 transgene in BAT also show improved BAT development, normal levels of insulin and significantly lower body weights. Stat3 binds to PRDM16, a master regulator of BAT differentiation, and enhances the stability of PRDM16 protein. These results define Tyk2 and Stat3 as critical determinants of brown fat-lineage and suggest that altered levels of Tyk2 are associated with obesity in both rodents and humans.

The transcription factor STAT1 plays a central role in orchestrating responses to various pathogens by activating the transcription of nuclear-encoded genes that mediate the antiviral, the antigrowth, and immune surveillance effects of interferons and other cytokines. In addition to regulating gene expression, we report that STAT1 -/- mice display increased energy expenditure and paradoxically decreased release of triglycerides from white adipose tissue (WAT). Liver mitochondria from STAT1 -/- mice show both defects in coupling of the electron transport chain (ETC) and increased numbers of mitochondria. Consistent with elevated numbers of mitochondria, STAT1 -/- mice expressed increased amounts of PGC1α, a master regulator of mitochondrial biogenesis. STAT1 binds to the PGC1α promoter in fed mice but not in fasted animals, suggesting that STAT1 inhibited transcription of PGC1α. Since STAT1 -/- mice utilized more lipids we examined white adipose tissue (WAT) stores. Contrary to expectations, fasted STAT1 -/- mice did not lose lipid from WAT. β-adrenergic stimulation of glycerol release from isolated STAT1 -/- WAT was decreased, while activation of hormone sensitive lipase was not changed. These findings suggest that STAT1 -/- adipose tissue does not release glycerol and that free fatty acids (FFA) re-esterify back to triglycerides, thus maintaining fat mass in fasted STAT1 -/- mice.

In the central nervous system, the formation of the myelin sheath and the differentiation of the myelinating cells, namely oligodendrocytes, are regulated by complex signaling networks that involve purinergic receptors and the extracellular matrix. However, the exact nature of the molecular interactions underlying these networks still needs to be defined. In this respect, the data presented here reveal a signaling mechanism that is characterized by an interaction between the purinergic P2Y 12 receptor and the matricellular extracellular matrix protein autotaxin (ATX), also known as ENPP2, phosphodiesterase-Iα/ATX, or lysoPLD. ATX has been previously described by us to mediate intermediate states of oligodendrocyte adhesion and to enable changes in oligodendrocyte morphology that are thought to be crucial for the formation of a fully functional myelin sheath. This functional property of ATX is mediated by ATX's modulator of oligodendrocyte remodeling and focal adhesion organization (MORFO) domain. Here, we show that the expression of the P2Y 12 receptor is necessary for ATX's MORFO domain to exert its effects on differentiating oligodendrocytes. In addition, our data demonstrate that exogenous expression of the P2Y 12 receptor can render cells responsive to the known effects of ATX's MORFO domain, and they identify Rac1 as an intracellular factor mediating the effect of ATX-MORFO-P2Y 12 signaling on the assembly of focal adhesions. Our data further support the idea that a physical interaction between ATX and the P2Y 12 receptor provides the basis for an ATX-MORFO-P2Y 12 signaling axis that is crucial for mediating cellular states of intermediate adhesion and morphological/structural plasticity.

Type II diabetes, cardiovascular disease, non‐alcoholic fatty liver disease and Alzheimer's disease are some of the numerous disorders associated with the obesity epidemic. Two functionally different types of fat that maintain energy balance contribute to the development of obesity. White adipose (WAT) is the primary site of energy storage, and brown adipose tissue (BAT) is responsible for energy expenditure in a process termed thermogenesis.We have made the novel observations that mice which do not express the Jak tyrosine kinase Tyk2 become obese with age, and Tyk2 is required for BAT differentiation. In addition to Tyk2, expression of the constitutively active form of the transcription factor Stat3, (CAStat3) restores BAT differentiation and the expression of BAT‐specific genes in Tyk2−/−‐preadipocytes as well as Tyk2−/− mice that express CAStat3 in BAT. In contrast, disruption of Stat3 expression in Tyk2+/+ preadipocytes prevents proper development of brown adipocytesExpression of CEBP/B and PRDM16, a master‐regulator of BAT differentiation, restores BAT differentiation in Tyk2−/− preadipocytes. Consistent with the observation that Stat3 and PRDM16 form a complex with C/EBPB□ Stat3 is also required for CEBP/B and PRDM16 mediated differentiation of brown adipocytes.. These studies define a novel role for the tyrosine kinase Tyk2 and Stat3 as determinants of brown fat‐lineage.