The JAK kinase Tyk2 and the Signal Transducer and Activator of Transcription 3 (Stat3) are required for Brown Adipose Tissue Differentiation

Abstract

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.