SUN-589 MED1 Is a Lipogenesis Coactivator Required for Postnatal Adipose Tissue Expansion

Mediator is a multi-subunit transcription coactivator complex that controls gene activation by connecting enhancer-binding transcription factors (TFs) with RNA polymerase II (Pol II). The Med1 subunit of Mediator is required for PPARγ-stimulated conversion of mouse embryonic fibroblasts to adipocytes in culture. However, it has remained unclear whether MED1 is required for adipose tissue development in vivo. Using Med1 conditional knockout mice, here we report that MED1 is required for postnatal adipose tissue development/expansion, a process that involves dramatic induction of lipogenic enzymes such as SCD1. Mice with Myf5-Cre-mediated MED1 knockout in progenitor cells show normal embryonic development of brown adipose tissue (BAT) but become runts with reduced BAT and white adipose tissue (WAT) after birth. Furthermore, mice with Adipoq-Cre-mediated MED1 knockout in adipocytes show reduced accumulation of lipid droplets and impaired induction of SCD1 in BAT and WAT. These mice display severe lipodystrophy, cold intolerance, and insulin resistance. In culture, Med1 is dispensable for the induction of adipogenesis markers including PPARγ and C/EBPα in the early phase of preadipocyte differentiation. However, Med1 is required for SCD1 induction, lipogenesis and lipid accumulation in the late phase of adipogenesis. Our preliminary data suggest that MED1 controls the induction of SCD1 by facilitating the recruitment of Mediator and subsequently Pol II to active enhancers bound by the lipogenic TF ChREBP. Taken together, our ndings indicate that MED1 is a lipogenesis coactivator required for postnatal adipose tissue expansion.