Regulation of white and brown adipocyte differentiation by RhoGAP DLC1

Adipose tissues constitute an important component of metabolism, the dysfunction of which can cause obesity and type II diabetes. Here we show that differentiation of white and brown adipocytes requires Deleted in Liver Cancer 1 (DLC1), a Rho GTPase Activating Protein (RhoGAP) previously studied for its function in liver cancer. We identified DIcl as a super enhancer associated gene in both white and brown adipocytes through analyzing the genome-wide binding profiles of PPAR gamma, the master regulator of adipogenesis. We further observed that DIcl expression increases during differentiation, and knockdown of DIcl by siRNA in white adipocytes reduces the formation of lipid droplets and the expression of fat marker genes. Moreover, knockdown of DIcl in brown adipocytes reduces expression of brown fat-specific genes and diminishes mitochondrial respiration. DIc1(-/-)knockout mouse embryonic fibroblasts show a complete inability to differentiate into adipocytes, but this phenotype can be rescued by inhibitors of Rho-associated kinase (ROCK) and filamentous actin (F-actin), suggesting the involvement of Rho pathway in DLC1-regulated adipocyte differentiation. Furthermore, PPAR gamma binds to the promoter of DIcl gene to regulate its expression during both white and brown adipocyte differentiation. These results identify DLC1 as an activator of white and brown adipocyte differentiation, and provide a molecular link between PPAR gamma and Rho pathways.