Abstract 1098: Rad51 Plays a Pivotal Role in Adipocyte Hyperplasia and Adipose Tissue Inflammation
Metabolic syndrome is an important risk factor of coronary artery disease (CAD). Adipose tissue is thought to play a central role in metabolic syndrome by producing various adipokines and controlling systemic energy metabolism. Therefore, identification of key regulators of adipocyte differentiation and function is important to understand pathogenesis of metabolic syndrome and CAD. We developed a high-throughput, functional imaging-based screening strategy to identify genes involved in adipocyte differentiation and function. Using this strategy, we found that Rad51, a key molecule of homologous-recombination and DNA-repair, is required for adipocyte differentiation. Knocking down Rad51 resulted in suppression of adipocyte differentiation of 3T3-L1 preadipocytes by inhibiting the cell cycle progression during differentiation, known as mitotic clonal expansion. We analyzed Rad51-dependent molecular steps of adipogenesis and found that the transcription factor E2F4 inhibited Rad51 expression in preadipocytes. Upon hormonal stimulation, E2F4 binding to the Rad51 promoter was decreased, activating Rad51 transcription. Subsequently, Rad51 promoted G2/M transition and differentiation. Interestingly, Rad51 expression was increased in white adipose tissues (WAT) in obese mice. High fat diet-induced adipocyte hyperplasia was much reduced in WAT in Rad51+/− mice as compared with wild-type. Moreover, laser confocal microscopy showed that the obesity-induced adipose inflammation was much suppressed in Rad51+/−. Consequently, Rad51+/− were protected from high fat diet-induced systemic insulin resistance. These results clearly demonstrate that Rad51 is a key molecule that controls diet-induced adipose hyperplasia and inflammation.