Abstract 16425: Rad51 Is A Novel Key Molecule of Adipose Tissue Inflammation In Obesity
Adipose tissue plays a central role in metabolic syndrome, by producing various adipokines and controlling systemic energy metabolism. Recent studies indicated that active inflammation takes place in obese adipose tissue, which affects not only adipose function but also systemic insulin sensitivity. We developed a high-throughput, functional imaging-based screening strategy to identify new regulators involved in adipocyte differentiation and function. Using this strategy, we found that Rad51, a key molecule of homologous-recombination and DNA-repair, was required for adipocyte differentiation. Rad51 knockdown suppressed adipocyte differentiation in 3T3-L1 preadipocytes by inhibiting the differentiation-associated cell cycle progression (“mitotic clonal expansion”). We identified the novel insulin/E2F4/Rad51 pathway, in which transcription factor E2F4 inhibits Rad51 expression in preadipocytes and insulin eliminate E2F4 from the Rad51 promoter. In obese mice, Rad51 expression was increased in white adipose tissues (WAT). Lin-/CD29+/CD34+/Sca1+ adipocyte progenitors isolated from Rad51+/− mice exhibited a lower propensity to differentiate into adipocytes. Moreover, proliferation of the progenitor cells was also reduced in Rad51+/−. Indeed, high-fat diet-induced adipocyte hyperplasia was reduced in Rad51+/− as compared with wild-type. Interestingly, Rad51+/− mice also showed reduced macrophage infiltration into epididymal WAT and were protected from high fat diet-induced systemic insulin resistance. These results demonstrate that Rad51 is a novel key molecule that controls diet-induced adipocyte hyperplasia as well as adipose inflammation.
- © 2010 by American Heart Association, Inc.