Xanthine oxidoreductase is a regulator of adipogenesis and PPARγ activity

In an effort to identify novel candidate regulators of adipogenesis, gene profiling of differentiating 3T3-L1 preadipocytes was analyzed using a novel algorithm. We report here the characterization of xanthine oxidoreductase (XOR) as a novel regulator of adipogenesis. XOR lies downstream of C/EBP beta and upstream of PPAR gamma, in the cascade of factors that control adipogenesis, and it regulates PPAR gamma activity. In vitro, knockdown of XOR inhibits adipogenesis and PPAR gamma activity while constitutive overexpression increases activity of the PPAR gamma receptor in both adipocytes and preadipocytes. In vivo, XOR -/- mice demonstrate 50% reduction in adipose mass versus wild-type littermates while obese ob/ob mice exhibit increased concentrations of XOR mRNA and urate in the adipose tissue. We propose that XOR is a novel regulator of adipogenesis and of PPAR gamma activity and essential for the regulation of fat accretion. Our results identify XOR as a potential therapeutic target for metabolic abnormalities beyond hyperuricemia.