Prostaglandin reductase-3 negatively modulates adipogenesis through regulation of PPARγ activity

Adipocyte differentiation is a multistep program under regulation by several factors. Peroxisome proliferator-activated receptor gamma (PPAR gamma) serves as a master regulator of adipogenesis. However, the endogenous ligand for PPAR gamma remained elusive until 15-keto-PGE(2) was identified recently as an endogenous PPAR gamma ligand. In this study, we demonstrate that zinc-containing alcohol dehydrogenase 2 (ZADH2; here termed prostaglandin reductase-3, PTGR-3) is a new member of prostaglandin reductase family that converts 15-keto-PGE(2) to 13,14-dihydro-15-keto-PGE(2). Adipogenesis is accelerated when endogenous PTGR-3 is silenced in 3T3-L1 preadipocytes, whereas forced expression of PTGR-3 significantly decreases adipogenesis. PTGR-3 expression decreased during adipocyte differentiation, accompanied by an increased level of 15-keto-PGE(2). 15-keto-PGE(2) exerts a potent proadipogenic effect by enhancing PPAR gamma activity, whereas overexpression of PTGR-3 in 3T3-L1 preadipocytes markedly suppressed the proadipogenic effect of 15-keto-PGE(2) by repressing PPAR gamma activity. Taken together, these findings demonstrate for the first time that PTGR-3 is a novel 15-oxoprostaglandin-Delta(13)-reductase and plays a critical role in modulation of normal adipocyte differentiation via regulation of PPAR gamma activity.jlr Thus, modulation of PTGR-3 might provide a novel avenue for treating obesity and related metabolic disorders.