Peroxisome proliferator-activated receptor-g (PPARg) is a nuclear receptor that plays a pivotal role in adipocyte differentiation and insulin sensitivity.The biological ligand which activates PPARg to modulate adipocyte differentiation so far has been elusive.Here we report a newly identified ligand of PPARg,15-keto-prostaglandin E2 (15-keto-PGE2).Addition of 15-keto-PGE2to cultured 3T3-L1 cells not only results in an increase of PPARg-mediated transcription but also enhances adipogenesis remarkably.In this study,we found that 15-keto-PGE2 can serve as a substrate of 15-oxoprostaglandin-Δ3-reductase (PGR-2) which was newly identified by differential display of gene expression during 3T3-L1 adipocyte differentiation.Constitutive expression of PGR-2 in cells down-regulates 15-keto-PGE2-mediated activation of PPARg-dependent transcription and prohibits adipocyte differentiation.These results illuminate the importance of PGE2 metabolism in regulation of PPARg activation.