PPARγ and the control of adipogenesis

Abstract We recently cloned PPARγ as a factor that binds to an enhancer which has specificity for adipose cells. When expressed ectopically, PPARγ converts fibroblasts into bona fide preadipose cells. Upon application of activators or PPARγ ligands, these cells differentiate into fat cells. Most recently, we have been trying to understand the nature of natural ligands that activate PPARγ and the protein domains that control adipogenesis. With regards to ligands, we have shown that an unusual prostanoid, 15-deoxy Δ 12,14 PG 12, can bind to PPARγ and activate it. A second transcription factor that is induced early in differentiation, ADD1/SREBP1, appears to promote the formation of PPARγ ligands. Transfection of this molecule, a member of the bHLH family, causes the secretion of molecules that can serve as ligands for PPARγ. This ligand-like activity is specific for the γ isoform of PPAR. Current studies are attempting to identify these potentially novel ligands. With regard to structure-function of PPARγ, we first analyzed the adipogenic activity of the three isoforms of PPAR: α, γ and δ. Using appropriate activators of each it is clear that PPARγ has the most adipogenic action. PPARα can be adipogenic with high levels of the strongest activators and PPARδ does not stimulate fat cell differentiation. To identify the domain(s) of PPARγ responsible for differentiation, chimeras between PPARγ and PPARδ were created and transfected into fibroblasts. This has allowed the isolation of relatively small regions of this molecule that are responsible for differentiation.