PPAR-GAMMA AND THE CONTROL OF ADIPOGENESIS

We recently cloned PPAR gamma as a factor that binds to an enhancer wh ich has specificity for adipose cells. When expressed ectopically, PPA R gamma converts fibroblasts into bona fide preadipose cells. Upon app lication of activators or PPAR gamma ligands, these cells differentiat e into fat cells. Most recently, we have been trying to understand the nature of natural ligands that activate PPAR gamma and the protein do mains that control adipogenesis. With regards to ligands, we have show n that an unusual prostanoid, 15-deoxy Delta(12,14)PG J2, can bind to PPAR gamma and activate it. A second transcription factor that is indu ced early in differentiation, ADD1/SREBP1, appears to promote the form ation of PPAR gamma ligands. Transfection of this molecule, a member o f the bHLH family, causes the secretion of molecules that can serve as ligands for PPAR gamma. This ligand-like activity is specific for the gamma isoform of PPAR. Current studies are attempting to identify the se potentially novel ligands. With regard to structure-function of PPA R gamma, we first analyzed the adipogenic activity of the three isofor ms of PPAR: alpha, gamma and delta. Using appropriate activators of ea ch it is clear that PPAR gamma has the most adipogenic action. PPAR al pha can be adipogenic with high levels of the strongest activators and PPAR delta does not stimulate fat cell differentiation. To identify t he domain(s) of PPAR gamma responsible for differentiation, chimeras b etween PPAR gamma and PPAR delta were created and transfected into fib roblasts. This has allowed the isolation of relatively small regions o f this molecule that are responsible for differentiation.