DIFFERENTIAL ACTIVATION OF ADIPOGENESIS BY MULTIPLE PPAR ISOFORMS

Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuc lear hormone receptor expressed predominantly in adipose tissue, where it plays a central role in the control of adipocyte gene expression a nd differentiation. Because there are two additional PPAR isoforms, PP AR alpha and PPAR delta, and these are also expressed at some level in certain adipose depots, we have compared directly the adipogenic pote ntial of all three receptors. Ectopically expressed PPAR gamma powerfu lly induces adipogenesis at a morphological and molecular level in res ponse to a number of PPAR gamma activators. PPAR alpha is less adipoge nic but is able to induce significant differentiation in response to s trong PPAR alpha activators. Expression and activation of PPAR delta d id not stimulate adipogenesis. Of the three PPARs, only PPAR gamma can cooperate with C/EBP alpha in the promotion of adipogenesis. To begin to investigate the functional basis for the differential adipogenic a ctivity of the PPAR isoforms, we have examined their ability to bind t o several PPAR DNA response sequences. Compared with PPAR alpha and PP AR delta, PPAR gamma shows preferential binding to two well-characteri zed regulatory sequences derived from a fat-specific gene, ARE6 and AR E7. These data strongly suggest that PPAR gamma is the predominant rec eptor regulating adipogenesis; however, they also suggest that PPAR al pha may play a role in differentiation of certain adipose depots in re sponse to a different set of physiologic activators or in certain dise ase states.