Differential activation of adipogenesis by multiple PPAR isoforms

Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear hormone receptor expressed predominantly in adipose tissue, where it plays a central role in the control of adipocyte gene expression and differentiation. Because there are two additional PPAR isoforms, PPAR alpha and PPAR delta, and these are also expressed at some level in certain adipose depots, we have compared directly the adipogenic potential of all three receptors. Ectopically expressed PPAR gamma powerfully induces adipogenesis at a morphological and molecular level in response to a number of PPAR gamma activators. PPAR alpha is less adipogenic but is able to induce significant differentiation in response to strong PPAR alpha activators. Expression and activation of PPAR delta did 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 activity of the PPAR isoforms, we have examined their ability to bind to several PPAR DNA response sequences. Compared with PPAR alpha and PPAR delta, PPAR gamma shows preferential binding to two well-characterized regulatory sequences derived from a fat-specific gene, ARE6 and ARE7. These data strongly suggest that PPAR gamma is the predominant receptor regulating adipogenesis; however, they also suggest that PPAR alpha may play a role in differentiation of certain adipose depots in response to a different set of physiologic activators or in certain disease states.