Differential activation of adipogenesis by multiple PPAR isoforms

Abstract

Peroxisome proliferator-activated receptor γ (PPARγ) 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, PPARα and PPARδ, 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 PPARγ powerfully induces adipogenesis at a morphological and molecular level in response to a number of PPARγ activators. PPARα is less adipogenic but is able to induce significant differentiation in response to strong PPARα activators. Expression and activation of PPARδ did not stimulate adipogenesis. Of the three PPARs, only PPARγ can cooperate with C/EBPα 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 PPARα and PPARδ, PPARγ shows preferential binding to two well-characterized regulatory sequences derived from a fat-specific gene, ARE6 and ARE7. These data strongly suggest that PPARγ is the predominant receptor regulating adipogenesis; however, they also suggest that PPARα may play a role in differentiation of certain adipose depots in response to a different set of physiologic activators or in certain disease states.