An adipogenic cofactor bound by the differentiation domain of PPAR gamma

Ligand activation of the nuclear receptor PPAR gamma induces adipogenesis a nd increases insulin sensitivity, while activation of other PPAR isoforms ( -alpha and -delta) induces little or no fat cell differentiation. Expressio n and activation of chimeras formed between PPAR gamma and PPAR delta in fi broblasts has allowed us to localize a major domain of PPAR gamma responsib le for adipogenesis to the N-terminal 138 amino acids, a region with AF-1 t ranscriptional activity. Using this region of PPAR gamma as bait, we have u sed a yeast two-hybrid screen to clone a novel protein, termed PGC-2, conta ining a partial SCAN domain. PGC-2 binds to and increases the transcription al activity of PPAR gamma but does not interact with other PPARs or most ot her nuclear receptors. Ectopic expression of PGC-2 in preadipocytes contain ing endogenous PPAR gamma causes a dramatic increase in fat cell differenti ation at both the morphological and molecular levels. These results suggest that interactions between PGC-2, a receptor isoform-selective cofactor and PPAR gamma contribute to the adipogenic action of this receptor.