Identification, Characterization, and Tissue Distribution of Human Peroxisome Proliferator-activated Receptor (PPAR) Isoforms PPARγ2 versus PPARγ1 and Activation with Retinoid X Receptor Agonists and Antagonists

Abstract We describe the cloning, characterization, and tissue distribution of the two human peroxisome proliferator activated receptor isoforms hPPARγ2 and hPPARγ1. In cotransfection assays the two isoforms were activated to approximately the same extent by known PPARγ activators. Human PPARγ binds to DNA as a heterodimer with the retinoid X receptor (RXR). This heterodimer was activated by both RXR agonists and antagonists and the addition of PPARγ ligands with retinoids resulted in greater than additive activation. Such heterodimer-selective modulators may have a role in the treatment of PPARγ/RXR-modulated diseases like diabetes. Northern blot analysis indicated the presence of PPARγ in skeletal muscle, and a sensitive RNase protection assay confirmed the presence of only PPARγ1 in muscle that was not solely due to fat contamination. However, both PPARγ1 and PPARγ2 RNA were detected in fat, and the ratio of PPARγ1 to PPARγ2 RNA varied in different individuals. The presence of tissue-specific distribution of isoforms and the variable ratio of PPARγ1 to PPARγ2 raised the possibility that isoform expression may be modulated in disease states like non-insulin-dependent diabetes mellitus. Interestingly, a third protected band was detected with fat RNA indicating the possible existence of a third human PPARγ isoform.