Identification, characterization, and tissue distribution of human peroxisome proliferator-activated receptor (PPAR) isoforms PPAR gamma 2 versus PPAR gamma 1 and activation with retinoid X receptor agonists and antagonists

We describe the cloning, characterization, and tissue distribution of the two human peroxisome proliferator activated receptor isoforms hPPAR gamma 2 and hPPAR gamma 1. In cotransfection assays the two isoforms were activated to approximately the same extent by known PPAR gamma activators. Human PPAR gamma 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 PPAR gamma ligands with retinoids resulted in greater than additive activation. Such heterodimer-selective modulators may have a role in the treatment of PPAR gamma /RXR-modulated diseases like diabetes. Northern blot analysis indicated the presence of PPAR gamma in skeletal muscle, and a sensitive RNase protection assay confirmed the presence of only PPAR gamma 1 in muscle that was not solely due to fat contamination. However, both PPAR gamma 1 and PPAR gamma 2 RNA were detected in fat, and the ratio of PPAR gamma 1 to PPAR gamma 2 RNA varied in different individuals. The presence of tissue-specific distribution of isoforms and the variable ratio of PPAR gamma 1 to PPAR gamma 2 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 PPAR gamma isoform.