Objective— Drugs that activate peroxisome proliferator–activated receptor (PPAR) γ improve glucose sensitivity and lower blood pressure, whereas dominant-negative mutations in PPARγ cause severe insulin resistance and hypertension. We hypothesize that these PPARγ mutants regulate target genes opposite to those of ligand-mediated activation, and we tested this hypothesis on a genomewide scale.

Methods and Results— We integrated gene expression data in aorta specimens from mice treated with the PPARγ ligand rosiglitazone with data from mice containing a globally expressed knockin of the PPARγ P465L dominant-negative mutation. We also integrated our data with publicly available data sets containing the following: (1) gene expression profiles in many human tissues, (2) PPARγ target genes in 3T3-L1 adipocytes, and (3) experimentally validated PPARγ binding sites throughout the genome. Many classic PPARγ target genes were induced by rosiglitazone and repressed by dominant-negative PPARγ. A similar pattern was observed for about 90% of the gene sets regulated by both rosiglitazone and dominant-negative PPARγ. Genes exhibiting this pattern of contrasting regulation were significantly enriched for nearby PPARγ binding sites.

Conclusion— These results provide convincing evidence that the PPARγ P465L mutation causes transcriptional effects that are opposite to those mediated by PPARγ ligand, thus validating mice carrying the mutation as a model of PPARγ interference.