Novel Transcriptome Profiling Analyses Demonstrate that Selective PPAR γ Modulators Display Attenuated and Selective Gene Regulatory Activity in Comparison with PPAR γ Full Agonists

Selective PPAR γ modulators (SPPAR γ Ms) have been actively pursued as the next generation of insulin sensitizing anti-diabetic drugs since the currently marketed PPAR γ full agonists, pioglitazone (Actos) and rosiglitazone (Avandia), have been reported to produce serious adverse effects in type 2 diabetics. We conducted extensive transcriptome profiling studies to characterize and contrast the activities of 70 SPPAR γ Ms and 7 PPAR γ full agonists. In both 3T3-L1 adipocytes and adipose tissue of db / db mice, the SPPAR γ Ms generated attenuated and selective gene regulatory responses in comparison with full agonists. More importantly, SPPAR γ Ms regulated the expression of anti-diabetic efficacy-associated genes to a greater extent than that of adverse effect-associated genes, while PPAR γ full agonists regulated both gene sets proportionally. Such SPPAR γ M selectivity demonstrates that PPAR γ ligand regulation of gene expression can be fine-tuned, not just turned on and off, to achieve precise control of complex cellular and physiological functions. It also provides a potential molecular basis for the superior therapeutic window previously observed with SPPAR γ Ms vs. full agonists. On the basis of our profiling results, we introduce two novel gene expression based scores, the Gamma Activation Index (GAI) and the Selectivity Index (SI), to aid in the detection and characterization of novel SPPAR γ Ms. In sum, these studies provide new insights into the gene regulatory activity of SPPAR γ Ms as well as novel quantitative indices to facilitate the identification of PPAR γ ligands with robust insulin sensitizing activity and improved tolerance in type 2 diabetes patients compared with presently available PPAR γ agonist drugs.