TY - JOUR T1 - Novel Transcriptome Profiling Analyses Demonstrate that Selective PPARγ Modulators Display Attenuated and Selective Gene Regulatory Activity in Comparison with PPARγ Full Agonists JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.111.076679 SP - mol.111.076679 AU - Yejun Tan AU - Eric S. Muise AU - Hongyue Dai AU - Richard Raubertas AU - Kenny K. Wong AU - G Marie Thompson AU - Harold B. Wood AU - Peter T. Meinke AU - Pek Yee Lum AU - John R. Thompson AU - Joel P. Berger Y1 - 2012/01/01 UR - http://molpharm.aspetjournals.org/content/early/2012/04/11/mol.111.076679.abstract N2 - Selective PPARγ modulators (SPPARγMs) have been actively pursued as the next generation of insulin sensitizing anti-diabetic drugs since the currently marketed PPARγ 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 SPPARγMs and 7 PPARγ full agonists. In both 3T3-L1 adipocytes and adipose tissue of db/db mice, the SPPARγMs generated attenuated and selective gene regulatory responses in comparison with full agonists. More importantly, SPPARγMs regulated the expression of anti-diabetic efficacy-associated genes to a greater extent than that of adverse effect-associated genes, while PPARγ full agonists regulated both gene sets proportionally. Such SPPARγM selectivity demonstrates that PPARγ 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 SPPARγMs 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 SPPARγMs. In sum, these studies provide new insights into the gene regulatory activity of SPPARγMs as well as novel quantitative indices to facilitate the identification of PPARγ ligands with robust insulin sensitizing activity and improved tolerance in type 2 diabetes patients compared with presently available PPARγ drugs. ER -