PT  - JOURNAL ARTICLE
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
TI  - Novel Transcriptome Profiling Analyses Demonstrate that Selective Peroxisome Proliferator-Activated Receptor γ (PPARγ) Modulators Display Attenuated and Selective Gene Regulatory Activity in Comparison with PPARγ Full Agonists
AID  - 10.1124/mol.111.076679
DP  - 2012 Jul 01
TA  - Molecular Pharmacology
PG  - 68--79
VI  - 82
IP  - 1
4099  - http://molpharm.aspetjournals.org/content/82/1/68.short
4100  - http://molpharm.aspetjournals.org/content/82/1/68.full
SO  - Mol Pharmacol2012 Jul 01; 82
AB  - Selective peroxisome proliferator-activated receptor γ (PPARγ) modulators (SPPARγMs) have been actively pursued as the next generation of insulin-sensitizing antidiabetic drugs, because the currently marketed PPARγ full agonists, pioglitazone and rosiglitazone, have been reported to produce serious adverse effects among patients with type 2 diabetes mellitus. We conducted extensive transcriptome profiling studies to characterize and to contrast the activities of 70 SPPARγMs and seven PPARγ full agonists. In both 3T3-L1 adipocytes and adipose tissue from db/db mice, the SPPARγMs generated attenuated and selective gene-regulatory responses, in comparison with full agonists. More importantly, SPPARγMs regulated the expression of antidiabetic efficacy-associated genes to a greater extent than that of adverse effect-associated genes, whereas PPARγ full agonists regulated both gene sets proportionally. Such SPPARγM selectivity demonstrates that PPARγ ligand regulation of gene expression can be fine-tuned, and 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 versus full agonists. On the basis of our profiling results, we introduce two novel, gene expression-based scores, the γ activation index and the selectivity index, to aid in the detection and characterization of novel SPPARγMs. 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 among patients with type 2 diabetes, compared with presently available PPARγ agonist drugs.