Abstract
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.
Footnotes
↵ The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.
All authors are current or former full-time employees of Merck and Co., Inc. Y.T., J.R.T. and J.P.B. are co-senior authors.
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
ABBREVIATIONS:
- PPAR
- peroxisome proliferator-activated receptor
- EWAT
- epididymal white adipose tissue
- FABP4
- fatty acid binding protein 4
- GAI
- γ activation index
- LBD
- ligand binding domain
- LXR
- liver X receptor
- T2D
- type 2 diabetes
- nTZDpa
- nonthiazolidinedione peroxisome proliferator-activated receptor γ partial agonist
- SD
- Sprague-Dawley
- SI
- selectivity index
- SPPARγM
- selective peroxisome proliferator-activated receptor γ modulator
- TA
- transactivation
- TZD
- thiazolidinedione
- MK-0533
- (2R)-2-(3-{3-[(4-methoxyphenyl)carbonyl]-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl}phenoxy)butanoic acid
- S26948
- dimethyl-2-{4-[2-(6-benzoyl-2-oxo-1,3-benzothiazol-3(2H)yl)ethoxy]benzyl}malonate
- PAR-1622
- (S)-2-ethoxy-3-[4-(5-[4-[5-(methoxymethylisoxazol-3-yl)phenyl]-3-methylthiophen-2-yl]methoxy)phenyl]propanoic acid.
- Received November 2, 2011.
- Accepted April 10, 2012.
- Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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