title: 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.
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.
authors.affiliation: Department of Informatics and Analysis, Merck Research Laboratories, Rahway, New Jersey 07065, USA.
authors.forename: Yejun
authors.initials: Y
authors.lastname: Tan
authors.forename: Eric S
authors.initials: ES
authors.lastname: Muise
authors.forename: Hongyue
authors.initials: H
authors.lastname: Dai
authors.forename: Richard
authors.initials: R
authors.lastname: Raubertas
authors.forename: Kenny K
authors.initials: KK
authors.lastname: Wong
authors.forename: G Marie
authors.initials: GM
authors.lastname: Thompson
authors.forename: Harold B
authors.initials: HB
authors.lastname: Wood
authors.forename: Peter T
authors.initials: PT
authors.lastname: Meinke
authors.forename: Pek Yee
authors.initials: PY
authors.lastname: Lum
authors.forename: John R
authors.initials: JR
authors.lastname: Thompson
authors.forename: Joel P
authors.initials: JP
authors.lastname: Berger
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007333:Insulin Resistance / Q000235:genetics; D008024:Ligands; D008297:Male; D053858:Metabolic Networks and Pathways / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics*
chemical_list: D007004:Hypoglycemic Agents; D008024:Ligands; D047495:PPAR gamma