Distinct Properties and Advantages of a Novel Peroxisome Proliferator-Activated Protein γ Selective Modulator

Abstract

Antidiabetic thiazolidinediones (TZDs) and non-TZD compounds have been shown to serve as agonists of the peroxisome proliferator-activated receptor gamma (PPARgamma). Here, we report the identification and characterization of a novel non-TZD selective PPARgamma modulator (nTZDpa). nTZDpa bound potently to PPARgamma with high selectivity vs. PPARalpha or PPARdelta. In cell-based assays for transcriptional activation, nTZDpa served as a selective, potent PPARgamma partial agonist and was able to antagonize the activity of PPARgamma full agonists. nTZDpa also displayed partial agonist effects when its ability to promote adipogenesis in 3T3-L1 cells was evaluated. Assessment of protein conformation using protease protection or solution nuclear magnetic resonance spectroscopy methods showed that nTZDpa produced altered PPARgamma conformational stability vs. full agonists, thereby establishing a physical basis for its observed partial agonism. DNA microarray analysis of RNA from 3T3-L1 adipocytes treated with nTZDpa or several structurally diverse PPARgamma full agonists demonstrated qualitative differences in the affected gene expression profile for nTZDpa. Chronic treatment of fat-fed, C57BL/6J mice with nTZDpa or a TZD full agonist ameliorated hyperglycemia and hyperinsulinemia. However, unlike the TZD, nTZDpa caused reductions in weight gain and adipose depot size. Feed efficiency was also substantially diminished. Unlike TZDs, nTZDpa did not cause cardiac hypertrophy in mice. When a panel of PPARgamma target genes was examined in white adipose tissue, nTZDpa produced a different in vivo expression pattern vs. the full agonist. These findings establish that novel selective PPARgamma modulators can produce altered receptor conformational stability leading to distinctive gene expression profiles, reduced adipogenic cellular effects, and potentially improved in vivo biological responses. Such compounds may lead to preferred therapies for diabetes, obesity, or metabolic syndrome.

Telmisartan and Irbesartan Therapy in Type 2 Diabetic Patients Treated with Rosiglitazone: Effects on Insulin-Resistance, Leptin and Tumor Necrosis Factor-.ALPHA.

“…Telmisartan and irbesartan act as selective modulator of PPAR γ and selective gene regulation, which then triggers specific metabolic effects in vitro (37)(38)(39). Analysis of PPAR γ protein conformation using protease protection has shown that telmisartan and irbesartan directly interact with the receptor, producing a different conformational change than pioglitazone (8).…”

Fat poetry: a kingdom for PPARγ

“…SPPARgMs would separate the effects of PPARg on lipid and glucose metabolisms as well as on different organ systems (gastrointestinal, immune, cardiovascular). The selective action of such compounds is thought to depend on different structural configurations induced in the ligand-binding domain by their interaction with the receptor, allowing recruitment of different complexes of cofactors that impact on the activation or repression of specific sets of target genes in different tissues [146,218,[226][227][228][229][230][231].…”

The antiproliferative and proapoptotic effects of cladosporols A and B are related to their different binding mode as PPARγ ligands

“…[25][26][27]. More recently, identification and characterization of specific PPARc ligands known as SPPARMs (Selective PPARc Modulators), displaying beneficial antidiabetic action with no or reduced side-effects, are gaining interest [28][29][30].…”