A Synthetic Antagonist for the Peroxisome Proliferator-activated Receptor γ Inhibits Adipocyte Differentiation

Abstract

While searching for natural ligands for the peroxisome proliferator-activated receptor (PPAR) ␥, we identified a synthetic compound that binds to this receptor. Bisphenol A diglycidyl ether (BADGE) is a ligand for PPAR␥ with a K d(app) of 100 M. This compound has no apparent ability to activate the transcriptional activity of PPAR␥; however, BADGE can antagonize the ability of agonist ligands such as rosiglitazone to activate the transcriptional and adipogenic action of this receptor. BADGE also specifically blocks the ability of natural adipogenic cell lines such as 3T3-L1 and 3T3-F442A cells to undergo hormone-mediated cell differentiation. These results provide the first pharmacological evidence that PPAR␥ activity is required for the hormonally induced differentiation of adipogenic cells. Peroxisome proliferator-activated receptor (PPAR)1 ␥ is a nuclear hormone receptor that is expressed at highest levels in adipose tissue and lower levels in several other tissues. PPAR␥ is a major coordinator of adipocyte gene expression and differentiation (1). The expression of this receptor occurs early during the differentiation of preadipocytes, and it is expressed in a highly adipose-selective manner.PPAR␥ has been considered an orphan member of the nuclear hormone receptor superfamily, because no high affinity endogenous ligand has been identified for this receptor. However, a number of synthetic compounds have been shown to bind and activate PPAR␥ including a relatively new class of antidiabetic drugs, the thiazolidinediones (2). Thiazolidinediones (TZD) can ameliorate glucose metabolism and improve whole body insulin sensitivity in many animal models of obesity and diabetes. One TZD, troglitazone (Rezulin TM ), is currently used in the treatment of Type II diabetes in humans, and a second, rosiglitazone (Avandia TM ), was recently approved by the United States Food and Drug Administration. In addition to synthetic ligands, a number of natural ligands have been described for PPAR␥ that include primarily fatty acids and their metabolites (3-5). These ligands, however, have relatively low affinities with K d Ϸ 2-50 M, and hence it is possible that, analogous to other nuclear hormone receptors, a higher affinity ligand for PPAR␥ might exist.The evidence supporting a key role for PPAR␥ in adipogenesis is strong, but it is entirely based on "gain of function" experiments. For example, it has been shown that the ectopic expression and activation of PPAR␥ in undetermined fibroblasts are sufficient to induce an adipogenic response that includes morphological changes, lipid accumulation, and expression of most of the genes characteristic of this cell type (6). However, until now no experiments have addressed whether PPAR␥ function is required for adipocyte differentiation. During a screen for endogenous ligands of PPAR␥ we purified and characterized a compound that exhibited PPAR␥ binding activity. High pressure liquid and gas chromatography/mass spectrometry (LC/MS/MS and GC/MS, respectively)-based analyses identified this ...

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