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Molecular Endocrinology, doi:10.1210/me.2002-0036
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Molecular Endocrinology 16 (11): 2628-2644
Copyright © 2002 by The Endocrine Society

A New Selective Peroxisome Proliferator-Activated Receptor {gamma} Antagonist with Antiobesity and Antidiabetic Activity

Jennifer Rieusset1,2, Fethi Touri1, Liliane Michalik, Pascal Escher3, Béatrice Desvergne, Eric Niesor and Walter Wahli

Institut de biologie animale (J.R., L.M., P.E., B.D., W.W.), Université de Lausanne, CH-1015 Lausanne, Switzerland; and Ilex Oncology (F.T., E.N.), CH-1290 Versoix/Geneva, Switzerland

Address all correspondence and requests for reprints to: Pr. Walter Wahli, Institut de biologie animale, Université de Lausanne, Bâtiment de biologie, CH-1015 Lausanne, Switzerland. E-mail: Walter.Wahli{at}iba.unil.ch.

Peroxisome proliferator-activated receptor {gamma} (PPAR-{gamma}) plays a key role in adipocyte differentiation and insulin sensitivity. Its synthetic ligands, the thiazolidinediones (TZD), are used as insulin sensitizers in the treatment of type 2 diabetes. These compounds induce both adipocyte differentiation in cell culture models and promote weight gain in rodents and humans. Here, we report on the identification of a new synthetic PPAR{gamma} antagonist, the phosphonophosphate SR-202, which inhibits both TZD-stimulated recruitment of the coactivator steroid receptor coactivator-1 and TZD-induced transcriptional activity of the receptor. In cell culture, SR-202 efficiently antagonizes hormone- and TZD-induced adipocyte differentiation. In vivo, decreasing PPAR{gamma} activity, either by treatment with SR-202 or by invalidation of one allele of the PPAR{gamma} gene, leads to a reduction of both high fat diet-induced adipocyte hypertrophy and insulin resistance. These effects are accompanied by a smaller size of the adipocytes and a reduction of TNF{alpha} and leptin secretion. Treatment with SR-202 also dramatically improves insulin sensitivity in the diabetic ob/ob mice. Thus, although we cannot exclude that its actions involve additional signaling mechanisms, SR-202 represents a new selective PPAR{gamma} antagonist that is effective both in vitro and in vivo. Because it yields both antiobesity and antidiabetic effects, SR-202 may be a lead for new compounds to be used in the treatment of obesity and type 2 diabetes.

NURSA Molecule Pages Link:

Nuclear Receptors:   PPARα  |  PPARδ  |  PPARγ  |  FXRα
Coregulators:   SRC-1
Ligands:   Pirinixic acid  |  Rosiglitazone



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