A new selective peroxisome proliferator-activated receptor gamma antagonist with antiobesity and antidiabetic activity.

Details

Serval ID
serval:BIB_97AFF84382BD
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
A new selective peroxisome proliferator-activated receptor gamma antagonist with antiobesity and antidiabetic activity.
Journal
Molecular Endocrinology
Author(s)
Rieusset J., Touri F., Michalik L., Escher P., Desvergne B., Niesor E., Wahli W.
ISSN
0888-8809[print], 0888-8809[linking]
Publication state
Published
Issued date
2002
Volume
16
Number
11
Pages
2628-2644
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. Publication Status: ppublish
Abstract
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 PPARgamma 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 PPARgamma activity, either by treatment with SR-202 or by invalidation of one allele of the PPARgamma 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 TNFalpha 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 PPARgamma 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.
Keywords
3T3 Cells, Adipocytes/cytology, Adipocytes/drug effects, Adipose Tissue/drug effects, Adipose Tissue/physiology, Adipose Tissue, Brown/drug effects, Adipose Tissue, Brown/physiology, Aged, Animals, Anti-Obesity Agents/pharmacology, Cell Differentiation/drug effects, Epididymis, Hela Cells, Humans, Hypoglycemic Agents/pharmacology, Insulin/pharmacology, Insulin Resistance/genetics, Male, Mice, Mice, Knockout, Molecular Structure, Organophosphorus Compounds/pharmacology, Receptors, Cytoplasmic and Nuclear/antagonists & inhibitors, Receptors, Cytoplasmic and Nuclear/deficiency, Thiazoles/pharmacology, Thiazolidinediones, Transcription Factors/antagonists & inhibitors, Transcription Factors/deficiency
Pubmed
Web of science
Open Access
Yes
Create date
24/01/2008 15:27
Last modification date
20/08/2019 14:59
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