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

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.

• Authors: Jennifer Rieusset, Fethi Touri, Liliane Michalik, Pascal Escher, Béatrice Desvergne, Eric Niesor, Walter Wahli
• Journal: Molecular endocrinology (Baltimore, Md.) (Mol Endocrinol) Vol. 16 Issue 11 Pg. 2628-44 (Nov 2002) ISSN: 0888-8809 [Print] United States
• PMID: 12403851 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Anti-Obesity Agents
• Hypoglycemic Agents
• Insulin
• Organophosphorus Compounds
• Receptors, Cytoplasmic and Nuclear
• Thiazoles
• Thiazolidinediones
• Transcription Factors
• Rosiglitazone
• mifobate

Topics

• 3T3 Cells
• Adipocytes (cytology, drug effects, physiology)
• Adipose Tissue (drug effects, physiology)
• Adipose Tissue, Brown (drug effects, 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, deficiency, physiology)
• Rosiglitazone
• Thiazoles (pharmacology)
• Thiazolidinediones
• Transcription Factors (antagonists & inhibitors, deficiency, physiology)