title: 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.affiliation: Institut de biologie animale, Université de Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Rieusset
authors.forename: Fethi
authors.initials: F
authors.lastname: Touri
authors.forename: Liliane
authors.initials: L
authors.lastname: Michalik
authors.forename: Pascal
authors.initials: P
authors.lastname: Escher
authors.forename: Béatrice
authors.initials: B
authors.lastname: Desvergne
authors.forename: Eric
authors.initials: E
authors.lastname: Niesor
authors.forename: Walter
authors.initials: W
authors.lastname: Wahli
mesh_terms: D016475:3T3 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D000273:Adipose Tissue / Q000187:drug effects / Q000502:physiology*; D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000502:physiology; D000368:Aged; D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D004822:Epididymis; D006367:HeLa Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015394:Molecular Structure; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000502:physiology; D000077154:Rosiglitazone; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000502:physiology
chemical_list: D019440:Anti-Obesity Agents; D007004:Hypoglycemic Agents; D007328:Insulin; D009943:Organophosphorus Compounds; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone; C051602:mifobate