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

Mol Endocrinol. 2002 Nov;16(11):2628-44. doi: 10.1210/me.2002-0036.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 3T3 Cells
  • Adipocytes / cytology
  • Adipocytes / drug effects
  • Adipocytes / physiology
  • 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
  • Receptors, Cytoplasmic and Nuclear / physiology
  • Rosiglitazone
  • Thiazoles / pharmacology
  • Thiazolidinediones*
  • Transcription Factors / antagonists & inhibitors*
  • Transcription Factors / deficiency
  • Transcription Factors / physiology


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