Do peroxisome proliferation receptor-gamma antagonists have clinical potential as combined antiobesity and antidiabetic drugs?

Abstract

There is genetic evidence that reducing the activity of peroxisome proliferation receptor-gamma (PPAR-gamma) may increase insulin sensitivity. SR-202 is a selective antagonist at PPAR-gamma, which inhibits the adipocyte differentiation normally seen with the PPAR-gamma agonist rosiglitazone. SR-202 also reduces the ability of young mice to put on weight and accumulate fat. The levels of circulating TNF-alpha correlates with body fat stores and/or hyperinsulinaemia. SR-202- treated wild-type mice have reduced TNF-alpha levels. When wild-type mice are fed a high-fat diet, the plasma levels of TNF-alpha are raised, and SR-202 treatment protects against this rise. Feeding mice with a high-fat diet induced insulin resistance measured as increased plasma levels of glucose, insulin and free fatty acids, and SR-202 protected against these changes. The ob/ob mouse is diabetic at 8 weeks and plasma glucose and insulin levels continue to rise over the next 3 weeks, and treatment with SR-202 prevents these increases. The development of PPAR-gamma antagonists should continue as the results to date suggest that they have clinical potential for the treatment of diabetes Type 2 and obesity.

• Authors: Sheila Doggrell
• Journal: Expert opinion on investigational drugs (Expert Opin Investig Drugs) Vol. 12 Issue 4 Pg. 713-6 (Apr 2003) ISSN: 1354-3784 [Print] England
• PMID: 12665425 (Publication Type: Journal Article, Review)

Chemical References

• Anti-Obesity Agents
• Hypoglycemic Agents
• Organophosphorus Compounds
• Receptors, Cytoplasmic and Nuclear
• Thiazoles
• Thiazolidinediones
• Transcription Factors
• 2,4-thiazolidinedione
• mifobate

Topics

• Animals
• Anti-Obesity Agents (chemistry, therapeutic use)
• Drug Therapy, Combination
• Humans
• Hypoglycemic Agents (chemistry, therapeutic use)
• Organophosphorus Compounds (chemistry, therapeutic use)
• Receptors, Cytoplasmic and Nuclear (antagonists & inhibitors, physiology)
• Thiazoles (chemistry, therapeutic use)
• Thiazolidinediones
• Transcription Factors (antagonists & inhibitors, physiology)