Do peroxisome proliferation receptor-gamma antagonists have clinical potential as combined antiobesity and antidiabetic drugs?
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.
Doggrell
Sheila
S
School of Biomedical Sciences, The University of Queensland, QLD 4072, Australia. s_doggrell@yahoo.com
D000818:Animals; D019440:Anti-Obesity Agents / Q000737:chemistry / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000627:therapeutic use*; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000627:therapeutic use; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000502:physiology; D013844:Thiazoles / Q000737:chemistry / Q000627:therapeutic use; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000502:physiology
D019440:Anti-Obesity Agents; D007004:Hypoglycemic Agents; D009943:Organophosphorus Compounds; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; C089946:2,4-thiazolidinedione; C051602:mifobate