rivoglitazone and Disease-Models--Animal

Accumulating evidence indicates that the regimen to increase adiponectin will provide a novel therapeutic strategy for metabolic syndrome. Here, we tested the effect of a potent and selective peroxisome proliferator-activated receptor-γ agonist, rivoglitazone (Rivo), a newly synthesized thiazolidinedione derivative, on adiponectin, insulin resistance, and atherosclerosis.. ob/ob mice, apolipoprotein E knockout (apoE KO) mice, and apoE and adiponectin double knockout mice were administered pioglitazone, Rivo, or no compound. Remarkable elevation of plasma adiponectin was observed, especially in Rivo-treated ob/ob mice. Rivo ameliorated insulin resistance in ob/ob mice and reduced atherosclerotic areas in apoE KO mice compared with the pioglitazone group but failed to decrease atherosclerotic areas in double knockout mice. Among adipose mRNAs, adipose S100A8, which activates Toll-like receptor 4-dependent signal transduction cascades and locates upstream of inflammation, was markedly increased in ob/ob mice, and its increase was completely reversed by Rivo treatment. In RAW264.7 macrophage cells and 3T3-L1 adipocytes, Rivo significantly reduced S100A8 mRNA levels.. The peroxisome proliferator-activated receptor-γ agonist Rivo remarkably enhanced adiponectin in plasma and decreased adipose S100A8 mRNA levels in obese mice. Rivo treatment apparently ameliorated insulin resistance in ob/ob mice and reduced atherosclerosis in apoE KO mice, partly through adiponectin.

Topics: 3T3-L1 Cells; Adipocytes; Adiponectin; Adipose Tissue, White; Animals; Apolipoproteins E; Atherosclerosis; Blood Glucose; Calgranulin A; Cytokines; Disease Models, Animal; Gene Expression Regulation; Hyperglycemia; Hypoglycemic Agents; Inflammation Mediators; Insulin Resistance; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Obesity; Pioglitazone; PPAR gamma; Reactive Oxygen Species; Thiazolidinediones; Time Factors

The pharmacological effects of rivoglitazone, a novel thiazolidinedione-derivative peroxisome proliferator-activated receptor (PPAR)-gamma agonist, were characterized in vitro and in vivo. Rivoglitazone activated human PPARgamma more potently compared with rosiglitazone and pioglitazone and had little effect on PPARalpha and PPARdelta activity in luciferase reporter assays. In Zucker diabetic fatty (ZDF) rats, 14-day administration of rivoglitazone decreased the plasma glucose and triglyceride (TG) levels in a dose-dependent manner. The glucose-lowering effect of rivoglitazone was much more potent than those of pioglitazone (ED(50): 0.19 vs. 34 mg/kg) and rosiglitazone (ED(50): 0.20 vs. 28 mg/kg). In addition, rivoglitazone showed potent antidiabetic effects in diabetic db/db mice. In Zucker fatty rats, rivoglitazone at a dose of 0.1 mg/kg clearly ameliorated insulin resistance and lowered plasma TG levels by accelerating the clearance of plasma TG. Gene expression analysis in the liver and heart of ZDF rats treated with rivoglitazone for 14 days suggested that rivoglitazone may reduce hepatic glucose production and modulate the balance of the cardiac glucose/fatty acid metabolism in diabetic animals. In summary, we showed that rivoglitazone is a potent and selective PPARgamma agonist and has a potent glucose-lowering effect via improvement of the insulin resistance in diabetic animal models.

Topics: Adiponectin; Animals; Blood Glucose; Diabetes Mellitus, Experimental; Disease Models, Animal; Dose-Response Relationship, Drug; Gene Expression Regulation; Glucose; Hypoglycemic Agents; Inhibitory Concentration 50; Insulin; Insulin Resistance; Liver; Male; Metabolic Clearance Rate; Mice; Mice, Obese; Myocardium; Obesity; Pancreas; PPAR gamma; Rats; Rats, Zucker; Sensitivity and Specificity; Thiazolidinediones; Time Factors; Triglycerides