The importance of cyclooxygenase 2-mediated oxidative stress in obesity-induced muscular insulin resistance in high-fat-fed rats

AimThis study was undertaken to examine the effect of cyclooxygenase (COX) 2 inhibition on the development of muscular insulin resistance in high-fat-induced obese rats.Main methodsThe rats were on a regular chow diet (C) or high-fat enriched diet (HFD) energy-restrictedly (HFr), or ad libitum (HFa) for 12 weeks. The rats fed HFD ad libitum were further divided into 3 groups: oral gavage with vehicle (HFa), selective COX-2 inhibitors-celecoxib (HFa + C) or nimesulid (HFa + N), 30 mg/kg/day, respectively.Key findingsIncreased fasting plasma insulin, triglyceride and 8-isoprostane levels in HFa were significantly suppressed in those of HFa + C and HFa + N. The whole body insulin resistance of HFa indicated by the increased fasting plasma insulin levels and the elevated area under curve of insulin obtained from the oral glucose tolerance test were significantly reversed in those combined with celecoxib and nimesulid administration compared with those in HFr. The gene expression of COX-2 was significantly increased in epididymal fat but not in soleus muscle in HFa and the enhanced adipose COX-2 expression in high-fat fed rats was suppressed by those with drug treatment. Both selective COX-2 inhibitors reversed the diminished insulin-stimulated glucose uptake and GLUT4 translocation in skeletal muscles of HFa. Obesity-induced oxidative stress indicated by the elevated plasma 8-isoprostane,the decreased ratio of GSH/GSSG and increased TBARS in soleus muscle were significantly reversed by COX-2 inhibition.SignificanceThe results suggest that COX-2 inhibition might suppress the muscular insulin resistance indirectly through decreasing the COX-2-mediated systemic oxidative stress in this diet-induced obese model.