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

Life Sci. 2011 Jul 18;89(3-4):107-14. doi: 10.1016/j.lfs.2011.05.006. Epub 2011 May 27.

Abstract

Aim: This 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 methods: The rats were on a regular chow diet (C) or high-fat enriched diet (HFD) energy-restrictedly (HFr), or ad libitum (HFa) for 12weeks. 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), 30mg/kg/day, respectively.

Key findings: Increased 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.

Significance: The 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / drug effects
  • Adipose Tissue / metabolism
  • Animals
  • Biomarkers / blood
  • Celecoxib
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism*
  • Cyclooxygenase Inhibitors / pharmacology
  • Diet, Reducing
  • Dietary Fats / adverse effects*
  • Gene Expression
  • Glucose Tolerance Test
  • Glucose Transporter Type 4 / genetics
  • Glucose Transporter Type 4 / metabolism
  • Insulin / blood
  • Insulin Resistance / physiology*
  • Male
  • Muscle, Skeletal / drug effects*
  • Muscle, Skeletal / enzymology
  • Obesity / chemically induced*
  • Obesity / enzymology
  • Oxidative Stress / drug effects*
  • Pyrazoles / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Sulfonamides / pharmacology

Substances

  • Biomarkers
  • Cyclooxygenase Inhibitors
  • Dietary Fats
  • Glucose Transporter Type 4
  • Insulin
  • Pyrazoles
  • Slc2a4 protein, rat
  • Sulfonamides
  • Cyclooxygenase 2
  • Ptgs2 protein, rat
  • Celecoxib
  • nimesulide