Oxidative stress and dysregulation of NAD(P)H oxidase and antioxidant enzymes in diet-induced metabolic syndrome

Metabolism. 2006 Jul;55(7):928-34. doi: 10.1016/j.metabol.2006.02.022.


Previously, we have demonstrated that chronic consumption of a high-fat, high-refined sugar (HFS) diet results in metabolic syndrome which is marked by obesity, insulin resistance, hyperlipidemia, and hypertension in Fischer rats. Metabolic syndrome in this model is associated with oxidative stress, avid nitric oxide (NO) inactivation by reactive oxygen species (ROS), diminished NO bioavailability, and dysregulation of NO synthase isotypes. Although occurrence of oxidative stress and its impact on NO metabolism are well established, the molecular source(s) of ROS in this model is unknown. In an attempt to explore this issue, we measured protein expressions of the key ROS-producing enzyme, NAD(P)H oxidase, and the main antioxidant enzymes, superoxide dismutase (CuZn SOD and Mn SOD), catalase, glutathione peroxidase (GPX), and heme oxygenase-2 (HO-2), in the kidney and aorta of Fischer rats fed an HFS or low-fat, complex-carbohydrate diet for 7 months. In addition, plasma lipid peroxidation product (malondialdehyde) as well as endothelium-dependent and -independent vasorelaxation (aorta rings) was determined. The results showed a significant upregulation of gp91(phox) subunit of NAD(P)H oxidase and downregulations of SOD isoforms, GPX, and HO-2 in the kidney and aorta of the HFS-fed animals. This was associated with increased plasma malondialdehyde concentration and impaired vasodilatory response to acetylcholine, but not the NO donor, Na nitroprusside. The latter findings confirm the presence of oxidative stress and endothelial dysfunction in the HFS-fed rats. Oxidative stress and endothelial dysfunction in the diet-induced metabolic syndrome are accompanied by upregulation of NAD(P)H oxidase, pointing to increased ROS production capacity, and downregulation of SOD isoforms, GPX, and HO-2, the key enzymes in the antioxidant defense system.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blood Pressure
  • Carbohydrates / administration & dosage
  • Dietary Fats / administration & dosage
  • Endothelium, Vascular / physiology
  • Female
  • Glutathione Peroxidase / analysis
  • Heme Oxygenase (Decyclizing) / analysis
  • Malondialdehyde / blood
  • Metabolic Syndrome / etiology
  • Metabolic Syndrome / metabolism*
  • NADPH Oxidases / analysis*
  • Nitric Oxide / biosynthesis
  • Oxidative Stress*
  • Rats
  • Rats, Inbred F344
  • Superoxide Dismutase / analysis
  • Vasodilation


  • Carbohydrates
  • Dietary Fats
  • Nitric Oxide
  • Malondialdehyde
  • Glutathione Peroxidase
  • Heme Oxygenase (Decyclizing)
  • heme oxygenase-2
  • Superoxide Dismutase
  • NADPH Oxidases