Crucial roles of Nox2‐derived oxidative stress in deteriorating the function of insulin receptors and endothelium in dietary obesity of middle‐aged mice

Background and Purpose Systemic oxidative stress associated with dietary calorie overload plays an important role in the deterioration of vascular function in middle‐aged patients suffering from obesity and insulin resistance. However, effective therapy is still lacking. Experimental Approach In this study, we used a mouse model of middle‐aged obesity to investigate the therapeutic potential of pharmaceutical inhibition (apocynin, 5 mM supplied in the drinking water) or knockout of Nox2, an enzyme generating reactive oxygen species (ROS), in high‐fat diet (HFD)–induced obesity, oxidative stress, insulin resistance and endothelial dysfunction. Littermates of C57BL/6J wild‐type (WT) and Nox2 knockout (KO) mice (7 months old) were fed with a HFD (45% kcal fat) or normal chow diet (NCD, 12% kcal fat) for 16 weeks and used at 11 months of age. Key Results Compared to NCD WT mice, HFD WT mice developed obesity, insulin resistance, dyslipidaemia and hypertension. Aortic vessels from these mice showed significantly increased Nox2 expression and ROS production, accompanied by significantly increased ERK1/2 activation, reduced insulin receptor expression, decreased Akt and eNOS phosphorylation and impaired endothelium‐dependent vessel relaxation to acetylcholine. All these HFD‐induced abnormalities (except the hyperinsulinaemia) were absent in apocynin‐treated WT or Nox2 KO mice given the same HFD. Conclusions and Implications In conclusion, Nox2‐derived ROS played a key role in damaging insulin receptor and endothelial function in dietary obesity after middle‐age. Targeting Nox2 could represent a valuable therapeutic strategy in the metabolic syndrome.