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

Abstract

BACKGROUND AND PURPOSESystemic 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 APPROACHIn 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 RESULTSCompared 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 IMPLICATIONSIn 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.

The −930A>G polymorphism of the CYBA gene is associated with premature coronary artery disease. A case–control study and gene–risk factors interactions

“…These findings were complemented by results of another study [19]. Aortic vessels from obese mice after middle age had significant increases in NOX2 expression and ROS production, which were accompanied by a reduced insulin receptor expression [19]. Interestingly, there are presumptions that the −930G allele of the CYBA polymorphism is associated with insulin resistance in obese adult humans ( P  < 0.05) [22].…”

Flavonoid-rich Chardonnay grape seed flour supplementation ameliorates diet-induced visceral adiposity, insulin resistance, and glucose intolerance via altered adipose tissue gene expression

“…Previously another study also showed that grape seed extract increased the levels of insulin signalling-related proteins in the muscle of fructose-fed rats (Meeprom, Sompong, Suwannaphet, Yibchok-anun, & Adisakwattana, 2011). Alternatively, systemic oxidative stress down-regulated expression of insulin receptor in aortas of HF-induced DIO mice (Du, Fan, Mai, & Li, 2013). Therefore, improved insulin resistance and glucose intolerance appear to be mediated through a reduction of oxidative stress and inflammation, as well as increased insulin receptor expression in adipose tissue of HF DIO mice fed ChrSdsupplemented diet.…”

Endothelial dysfunction and vascular disease - a 30th anniversary update

“…The endothelial dysfunction and/or insulin resistance accompanying obesity, metabolic syndrome and diabetes has been attributed to: (i) increased ROS production by NOX leading to damages of the insulin receptors (Du et al . ); (ii) increased insulin receptor substrate (IRS)‐1 phosphorylation at Ser307 (Nemoto et al . ); (iii) reduced production of epoxyeicosatrienoic acids (EETs) by cytochrome P450 (CYP 450) and augmented degradation of epoxy fatty acids by soluble epoxide hydrolase (sHE) (Abraham et al .…”