Endothelial Dysfunction in Cerebral Arterioles in a Model of Diet‐Induced Obesity and Type II Diabetes: Role of Superoxide and NAD(P)H Oxidase

The goal of this study was to characterize responses in the cerebral circulation in a mouse model of diet‐induced obesity and type II diabetes and to examine the mechanisms involved. Diameter of cerebral arterioles (31±1 μm; mean±SE) was measured using a cranial window preparation in anesthetized C57Bl/6 and gp91phox‐deficient mice fed either a control (10% kcal fat) or a high‐fat (45% kcal fat) diet for 12 weeks. Blood glucose levels were higher in high‐fat fed mice compared to controls (160±10 vs. 120±16 mg/dl, respectively). Dilatation in response to acetylcholine (ACh; 1 and 10 μmol/L), but not to nitroprusside (NP), was markedly reduced (P<0.05) in C57Bl/6 mice fed a high‐fat diet (eg, 10 μmol/L ACh produced 33±4 and 18±1% dilatation in control and high‐fat fed mice, respectively). Responses to ACh in high‐fat fed C57Bl/6 mice were restored toward normal by tempol (a scavenger of superoxide; 1 mmol/L). Responses to ACh and NP in high‐fat fed gp91phox‐deficient were similar (P>0.05) to that observed in C57Bl/6 mice fed a control diet (eg, 10 μmol/L ACh produced 33±4 and 28±1% dilation in high‐fat fed gp91phox‐deficient mice compared to that in control‐diet fed C57Bl/6 mice, respectively). These findings provide the first evidence that endothelium‐dependent responses of cerebral vessels are markedly impaired in a mouse model of diet‐induced obesity and type II diabetes. Pharmacological and genetic evidence implicate a major role for NAD(P)H oxidase‐derived superoxide in impairment of cerebral microvessels in response to a high‐fat diet.