Abstract 17239: Mechanisms of Vascular Oxidative Stress Induction of Obesity

Abstract

The present study investigates whether and how vascular reactive oxygen species (ROS) induce obesity and insulin resistance/metabolic syndrome. Epidemiologically, pathological conditions like hypertension and hypercholesterolemia associated with obesity, and these diseases promote vascular ROS production. It has been thought that obesity is causal in these conditions. We instead propose that vascular ROS may play a causal role in obesity by promoting inflammation, adipogenesis and exercise intolerance. Wild-type (WT) mice and mice having excessive vascular ROS production (smooth muscle-specific overexpression of p22phox, a key component of NADPH oxidase, tg sm/p22phox , body weight (BW) elevated modestly but significantly at baseline) were fed high-fat diet for 6 weeks. Intriguingly, tg sm/p22phox mice developed exaggerated obesity. The BW increased from 32.16±2.34 g in the 6 mo old tg sm/p22phox mice to 43.03±1.44 g (vs. 30.81±0.71 g to 37.89±1.16 g in the WT mice). The percentage of increase is 34±3.35% vs. 23±3.08% respectively (p<0.01). Fat mass was also significantly further increased. Glucose tolerance tests indicate a more severe insulin resistance phenotype in the tg sm/p22phox mice, which was associated with reduced HDL cholesterol and increased leptin levels. These animals also had impaired spontaneous activity, increased ROS production and mitochondrial dysfunction in skeletal muscle. Oral administration with antioxidant ebselen prevented weight gain and insulin resistance in high-fat fed tg sm/p22phox mice. In mice having deficient vascular ROS production however (p22phox loxp/loxp crossed with mice expressing Cre recombinase driven by the tamoxifen-inducible smooth muscle myosin heavy chain promoter, tg smmhc/cre mice), high-fat feeding failed to induce weight gain and leptin resistance. These vascular p22phox knockout mice also had reduced T cell infiltration of perivascular fat. In conclusion, these data seem to provocatively implicate that vascular NADPH oxidase-derived ROS induce obesity and insulin resistance/metabolic syndrome. To our knowledge this represents the first evidence that vascular ROS play a causal role in the development of obesity and insulin resistance/metabolic syndrome.