Obesity is a risk factor for atherosclerosis and is a major cause of morbidity and mortality in the United States. Endothelium derived nitric oxide (NO) a key regulator of arterial homeostasis is lost in the early stages of atherosclerosis. Reduced NO bioavailability during obesity involves increased generation of reactive oxygen species (ROS) that scavenge NO. Most studies indicate that diet induced weight loss, the cornerstone of weight management strategies, improves endothelial function. The benefits of the recently popularized low carbohydrate (LC), Atkins' diet, on endothelial health are controversial since they require strict reductions of carbohydrate intake at the expense of high dietary fat content. For instance, a recent study in our laboratory showed divergent effects of isocaloric LC and low fat (LF) diets on NO- mediated endothelium- dependent flow mediated dilation (FMD). While FMD was improved on a LF diet, it was impaired on a LC diet suggesting that the potential benefits of weight loss on NO are negated on LC. The overall hypothesis of this study is that low carbohydrate diets reduce the benefits of weight loss on endothelial function by lowering the protective effect of adiponectin against endothelial reactive oxygen species generation compared to isocaloric low fat diets. Thus, LC diets impair NO- mediated endothelium-dependent dilation of isolated peripheral resistance arteries. This hypothesis is supported by preliminary data indicating adiponectin is reduced and resistance artery endothelial function is impaired on LC diets. This will be tested with a prospective, randomized, 6 week feeding trial in obese (BMI: 30- 39) subjects ages 18-40. Low fat or Low carbohydrate diets will be administered at caloric thresholds designed to either lose or maintain weight in each group. Endothelial- dependent vasodilation will be determined in isolated resistance arteries obtained from subcutaneous fat biopsies before and after 6 weeks of dietary intervention. In aim 1 we will determine the contribution of endothelial oxidant systems on reduced NO- mediated endothelial function in resistance arteries during low carbohydrate diets compared to isocaloric low fat diets. In aim 2 we will determine whether low carbohydrate diets increase pro-atherogenic adipokines, decrease anti-atherogenic adipokines, or both. In aim 3 we will test whether adiponectin improves endothelial function in resistance arteries of subjects on low carbohydrate diets and whether the mechanism involves eNOS regulation (phosphorylation) or superoxide dismutase expression. Pharmacologic inhibitors, fluorescent probes for ROS and NO, HPLC, and molecular approaches of measuring enzyme expression will determine the site and source of ROS and NO production in vascular tissue. Adipokine mediated endothelial dysfunction has been linked to high fat intake and if confirmed on a low carbohydrate diet will provide clinically important information regarding the mechanisms whereby diets differing in macronutrient contents can be optimized to improve vascular function during weight loss. These results will begin to address how lifestyle interventions that optimize adiponectin may be used to prevent the vascular risks associated with diets high in fat. PUBLIC HEALTH RELEVANCE: Obesity is a risk factor for heart disease and a major cause of death and disability in the United States. A variety of weight loss strategies have gained attention including traditional Low Fat (LF) and the recently popularized Low Carbohydrate (LC) diets. The proposed feeding trial will examine the impact of 6 weeks of LF and LC diets designed for body weight loss and maintenance on vascular endothelial function (an early prognostic indicator of the propensity for heart disease) in young men and women.