Objective-Obesity is associated with endothelial dysfunction that may contribute to the development of atherosclerosis.We studied whether weight reduction improves endothelial function in overweight individuals. Methods and Results-Flow-mediated endothelium-dependent vasodilation of the brachial artery was measured in 67 adults (age: 46Ϯ7 years, body mass index: 35.2Ϯ5.4 kg/m 2 ) before and after a 6-week weight reduction program induced by very-low-calorie diet (daily energy: 580 kcal/2.3 MJ). Caloric restriction reduced body weight from 101Ϯ18 to 90Ϯ17 kg. Flow-mediated vasodilation increased from 5.5%Ϯ3.7 to 8.8%Ϯ3.7% (PϽ0.0001). Nitrate-mediated vasodilation was not significantly affected. The improvement in flow-mediated dilation was associated with the reduction in plasma glucose concentration (Pϭ0.0003). This relationship was independent of changes in weight, serum lipids, oxidized LDL, C-reactive protein, adiponectin, blood pressure, and insulin. Key Words: endothelium Ⅲ obesity Ⅲ risk factors Ⅲ glucose Ⅲ weight reduction T he vascular endothelium plays an important role in the regulation of arterial tone, thrombosis, and inflammation. Endothelial dysfunction may predispose arteries to the development of atherosclerotic lesions and is pathophysiologically linked to acute cardiovascular syndromes. 1 A common condition associated with endothelial dysfunction is obesity. Endothelial-dependent vascular responses to both agoniststimulated 2,3 and flow-mediated vasodilation 4 have been shown to be blunted in obese individuals. The mechanisms of obesity-induced endothelial dysfunction may be multifactorial, because excess adipose tissue induces several metabolic changes that may interfere with normal endothelial function. These may include dyslipidemia, elevated blood pressure, increased inflammation, oxidative stress, and changes in glucose metabolism. 5 Although weight reduction is known to reduce several of these risk factors for endothelial dysfunction, it is inadequately known whether endothelial function can be improved by reducing weight. We hypothesized that weight loss induced by very-low-calorie diet would enhance flow-mediated endothelium-dependent vasodilation in overweight adults. To gain insight for possible mechanisms of weight-loss-mediated changes in flow-mediated dilation, we also measured changes in several potential biochemical determinants of endothelial function. Conclusions-Weight Methods SubjectsWe recruited overweight (body mass index Ͼ27kg/m 2 ) men and women from an occupational health service clinic. The exclusion criteria included diabetes, pregnancy, gout, gall stone disease, alcohol/drug abuse, liver/kidney disorder, psychiatric disorder, and use of cholesterol lowering medication.Of the 74 subjects enrolled, 47 women and 20 men completed the 6-week program (9.5% dropout rate). Sixteen women were postmenopausal (2 using hormone replacement therapy), 19 subjects had treatment for hypertension, and there were 7 smokers and 13 ex-smokers. Most participants (65%) were sedentary, engag...