Obesity, Adipocytokines, and Endothelial Dysfunction

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DESCRIPTION (provided by applicant): The obesity epidemic has become a major public health problem in this country with unprecedented exposure of individuals to cardiovascular risk. There is growing urgency to understand mechanisms of obesity-related cardiovascular disease and the beneficial effects of weight modification. The overall objective is to investigate the relationships between obesity, vascular endothelial dysfunction, adipocyte metabolism, and oxidative stress, and the effect of weight loss on these parameters. The vascular endothelium regulates vasomotor tone, platelet activity, and inflammation through the synthesis and elaboration of paracrine factors such as endothelium-derived nitric oxide (EDNO). Endothelium-dependent vasodilation and platelet inhibition are impaired in atherosclerosis and associated risk factors, possibly due to increased vascular oxidative stress and reduced NO bioactivity. Loss of normal vascular endothelial function supports a local vasospastic, prothrombotic, and proinflammatory milieu, and is linked to the pathophysiology of cardiovascular events including myocardial infarction, stroke, and unstable angina. There is growing recogition that metabolic activity of adipose tissue, through release of proatherogenic factors, may play a pathophysiologic role in mechanisms of vascular dysfunction and cardiovascular disease. No prior study has examined the effect of obesity and weight loss interventions on adipocyte and vascular endothelial function. This project proposes in specific aim 1: to characterize the relationship between overweight or obesity and vascular endothelial dysfunction, in specific aim 2: to determine whether weight reduction and risk factor modification improves vascular endothelial function and markers of oxidative stress and inflammation, and in specific aim 3: to examine the metabolic role of adipose tissue for vascular dysfunction, and investigate the effects of weight loss on adipocyte expression of proatherogenic factors. The proposed studies have the potential to provide important insights into mechanisms of obesity -associated cardiovascular disease and examine whether weight loss mediates its cardioprotective action via phenotypic modification of adipocyte and vascular endothelial function. The proposed project takes advantage of Boston Medical Center's NIH funded Center for Obesity Research (C.O.R.E) and a tightly integrated Nutrition and Weight Loss Center. In addition, the investigators bring a unique combination of expertise that will greatly enhance the project's ability to address these important clinical questions.