Obesity has arguably emerged as the most serious public health problem in this country with nearly 65% of the US population currently classified as overweight or obese. The growing epidemic imposes a devastating health care burden on the nation, and there are no signs of slowing. Unprecedented numbers of individuals are exposed to increased cardiovascular risk. Inflammatory mechanisms are critical to all stages of atherosclerosis and cardiovascular disease events. The goal of the present proposal is to characterize the role of inflammation in adipose stores as a coordinator of metabolic and vascular dysfunction in obese individuals. The project is consistent with the long-term goal of the applicant to investigate mechanisms of cardiovascular disease in obesity. In addition to serving as the primary site for energy stores, fat depots are increasingly recognized as an important hotbed of metabolic and inflammatory activity, and significant synthetic source of proatherogenic and proinflammatory adipokines that orchestrate mechanisms of vascular dysfunction, injury, and cardiovascular disease progression in obesity. The extent to which a maladaptive state of inflammation in adipose tissue and adipocyte dysfunction relates to individual vascular phenotype across a wide range of obese individuals, and the effects of targeted pharmacological intervention on these parameters are critically lacking. This project proposes in specific aim 1: to relate histological inflammatory activity in human fat biopsy specimens to impaired vascular phenotype in obesity using non-invasive measures of vascular endothelial function, in specific aim 2: to determine whether inflammatory activity in human adipose tissue relates to adipocyte expression of proatherogenic adipokines quantified by rt-PCR, and in specific aim 3: to determine whether treatment with the anti-inflammatory drug sulfasalazine improves vascular dysfunction in obese patients and whether these changes relate to the level of inflammation in adipose tissue. This project proposes a highly novel approach of investigation and takes advantage of a unique multidisciplinary partnership examining mechanisms of obesity-related vascular disease in a growing area of major public health concern. These proposed studies are highly likely to yield important novel information with regard to mechanisms of vascular disease in obesity and bring us closer to identifying optimal treatment strategies firmly relevant to the future management of overweight and obese patients.
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