Inflammation in obesity: Modulation by Weight Loss

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DESCRIPTION (provided by applicant): The prevalence of obesity has increased markedly over the last two decades in the United States and worldwide. Obesity is a major risk factor for diabetes type 2 and atherosclerosis, both of which are associated with inflammation. It has been suggested that obesity is a pro-oxidative and pro-inflammatory state which may be related to chronically increased macronutrient intake. Mononuclear cells (MNC) participate in atherogenicity in the arterial wall and also mediate inflammation in adipose tissue. This study will test the hypothesis that peripheral blood MNC in the obese are in a pro-inflammatory state when compared with those of normal lean subjects. Our first goal is to establish a link between obesity and the early steps of inflammation by showing an association between obesity and the pro-inflammatory transcription factor NFkappaB activation in MNC, which results in an increase in pro-inflammatory gene expressions (TNFalpha, IL-6, MIF and MMP-9). In addition, the differences in oxidative stress as reflected in reactive oxygen species (ROS) generation, NADPH oxidase, oxidized lipids, oxidized proteins and isoprostane between obese and lean subjects will be studied. Our second goal is to test the effect of weight loss on these inflammatory mediators and oxidative stress. Our third goal is to establish a correlation in the expression of these inflammatory mediators in MNC and adipose tissue from fat biopsies. Our fourth goal is to investigate whether the abnormal ischemic vasodilatation of the brachial artery known to occur in the obese will revert to normal following weight loss since abnormal vascular reactivity may be due to oxidative stress and inflammatory mediators like TNFalpha which reduce the availability of endothelial nitric oxide (NO), a vasodilator. Asymmetric dimethyl arginine (ADMA), an endogenous inhibitor of nitric oxide synthase known to be increased in obesity, will be measured before and after weight loss. In addition, the reduction of the inflammatory and oxidative stress mediators will be correlated with increased insulin sensitivity following weight loss. This study represents a unique opportunity to establish that 1) obesity is a pro-inflammatory and pro-oxidative stress state as observed in MNC and adipose tissue; 2) The reduction in inflammation and oxidative stress by weight loss may lead to improvement in abnormalities in vascular reactivity associated with obesity; 3) The reduction in oxidative stress and inflammation may in the long term potentially contribute to the prevention of atherosclerosis.