Obesity is a global public health problem of epidemic proportions. It is the source of considerable morbidity and early mortality in the U.S. and is associated with increased risk of diabetes, hypertension, cardiovascular disease, and cancer to name a few. All segments of the population are affected and the burden to society, in terms of general well-being and healthcare costs, is tremendous. In recent years, new and evolving concepts have emerged regarding obesity as a chronic endocrine disorder of inflammation. Moreover, a small, but growing body of evidence both in animals and in man indicates that obesity per se alters the profile of a constellation of genes and that at least some of these changes in biomarkers of inflammation and gene expression can be reversed by weight loss. The data in humans is rather scant, with just a handful of articles on this subject in the current literature. In this clinical protocol, we propose to extend the early and evolving work in humans by testing and reconfirming the idea that a particular set(s) of genes is activated (or deactivated) in overweight subjects using standard microarray techniques on samples of subcutaneous adipose tissue derived from biopsies. In addition, we will broaden and extend this work by studying the local adipose tissue microenvironment in vivo by means of a microdialysis procedure, a minimally invasive technique that allows the serial determination of components of the extracellular fluid under physiological conditions. The role of a number of adipokines (such as leptin and adiponectin) and inflammatory mediators, cytokines (e.g., TNF-alpha, IL-6), and eicosanoids (such as Prostaglandin E2, Lipoxin A4, and Leukotriene B4) will be analyzed using sensitive Liquid Chromatography-Tandem Mass Spectrometry and ELISA methods. The study design incorporates two basic objectives: (a) Comparison of Non-Overweight Controls vs. Overweight Subjects at Baseline and (b) Correlation of changes in Overweight patients over time as they lose weight through a calorie-restricted diet. To these ends, 30 Non-Overweight Controls (BMI 19.0 to 24.9) and 80 Overweight Subjects (BMI 25.0 to 45.0) will be enrolled. Baseline studies, to be obtained on all participants include: routine and specialized blood tests, anthropometric indices, body composition by air-displacement plethysmography, indirect calorimetry, intravenous glucose tolerance test as an index of insulin sensitivity, subcutaneous adipose tissue microdialysis procedures to sample the local microenvironment for various adipokines, cytokines, and eicosanoid mediators of inflammation, and subcutaneous adipose tissue biopsy for analysis of gene expression using standard microarray techniques. These procedures will require an overnight hospital admission to the Clinical Center. Overweight Subjects will then be prescribed a calorie-restricted diet and followed for one year. They will undergo the same repeat studies and procedures outlined above at regular, 3-month intervals so as to assess serial changes in the various parameters and to provide correlative data with the degree and rate of weight loss achieved. Studies are currently in progress and we continue to enroll patients in the protocol. At present, 30 Normal Weight and 70 Overweight study volunteers have successfully completed their first inpatient admissions (Baseline) to the Metabolic Unit of the Clinical Center. 63 Overweight subjects have been studied at 1.5 months, 56 at 3 months, 44 at 6 months, 35 at 9 months, and 33 at 12 months following the institution of the dietary intervention and nutritional counseling. The patients have been extraordinarily successful in losing weight, the average rate of weight loss being 0.5 lbs/week or 25 lbs/year (total weight loss for the group = 740 lbs). Identification and quantitation of adipokines, cytokines, and lipid mediators of inflammation in microdialysis fluids and serum have begun and results are being analyzed. The data indicate that different patterns exist for cytokines in relation to microdialysis fluid as compared to serum and that profound changes in levels of lipid mediators occur with weight loss, several of which correlate with improvements in insulin resistance. Taken together, these studies should shed light and provide fundamental insights into the nature of the altered gene expression and release of inflammatory cytokines and other mediators that characterize the overweight state and the dynamic series of events that take place when dietary intervention leads to weight loss. It is anticipated that a number of these changes will relate to macrophages and known inflammatory markers though doubtless there are other important leads yet to be discovered. Thus, our hope is that such studies will ultimately lead to the identification of novel genes that underlie the important metabolic derangements associated with obesity and their response to different treatment modalities.

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