Gene Expression and Inflammation in Overweight Subjects

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. In recent years, new and evolving concepts have emerged regarding obesity as a chronic endocrine disorder of inflammation. Moreover, a growing body of evidence indicates that obesity alters the profile of a constellation of genes and that some changes in biomarkers of inflammation and gene expression can be reversed by weight loss. In this clinical protocol, we propose to test the idea that a particular set 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 study the local adipose tissue microenvironment by means of microdialysis. The role of a number of adipokines, inflammatory mediators/cytokines, and novel lipid products will be analyzed using sensitive Liquid Chromatography-Mass Spectrometry and ELISA methods. The study design incorporates two basic objectives: 1. Comparison of Non-Overweight Controls vs. Overweight Subjects at Baseline and 2. 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 24.9) and 80 Overweight Subjects (BMI 25.0 45.0) will be enrolled. Baseline studies, to be obtained on all participants include: 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, and subcutaneous adipose tissue biopsy. 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 repeat studies at regular, 3-month intervals to assess serial changes in the various parameters and to provide correlative data with the degree and rate of weight loss achieved. 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.