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 altered gene expression and release of inflammatory cytokines and other mediators in obesity and the dynamic series of events that take place with weight loss. 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.

• INCLUSION CRITERIA:
• Age 25-45 years, male or female
• BMI 25.0-45.0 kg/m(2) for Overweight Subjects and 19.0-24.9 kg/m(2) for Non-Overweight Controls
• Healthy, as determined by medical history and laboratory tests
• Written informed consent

EXCLUSION CRITERIA:

• BMI less than 19.0 or greater than 45.0 kg/m(2)
• History or symptoms compatible with cardiovascular disease, including arrhythmias and syncopal episodes, or use of prescription medications for heart conditions, strokes, or peripheral vascular disease
• Allergy to lidocaine
• Pregnancy or breastfeeding
• Menopause or peri-menopausal period (FSH greater than 15 mIU/ml)
• Use of hormonal contraceptives or estrogen replacement therapy
• Alcohol (more than 2 drinks per day or CAGE greater than 2 questions and/or current/regular use of drugs such as amphetamines, cocaine, heroin, or marijuana
• Current use of tobacco products (smoking or chewing)
• History of Diabetes Mellitus, either type 1 or 2, or Fasting Glucose greater than 126 mg/dl
• Use of cholesterol- or lipid-lowering drugs, or fasting serum lipids in range requiring medication per Adult Treatment Panel III recommendations of the National Cholesterol Education Program
• Liver disease or ALT serum level greater than two-fold above the laboratory reference standard
• Renal insufficiency or estimated creatinine clearance less than or equal to 50 ml/min
• Current use of medications, dietary supplements (including fish oils), or alternative therapies known to alter thyroid function with the exception of occasional use of NSAIDs (3 tablets/week maximum) and Benzodiazepines; use of NSAIDs in the 10 days preceding the hospital admissions
• Current history, symptoms, or behavior compatible with psychiatric disorders or therapy with psychotropic medications that would be incompatible with safe and successful participation in this study
• History of drug or alcohol abuse within the last 5 years; current use of drugs or alcohol
• Keloid formation (relative to subcutaneous adipose tissue biopsies)
• Hypo- or hyperthyroidism (TSH greater than or equal to 10; less than or equal to 0.1 mIU/L)
• Blood pressure greater than 160/95 mm Hg or use of prescription medications for treatment of hypertension
• Cushing Syndrome