The Metabolic Clinical Research Unit (MRCU) and the Phenotyping Laboratory opened in January 2007 and are the primary sites where this research is conducted. The MCRU is comprised of ten private inpatient rooms modified to accommodate the needs and safety of patients with extreme obesity (class III). See http://www2.niddk.nih.gov/Research/ClinicalResearch/MCRU/. Dynamic metabolic testing (frequently sampled intravenous glucose tolerance test and mixed meal test), diurnal testing (hormones and temperature), sleep studies, resting energy expenditure, heart rate variability studies, muscle and fat biopsies, neurocognitive testing and psychological assessments are performed in the patient's room. An exercise testing room equipped with a full metabolic cart, treadmill, an upright and a reclining cycle ergometer, is used to perform gross mechanical efficiency, anaerobic threshold, VO2 Max, maximal power (peak Watt), resting and maximal heart rate, resting and exercise-induced cardiac output (cardiac impedance). In subjects unable to use the cycle ergometer or treadmill, the Cooper test is performed using portable exercise equipment. Nutritionist evaluate participant's seven day food records for caloric intake and micro- and macronutrient composition. The Phenotyping Laboratory contains three rapid response respiratory chambers for the assessment of total energy expenditure, sleeping metabolic rate and other components of energy expenditure. The chambers are equipped with a treadmill, telemetry, motion sensors and an isolette system for procuring blood samples. Body composition is measured by dual energy X-ray absorptiometry (DEXA) with a table rated to 450 lbs, air displacement plethysmography (ADP) and bioelectric impedence. As part of this natural history study, baseline phenotypic data is currently being obtained in subjects of normal weight, overweight and class I, II and III obesity. Subjects are invited to return for yearly evaluations. Validation studies to assess the dynamic range and reproducibility of the equipment including the cart and room calorimeters, DEXA and ADP and exercise equipment have been performed. A bank of skeletal muscle, fat and peripheral blood for genomic DNA is being created on the extensively phenotyped subjects. Participants are provided a summary of clinically useful results that they can share with their physicians in planning weight loss strategies. Subjects participating in weight loss interventions such as bariatric surgery are targeted for follow-up studies to assess changes in parameters of interest.