This study will investigate how to better predict why some individuals gain or lose weight more easily than others. It will examine whether the increase in the amount of energy a body burns in 24 hours with overeating or the decrease over 24 hours with fasting can help determine how easily someone gains or loses weight.

Healthy people between 18 and 60 years of age who have a body mass index (BMI) between 18.5 kg/m(2) and 24 kg/m(2) (for overfeeding study) or a BMI greater than 27 kg/m(2) with a body weight less than 350 pounds (weight loss study) may be eligible for this study. The study requires a 10-week admission to the NIH Clinical Center (2-week baseline, 6-week overfeeding/weight loss, 2-week post-weight change).

Participants undergo the following tests and procedures during the hospital admission:

• Medical history, physical examination and laboratory studies
• Questionnaires to assess eating behavior, food preferences, body composition, and activity level
• Body composition assessment (height, weight, waist circumference, and fat mass and muscle content through DXA and MRI scans)
• Oral glucose tolerance test
• Meal test to measure the response of certain hormones to food
• Activity monitors to determine activity level
• Metabolic chamber study to measure calories burned over 24 hours and monitor body temperature
• Free-living energy use study to measure calories burned under normal home conditions over 7 days
• Fat and muscle biopsies
• Dietary intervention: Measurements of food intake and energy loss over a 6-week overfeeding (1.5 times the subject s normal food intake) or weight loss (one-half the subject s normal food intake) program

Followup procedures after the inpatient stay:

• Height and weight measurements at 6 months (overfeeding study participants) and monthly for the first year, at 3-month intervals for the second year, and then yearly for 3 more years (weight loss study participants)
• Yearly visits (2-night inpatient stay) for all participants for repeat meal test, DXA, oral glucose tolerance test, behavioral questionnaires and, in women who can become pregnant, pregnancy test

For obese individuals, losing weight and keeping it off are extremely difficult, whereas some other individuals are thin and report trouble gaining weight. In most weight loss and overfeeding studies there is a large variation in the amount of weight lost or gained, and it is not clear whether an individual s response to an intervention can be predicted. Measurement of the amount of energy an individual uses over 24 hours (24 hour energy expenditure or 24-EE) and the response of 24-EE to overfeeding and fasting may help predict which individuals will have the greatest changes in weight with changes in energy balance. In previous work, 24-EE responses to overfeeding and fasting were related such that individuals with the greatest increase in 24-EE upon overfeeding tended to have the smallest decrease in 24-EE upon fasting ( spendthrift phenotype) and those individuals with less increase in 24-EE during overfeeding had a greater decrease in 24-EE with fasting ( thrifty phenotype). Those with the spendthrift phenotype who had a greater increase in 24-EE in response to overfeeding gained less weight over time. Furthermore, studies have shown that diets with very low protein content may magnify the variability in response to overfeeding.

The aim of this study is to determine if a phenotype defined by 24-EE responses to overfeeding and underfeeding is related to weight loss or gain in 4 different under- and overfeeding settings: an inpatient weight loss group for obese individuals who will be administered one of two diets based on a 50% reduction of their daily energy needs for six weeks (standard reduction diet or calorie reduced diet that is still high in protein; 6 week weight reduction, 10 week stay, n=20/standard reduction diet group and n=10/relative high protein diet), and two overfeeding groups for lean, weight gain resistant individuals: a low-protein overfeeding group at 150% of daily energy needs for 6 weeks overfeeding (6% protein, 64% carbohydrate, 30% fat; 10 week stay, n=10), and a normal protein overfeeding group at 150% of daily energy needs for 6 weeks overfeeding (20% protein, 50% carbohydrate, 30% fat; 10 week stay, n=10). We will also examine additional metabolic and behavioral measurements to determine how they relate to weight change and changes in 24-EE. These include sympathetic nervous system activity, behavior, adipose and muscle tissue energy content, and abdominal adipocyte size. The study will evaluate the relationship between the percent increase in 24-EE in response to overfeeding/underfeeding and the amount of weight change over time in each subject. These findings may provide important information for predicting and adapting specific individualized interventions for obesity.

• INCLUSION CRITERIA:
• BMI greater than or equal to 27 kg/m(2) for the weight loss protocol but body weight less than 350 pounds to accommodate the DXA scanner.
• BMI less than or equal to 24 kg/m(2) (and BMI greater than or equal to 18.5 kg/m(2) for the overfeeding protocols. A history of low BMI and difficulty gaining weight.
• Age 18-60 years, to minimize potential co-morbid conditions which may indirectly affect EE. Minors under the age of 18 will be excluded because growth and pubertal issues are significant parameters that could affect our outcomes and also because the time requirements of the study are such that they would interfere with school schedules. Women who are post-menopausal will be excluded from the study as changes in their metabolism could affect the baseline measurements which are hypothesized to predict weight change.
• Healthy, as determined by medical history, physical examination, and laboratory tests

EXCLUSION CRITERIA:

• Current smoking
• Type 2 diabetes (according to the World Health Organization diagnostic criteria)
• Impaired glucose tolerance (according to the World Health Organization diagnostic criteria) for those participating in the overfeeding study arms only
• Endocrine disorders (Cushing s Disease, pituitary disorders, and hypo- and hyperthyroidism)
• Chronic pulmonary disorders, including chronic obstructive pulmonary disease that would limit ability to follow the protocol (investigator judgment) and obstructive sleep apnea syndrome; only subjects with mild or exercise-induced asthma on no medications or on beta-adrenergic agonists only (such as albuterol) will be allowed to enter the study (provided use of these agents is not required for one week before study entry).
• Cardiovascular diseases (coronary heart disease, heart failure, arrhythmias, and peripheral artery disease)
• Hypertension (blood pressure measurement higher than 140/90 mm Hg (overfeeding study) or 160/95 (weight loss study) on two or more occasions or use of anti-hypertensive medications)
• Diagnosed gastrointestinal diseases, including inflammatory bowel diseases (e.g., Crohn s disease and ulcerative colitis), malabsorption syndromes (e.g., celiac disease), gastric ulcer (active); only subjects with gastro-esophageal reflux will be allowed to enter the study
• Presence of a pacemaker or other implantable devices/shrapnel which may interfere with the MRI or CorTemp measurements
• Liver disease (cirrhosis, active hepatitis B or C, and AST or ALT greater than or equal to 1.5 times normal)
• Renal disease (serum creatinine concentrations greater than or equal to 1.5 mg/dl and/or overt proteinuria)
• Central nervous system disease (cerebrovascular accidents, dementia, and neurodegenerative disorders)
• Cancer requiring treatment in the past five years, except for non-melanoma skin cancers or cancers that have clearly been cured or in the opinion of the investigator carry an excellent prognosis (e.g., Stage 1 cervical cancer)
• Alcohol (more than 3 drinks per day) and/or drug abuse (such as amphetamines, cocaine, heroin, or marijuana)
• Current or past history of: bipolar disorder, schizophrenia or presence of psychotic symptoms, bulimia nervosa or anorexia nervosa, or current major depressive disorder
• Pregnancy or lactation
• Taking weight loss medications
• Weight change of plus or minus 5% in the last 3 months

Conditions not specifically mentioned above may serve as criteria for exclusion at the discretion of the investigators. Additionally, potential subjects might be excluded if they demonstrate a style of interpersonal relationships that would inhibit successful completion of the study.