Popular weight loss strategies often involve reducing an individual's consumption of carbohydrates or fat. However, no controlled study has been carried out to evaluate the effects of reducing carbohydrate versus fat consumption while keeping the other nutrients at standard levels to maintain an individual's weight. Researchers are interested in investigating how different restrictions of carbohydrates or fats affect the many processes involved in weight loss, including brain activity and blood and brain chemical composition.

Popular weight loss strategies often prescribe a targeted reduction of dietary carbohydrate or fat. But surprisingly, no controlled human feeding study has ever investigated the effects of a selective reduction of dietary carbohydrate versus fat while keeping the other dietary macronutrients at their baseline weight-maintenance values. The present study was designed to address this knowledge gap and improve our understanding of how selective reduction of dietary fat versus carbohydrate may differentially impact the many feedback control processes that act to resist weight loss.

Objectives:

- To determine the comparative effects of two controlled fat- or carbohydrate-restricted diets and an outpatient weight loss program on blood and brain chemical composition, weight loss (fat and lean body mass), and regional brain activity in lean and obese individuals.

Eligibility:

- Healthy individuals between 18 and 45 years of age who are either lean (body mass index between 18.5 kg/m(2) and 25 kg/m(2)) or obese (body mass index above 30.0 kg/m(2), weight less than 350 pounds) and are right-handed.

Design:

• Lean participants: Participants will be screened with a medical history, physical examination, blood and urine tests, and weight maintenance observations (food diaries and physical activity monitors). For the scanning visit, participants will receive balanced meals from the National Institutes of Health to consume for 2 days before the visit. During the scanning visit, participants will continue to eat the weight maintenance diet, complete questionnaires, and have a series of imaging studies (including positron emission tomography and magnetic resonance imaging tests) to evaluate brain response to food and other stimuli.
• Obese participants: Participants will be screened with a medical history, physical examination, blood and urine tests, and weight maintenance observations (food diaries and physical activity monitors). During the first inpatient visit, obese participants will eat a weight-maintenance diet for 5 days to establish baseline measurements. After several days of eating a weight-maintenance diet, 20 obese adult volunteers (BMI above 30 kg/m2) will be admitted to the metabolic clinical research unit (MCRU) and, after 5 additional days of the baseline diet, their diets will be modified to result in either 85% reduction of the baseline dietary fat or a 60% reduction of the baseline dietary carbohydrate for the next 6 days. These diet modifications produce an equivalent caloric reduction. The primary outcome measurements will be changes of metabolism, brain reward circuitry and regional brain activity in response to food stimuli measured during the baseline and reduced calorie diet phases. Immediately following each controlled diet, we will measure 3 days of ad-libitum food intake using a computerized vending machine system. The subjects will return to the MCRU after a 2-10 week washout period to receive the opposite reduced calorie diet. Twenty control subjects with normal body weight (BMI between 18.5 - 25 kg/m2) will have measurements of brain reward circuitry and regional brain activity in response to food stimuli while on a balanced, weight-maintenance diet. Immediately following the second in-patient visit, all of the obese subjects will be assigned to a 12 week out-patient weight loss program with the goal of achieving at least 5% weight loss. We will investigate the relationship between short-term fat imbalances measured during the in-patient phases, and the body weight and fat changes during the weight loss program. We will evaluate the effects of weight loss on metabolism, brain reward circuitry, and regional brain activity in response to food stimuli. Finally, if the subjects are available for long-term follow-up, then we will investigate their metabolic phenotype, brain reward circuitry, and regional brain activity in response to food stimuli yearly over the subsequent 5 years following the weight loss intervention. This study will result in an improved understanding of the physiological mechanisms that sense and respond to negative energy balance acutely, after several weeks, and after several years, and may eventually lead to increased long-term success of obesity treatment.

• INCLUSION CRITERIA:
• Age 18-45 years, male or female
• Body mass less than 350 lbs. (max. weight dictated by table limit for functional magnetic resonance imaging (fMRI) scanner) when acquisition of large bore fMRI is complete, max. wt. limit will increase to 400 lbs.
• Weight stable (less than plus or minus 5 kg over past 6 months)
• Body mass index greater than or equal to 30.0 kg/m(2)
• Premenopausal (women only)
• Healthy, as determined by medical history and laboratory tests
• Able to complete daily bouts of walking at a moderate rate
• Written informed consent

EXCLUSION CRITERIA:

• Body mass greater than 350 lbs. (max. weight dictated by table limit for fMRI scanner) when acquisition of large bore fMRI is complete, max. wt. limit will increase to 400 lbs.
• BMI less than 30.0 kg/m(2)
• Evidence of metabolic or cardiovascular disease, or disease that may influence metabolism (e.g. cancer, diabetes, thyroid disease)
• Taking any prescription medication (except birth control) or other drug that may influence metabolism (e.g. diet/weight-loss medication)
• Hematocrit less than 34% (women only)
• Hematocrit less than 40% (men only)
• Pregnancy, lactation (women only)
• Allergy to lidocaine or ethanol
• Participating in a regular exercise program (greater than 2h/week of vigorous activity)
• Caffeine consumption greater than 150 mg/day (will be clamped at baseline intake during study)
• Regular use of alcohol (greater than 2 drinks per day), tobacco (smoking or chewing), amphetamines, cocaine, heroin, or marijuana over past 6 months
• Past or present history of eating disorder (including binge eating) or psychiatric disease
• Volunteers with strict dietary concerns (e.g. vegetarian or kosher diet, multiple food allergies)
• Are claustrophobic to a degree that they would feel uncomfortable in the MRI machine.
• Having any metal in their body (for example, pacemakers, metallic prostheses such as cochlear implants or heart valves, shrapnel fragments, etc.).
• Left-handedness
• Non-native English speakers
• Volunteers unwilling or unable to give informed consent

Control Subjects

INCLUSION CRITERIA:

• Age 18-45 years, male or female
• 18.5 kg/m(2) less than BMI less than 25.0 kg/m(2)
• Weight stable (less than plus or minus 5 kg over past 6 months)
• Premenopausal (women only)
• Healthy, as determined by medical history and laboratory tests
• Written informed consent

EXCLUSION CRITERIA:

• BMI less than 18.5 or greater than 25.0 kg/m(2)
• Evidence of metabolic or cardiovascular disease, or disease that may influence metabolism (e.g. cancer or diabetes)
• Taking any prescription medication (except birth control) or other drug that may influence metabolism (e.g. diet/weight-loss medication)
• Hyperlipidemia (fasting plasma triglyceride concentration greater than 150 mg/dl)
• Hematocrit less than 34% (women only)
• Hematocrit less than 40% (men only)
• Pregnancy, lactation (women only)
• Participating in a regular exercise program (greater than 2h/week of vigorous activity)
• Caffeine consumption greater than 150 mg/day
• Regular use of alcohol (greater than 2 drinks per day), tobacco (smoking or chewing), amphetamines, cocaine, heroin, or marijuana over the past 6 months
• Past or present history of eating disorder (including binge eating) or psychiatric disease
• Volunteers with strict dietary concerns (e.g vegetarian or kosher diet, multiple food allergies)
• Are claustrophobic to a degree that they would feel uncomfortable in the MRI machine.
• Having any metal in their body (for example, pacemakers, metallic prostheses such as cochlear implants or heart valves, shrapnel fragments, etc.).
• Left-handedness
• Non-native English speakers
• Volunteers unwilling or unable to give informed consent

Up to 12 weeks after the second in-patient visit