Metabolic and Neural Adaptations to Weight Loss, Plateau, and Regain
Metabolic and Neural Adaptations to Weight Loss, Plateau, and Regain
Background:

 - Many people can lose weight by changing their diet or exercise. However, most people
 eventually regain the weight over time. This weight regain may be related to changes in
 metabolism as well as changes in the brain caused by weight loss. Researchers want to learn
 more about these changes.

 Objective:

 - To see how weight loss and regain affects the body s metabolism and the brain of obese but
 healthy adults.

 Eligibility:

 - Obese but healthy adults age 18-55 who plan to participate in a weight loss program at one
 of several participating clinics or resorts.

 Design:

 -  Participants will first be screened at home through questionnaires and telephone
 interviews.

 -  Participants will then be screened at the NIH with blood tests, medical history,
 physical exam, electrocardiograms, and questionnaires. They will have a mock magnetic
 resonance imaging (MRI) scan.

 -  At visit 1, participants will stay at the NIH and will:

 -  have MRI and PET brain scans.

 -  have body composition scans and measurements.

 -  give blood samples.

 -  eat a special diet.

 -  wear a physical activity monitor.

 -  provide a urine sample and body weight daily.

 -  drink a special type of water to measure calorie burn.

 -  wear a clear plastic hood over their head while lying down, to collect exhaled air.

 -  spend 24 hours in a room that measures oxygen and carbon dioxide.

 -  complete questionnaires and computer tasks.

 -  After visit 1, participants will give daily urine samples and weight and physical
 activity measurements from home. Then they will follow a lifestyle intervention for
 weight loss and give daily weight and activity measurements.

 -  Visits 2, 3, and 4 occur 1-26 months after the start of the weight loss program.
 Participants will repeat procedures from visit 1. Visits 1-4 last 4 days each.

 -  Researchers will track participants weight and physical activity for up to 26 months
 after visit 2.
Lifestyle interventions can result in weight loss, but most people experience a plateau after
 6-10 months when weight stabilizes and many subsequently regain weight over the subsequent
 months. This pattern of weight plateau and regain is typical and appears to be independent of
 the lifestyle intervention used. The apparent resistance to further weight loss in not well
 understood.

 We recently demonstrated that participants engaged in an intensive intervention employing
 caloric restriction and vigorous exercise had a profound slowing of metabolism that was
 significantly greater than expected due to weight loss alone. This phenomenon is called
 metabolic adaptation and has also been observed following weight loss through caloric
 restriction without exercise and may persist long after weight loss has ceased. Metabolic
 adaptation has been hypothesized to limit weight loss and predispose individuals to weight
 regain, but this has yet to be demonstrated and the concept is controversial. In addition to
 the metabolic adaptations to weight loss, the brain also adapts in ways that enhance the
 activation of reward regions in response to palatable food cues and their receipt. In
 particular, the brain s dopamine circuitry is believed to be altered in obesity and it is
 presently unclear how this pathway responds to a weight loss intervention in humans.

 The primary aims of this study are to investigate the metabolic and neural adaptations in 60
 obese adult volunteers participating in lifestyle interventions resulting in weight loss
 through a structured meal replacement program or caloric restriction plus vigorous exercise.
 The secondary aim is to determine whether the magnitude of metabolic adaptation or the
 changes in the brain s reward circuitry or responsiveness to food cues are related to the
 ubiquitous weight loss plateau after 6-10 months or the rate of weight regain in the
 subsequent months.
-  INCLUSION CRITERIA:

 -  Age 18-55 years, male and female

 -  Recent weight stability (< plus and minus 2 % over past 1 month)

 -  Body mass index (BMI) greater than or equal to 30 kg/m2

 -  Able to complete daily bouts of moderate to vigorous exercise (when applicable)

 -  Written informed consent

 -  Have reserved a stay of at least 4 weeks at The Biggest Loser Resort or have enrolled
 in a structured meal replacement weight loss program at the Washington Center for
 Weight Management and Research, the National Center for Weight and Wellness, or the
 Johns Hopkins Weight Management Center.

 EXCLUSION CRITERIA:

 -  Body weight > 400 lbs (weight limit of PET and MRI scanners)

 -  BMI < 30 kg/m2

 -  Less than 80% of maximum lifetime weight

 -  Hypertension if

 -  (1) >160/100;

 -  (2) 140/90 to 159/99 with evidence of target organ damage (e.g. elevated serum
 creatinine, proteinuria, abnormal EKG, retinopathy);

 -  (3) >140/90 on antihypertensive medications.

 -  Evidence of metabolic or cardiovascular disease, or disease that may influence
 metabolism (e.g. cancer, thyroid disease)

 -  Past or present history of eating disorder (including binge eating) or psychiatric
 disease

 -  Taking any prescription medication or other drug that may influence metabolism (e.g.
 diet/weight-loss medication, asthma medication, psychiatric medications,
 corticosteroids, or other medications at the discretion of the PI and/or study team)

 -  Hematocrit < 34% (women only)

 -  Hematocrit < 40% (men only)

 -  Pregnancy, lactation (women only)

 -  Women who become pregnant during the two-year study period

 -  Recent participation in a regular exercise program (> 4h/week of vigorous activity)

 -  Previous bariatric surgery

 -  Caffeine consumption > 500 mg/day

 -  Regular use of alcohol (>2 drinks per day), tobacco (smoking or chewing) amphetamines,
 cocaine, heroin, or marijuana over past 6 months

 -  Volunteers with strict dietary concerns (e.g. vegetarian or kosher diet, multiple food
 allergies)

 -  Having metal implants incompatible with MRI (for example, pacemakers, metallic
 prostheses such as cochlear implants or heart valves, shrapnel fragments, etc.).

 -  Non-native English speakers

 -  Volunteers unwilling or unable to give informed consent