The goal of this clinical trial is to determine the physiological basis for the differences in weight regain among adults (25-59 years old) with obesity following participation in a behavioral weight loss program. Eligible participants will undergo a baseline evaluation after which they will enter an up to 20 week behavioral weight loss program with the goal of losing at least 7 percent of their baseline weight within 35 weeks. Participants who meet the weight loss goal will be asked to remain weight stable for 2 weeks after which they will undergo a clinical examination. They will then be observed for 1 year during which they will undergo 2 additional clinical examinations, one 4 months after completing the weight loss program, and the other 12 months after completing the weight loss program.

Primary Hypothesis:

Changes, integrated values and patterns in energy intake (EI), energy expenditure (EE), resting energy expenditure (REE) and non-resting energy expenditure (NREE), contribute to the variability in weight change during the 12 months following weight loss.

Assessment time points:

• Baseline (BL): prior to starting the weight loss intervention
• T0: at the end of a period of weight stabilization following at least 7 percent weight loss
• T4: four months (17 weeks) following T0
• T12: twelve months (52 weeks) following T0

Secondary Hypotheses:

Changes, integrated values and patterns in components of EI and EE (listed below) contribute to variability in weight change during the 12 months following weight loss.

EI:

• Psychosocial, food attitude, and food environment assessments
• Diet composition
• Neural activation in food choice/decision-making and cue/taste/reward (functional magnetic resonance imaging [fMRI])
• Measures of food choice, delay discounting, and eating in the absence of hunger
• Gastric emptying, appetite-related peptides, and glucose and lipid excursions in response to a meal

EE:

• Physical activity

• 24-hour urine catecholamine

• Muscle contractile efficiency

• Mitochondrial function in biopsied skeletal muscle

• Sleep quality and patterns

  • Muscle and adipose tissue gene expression
  • Plasma metabolome, proteome, exosomes and exposome
  • Stool microbiome

Specific Aims:

Specific Aim 1: Examine total energy expenditure (TEE) and energy intake (EI) at, and between, baseline, the end of the weight stabilization period following at least 7 percent weight loss, 17 weeks and 52 weeks after the end of the weight stabilization period following at least 7 percent weight loss with respect to variability in weight change between the end of the weight stabilization period following at least 7 percent weight loss and 52 weeks after the end of the weight stabilization period following at least 7 percent weight loss.

Specific Aim 2: Examine resting energy expenditure (REE) and non-resting energy expenditure (NREE) at, and between, baseline, the end of the weight stabilization period following at least 7 percent weight loss, 17 weeks and 52 weeks after the end of the weight stabilization period following at least 7 percent weight loss with respect to variability in weight change between the end of the weight stabilization period following at least 7 percent weight loss and 52 weeks after the end of the weight stabilization period following at least 7 percent weight loss.

Specific Aim 3: Assess endophenotypes of EI (e.g. diet composition, food-choice, decision-making, delay discounting, cue/taste reward, gastric emptying, appetite-related peptides, glucose and lipid excursions in response to a meal, sleep patterns, food and social environments) at and between time points at which they are measured (e.g., baseline, the end of the weight stabilization period following at least 7 percent weight loss, 17 weeks and 52 weeks after the end of the weight stabilization period following at least 7 percent weight loss) and examine their contributions to the variability in weight change between the end of the weight stabilization period following at least 7 percent weight loss and 52 weeks later.

Specific Aim 4: Assess endophenotypes of EE (e.g., actigraphy measures, sleep patterns, muscle contractile efficiency, mitochondrial function, muscle and adipose tissue gene expression, plasma metabolome, microbiome, exposome, and environment) at, and between, time points at which they are measured (e.g., baseline, the end of the weight stabilization period following at least 7 percent weight loss, 17 weeks and 52 weeks after the end of the weight stabilization period following at least 7 percent weight loss) and examine their contributions to the variability in weight change between the end of the weight stabilization period following at least 7 percent weight loss and 52 weeks later.

Inclusion Criteria:

1. Age: 25 - <60 years
2. BMI: 30 - <40 kg/m2 at the first screening visit
3. Within 5% of current weight, for the past 6 months at the first screening visit
4. Able to participate in ergometry testing
5. Has a smart phone, tablet or computer with access to the internet

Exclusion Criteria:

1. If 25-29 years old, > 5% deviation from maximum weight (excluding weights while pregnant) since age 25 years

2. If at least 30 years old, > 5% deviation from maximum weight (excluding weights while pregnant) in last 5 years or ≥ 10% deviation from maximum weight (excluding weights while pregnant) since age 30 years

3. History of pulmonary embolus in the past 6 months

4. Cardiovascular disease (e.g. myocardial infarction, stroke, hospitalization for unstable angina, or transient ischemic attack) within the past 6 months

5. Current major depressive disorder or history of major depressive disorder within 2 years

6. Any regular tobacco or nicotine use in the past year

7. Currently engaging in intense physical training or training for a sports event including, but not limited to, a marathon or body building

8. Currently pregnant, or less than one-year post-partum or actively planning to become pregnant within the next two years

9. Presently classified as being in New York Heart Association Class II or greater or dysrhythmia

10. Diabetes (type 1 or 2 - HbA1c ≥ 6.5%, fasting glucose ≥ 126 mg/dL) or currently taking a glucose lowering medication

11. Thyroid disease requiring hormones or medication or TSH < 0.5 or > 5 mIU/L

12. Renal disease requiring dialysis

13. Known HIV infection

14. ALT or AST greater than 5 times the upper limit of normal or active gall bladder disease

15. Significant anemia (Hgb < 10 g/dL) or thrombocytopenia (platelet count < 60,000 /mm3)

16. Leukopenia defined as:

    Males: WBC < 3,100 /mm3 or (WBC 3,100 - < 4,000 /mm3 and at least 1 Duffy antigen (A, B) positive or no result) Females: WBC < 3,400 /mm3 or (WBC 3,400 - < 4,000 /mm3 and at least 1 Duffy antigen (A, B) positive or no result)

17. Active cancer or current chemotherapy treatment, or history of cancer requiring treatment in the past 5 years except for non-melanoma skin cancers or cancers that have clearly been cured

18. Current or past history of anorexia nervosa or bulimia nervosa

19. Current or past diagnosis of binge eating disorder

20. Diagnosis of other severe psychiatric disorder (e.g. schizophrenia, bipolar disorder)

21. Unwillingness to abstain from marijuana/cannabis use for 3 weeks at each of the four assessment time points

22. Known or suspected abuse or misuse of alcohol, prescription drugs, or recreational drugs

23. Antiretroviral therapy (ART), including treatment for HIV, pre-exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP) within the past 3 months

24. Regularly taking medication or supplement known to affect appetite, energy expenditure, or weight (e.g. appetite suppressants, steroids-including inhaled steroids but not topical, alpha-blockers, beta-blockers, certain psychotropic medications)

25. Currently taking anticoagulant medication

26. Currently enrolled in a supervised weight reduction program

27. Prior or planned bariatric surgery, endoscopic therapy, device-based therapy for obesity, liposuction, cryolipolysis, or abdominoplasty

28. Severely restricted diets: Vegan (no meat, fish, dairy, eggs, or honey), very low carbohydrate (<15% calorie as carbohydrate), very low fat (<15% calories as fat), or strictly gluten free

29. Current celiac or diagnosed gluten intolerance or inflammatory bowel disease requiring specialized diet

30. Night or rotating shift worker

31. Known severe allergy (e.g. anaphylaxis) to nuts or other foods

32. Systolic blood pressure (BP) <90 mmHg and/or diastolic BP <60 mmHg on 2 measurements during the clinical screening visit.

33. Systolic blood pressure (BP) >160 mmHg and/or diastolic BP >100 mmHg on at least 2 measurements during the clinical screening visit or resting heart rate < 45 beats per minute or >100 on 2 measurements during the clinical screening visit.

34. Metal implants, piercings that cannot be removed, or metal-based tattoos or hair treatments

35. Exceeds limitations to fit dual-energy X-ray absorptiometry (DXA) field of view

36. Known allergy to lidocaine or acetaminophen

37. Non-compliance with appointments or tasks (food diaries, etc.) during the screening phase

38. Blood clotting disorder or INR > ULN or PT > ULN or (a)PTT > ULN

39. Tendency to form thick or raised scars

40. Inability to achieve weight stability (defined in section 4.2.1) during the 2 weeks prior to initiation of the baseline Doubly Labeled Water (DLW) assessment

41. At high risk for suicide, as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS)

Relevant individual participant data (IPD) will be provided to approved ancillary study investigators. All data will be archived, following the end of the study, at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)-supported data repository.

Following the end of data collection. Time frame is determined by the NIDDK.

Access to the data for approved ancillary studies will be through the data coordinating center. Access to the data at the NIDDK-repository will be through the NIDDK data repository's process.