A Study to Investigate Why Overweight People Regain Weight After Losing Weight in a Behavioral Weight Loss Program

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.

Inclusion Criteria: 1. Age: 25 - \ 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 (\ 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)