The use of glucagon-like peptide receptor agonists (GLP-1 RAs) may have clinically important effects on skeletal muscle mass (SMM), and physical function. The effects of exercise training in conjunction with GLP-1 RA therapy on these outcomes has not been studied. Additionally, most people treated with GLP-1-based weight loss medications stop taking these medications within 1 year of initiating treatment. This is an important clinical concern because weight regain can occur after weight loss pharmacotherapy is stopped and the impact of stopping GLP-1 RA therapy on physical and metabolic function has not been studied.

In this study, the investigators will conduct a 2-year randomized clinical trial to evaluate body composition, muscle, physical and metabolic function, muscle strength and appetite control and reward signaling in the brain in response to 1-year of GLP-1 RA therapy, with or without exercise training, and subsequent treatment cessation on muscle and appetite-related outcomes assessed 1-year after stopping treatment.

Inclusion Criteria:

• i) obesity (Body Mass Index ≥ 30 kg/m2)
• ii) decreased physical function (Modified Physical Performance Test score 17 to 31)
• iii) approval of their primary physician to participate in this study.

Exclusion Criteria:

• i) unstable weight (>4% change during the last 2 months before entering the study)
• ii) ≥150 min per week of structured exercise (e.g., jogging, activities that cause heavy breathing and sweating)
• iii) diabetes
• iv) significant cardiopulmonary disease (heart failure, angina, uncontrolled hypertension, chronic obstructive pulmonary disease) or other organ dysfunction (e.g., renal insufficiency [eGFR <30 mL/min/1.73 m2])
• v) therapy with a GLP-1 or other weight loss medications
• vi) clinically significant gastric emptying abnormality or chronically take drugs that directly affect gastrointestinal motility
• vii) history of chronic or acute pancreatitis
• viii) thyroid-stimulating hormone (TSH) >1.5X the upper limit of normal (patients receiving treatment for hypothyroidism may be included provided their thyroid hormone replacement dose has been stable for at least 3 months)
• ix) history of significantly active or unstable Major Depressive Disorder or other severe psychiatric disorder (e.g. schizophrenia, bipolar disorder, or other serious mood or anxiety disorder) within the last 2 months that would interfere with study participation
• x) acute or chronic hepatitis, or other liver disease other than Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD)
• xi) family or personal history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2
• xii) history of active or untreated malignancy or are in remission from a clinically significant malignancy (other than basal- or squamous cell skin cancer, in situ carcinomas of the cervix, or in situ prostate cancer) for less than 5 years
• xiii) tobacco use, excessive alcohol intake (≥3 drinks/day for men and ≥2 drinks/day for women) or active substance abuse with illegal drugs by self-report, or regular marijuana use within 3 months of enrollment and unwilling to abstain from marijuana during the trial
• xiv) Use of medications that are known to affect the study outcome measures or increase the risk of study procedures and that cannot be temporarily discontinued for this study
• xv) have had bariatric surgery or plan to have endoscopic or bariatric surgery therapy for obesity
• xvi) anemia (Hgb <10 g/dL)
• xvii) Conditions that render subject unable to complete all testing procedures (e.g., severe ambulatory impairments, limb amputations, or metal implants that interfere with imaging procedures; coagulation disorders)
• xii) history of seizure disorder
• xix) Female who is pregnant, breast-feeding or intends to become pregnant
• xx) allergy or hypersensitivity to GLP-1 RA medications
• xxi) unable to grant voluntary informed consent
• xxii) unable or unwilling to follow the study protocol or who, for any reason, the research team considers the participant is not an appropriate candidate for the study