High-protein plUs reSistance Training in gLucagon-like pEptide 1 Receptor Agonist Users (HUSTLE)

Inclusion criteria

• Age 30- 60 years
• BMI 27.0-37.0 kg/m² at screening
• English speaking (at this time, MyNetDiary, a food-logging app used for tracking protein-intake, is only set up for English, and our RDN is only capable of providing nutritional counseling in English)
• Received a prescription for tirzepatide, a second-generation oral or injectable dual GIP/GLP-1 receptor agonist (Zepbound/Mounjaro) that is FDA-approved for obesity; and

• Has not yet started tirzepatide and agrees to complete a 4-week run-in period at the initial dose with <3% weight loss from baseline; OR
• Has initiated tirzepatide and is within the first 4 weeks at the initial dose with <3% weight loss from pre-treatment baseline.
• On a stable regimen for major chronic conditions (e.g., antihypertensives, lipid-lowering agents, oral antidiabetics, hypothyroidism) for ≥ 8 weeks prior to enrollment.
• Willing and able to:

• (i) Receive high-protein diet counseling and attempt to achieve ~2.5 g/kg FFM /day protein;
• (ii) Attend scheduled nutrition telehealth visits with an RDN;
• (iii) Medically cleared for moderate-intensity resistance training 2 days/week (no condition that would preclude safe participation in either diet-only or diet plus resistance training).
• Willing and able to undergo whole-body MRI at baseline and 6 months without sedation.
• Able to understand procedures and provide written informed consent in English (at this time, MyNetDiary, a food-logging app used for tracking protein-intake, is only set up for English, and our RDN is only capable of providing nutritional counseling in English)

Exclusion criteria

• Patients currently prescribed oral or injectable incretin mimetics containing GLP-1RAs, including Exenatide, Liraglutide, Lixisenatide, Dulaglutide, Semaglutide. Participants who are currently prescribed tirzepatide and have been using for >4 weeks will also be excluded.
• Prior use of incretin mimetics containing GLP-1RAs with >3% weight loss in a 4-week period
• Lost >5% body weight in the past 6 months
• Has consistently resistance trained (>10 sessions) in the last year
• Currently taking medication or supplements that have been shown to impact muscle function and muscle mass in the last 6 months
• Participants who live outside of the tri-state area and/or are not willing to come to New York City for in-person visits outlined
• Plans to be out of town more than 2 consecutive weeks or >6 weeks total over the next 6 months
• Type 1 or 2 diabetes; uncontrolled diabetes (e.g., HbA1c > 6.4% if specified); recurrent severe hypoglycemia or hypoglycemia unawareness.
• Moderate-to-severe chronic kidney disease (e.g., eGFR < 45-60 mL/min/1.73 m2 final cutoff per protocol) or other renal disease
• Decompensated cirrhosis, severe chronic liver disease, or active liver disease
• Unstable cardiovascular disease (e.g., myocardial infarction (MI), stroke, coronary revascularization, or hospitalization for unstable angina or decompensated heart failure (HF) within <6 months)
• Active malignancy requiring systemic therapy in the past 6-months (excluding non-melanoma skin cancer)
• Serious medical/psychiatric conditions making participation unsafe or likely to impair adherence
• Pregnant, planning pregnancy within 6 months, or breastfeeding; women of childbearing potential unwilling to use effective contraception per institutional/drug-label guidance.
• Conditions requiring protein restriction (e.g., advanced Chronic Kidney Disease (CKD), relevant inborn errors of metabolism).
• Severe, poorly controlled gout/hyperuricemia
• Significant GI disease impairing tolerance or absorption (e.g., active Inflammatory Bowel Disease (IBD) with frequent flares, short bowel syndrome, severe gastroparesis beyond expected GLP-1 effects)
• Severe food allergies or intolerances that preclude a high-protein diet or ingestion of whey or pea protein and associated additives/ingredients of the protein powders used in this study.
• Has or previously had an eating disorder
• Severe musculoskeletal, neuromuscular, or other conditions that preclude moderate-intensity RT
• Advised not to exercise by their general practitioner or medical professional or refusal to obtain medical clearance if indicated by Physical Activity Readiness Questionnaire (PAR-Q) answers
• Standard contraindications to MRI: tattoos with metallic ink, pacemaker, cerebral and/or cochlear implant, metal in the eye, severe claustrophobia, presence of electronic devices or ferromagnetic metallic foreign or implanted objects that could constitute a hazard, inability to lie flat, or any other contraindication for MRI.
• Weight >200kg, or large body habitus which the MRI scanner cannot accommodate.
• Inability or unwillingness to attend a reasonable proportion of RT sessions and refusal of accommodations
• Concurrent enrollment in another weight management intervention
• Prior bariatric surgery within the past 12 months or planned bariatric surgery within the 6-month study period.
• Active alcohol or drug use disorder
• Significant cognitive impairment or language barrier precluding informed consent or adherence
• Any reason that could compromise the participants' safety, based on the judgment of the investigators and/or clinical coordinators.