The primary objective of this study is to examine the effects of a high-protein diet (HP) paired with resistance training (RT) compared with a HP diet alone, on skeletal muscle mass (SMM) volume of the (a) quadriceps and (b) rhomboids, and upper and lower body muscle strength in adults recently prescribed tirzepatide. The secondary objectives of this study are to compare changes in resting energy expenditure (REE), adaptive thermogenesis (AT), and body adiposity (SFV, VAT, and intramuscular FF) in the quadriceps and rhomboid muscles) between the high-protein diet with RT and the high-protein diet arms at 6 months.

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.

IPD will not be distrusted to other researchers for this study. The de-identified participant data from the final research dataset will be shared upon reasonable request beginning 9 to 36 months after publication or as required by a condition of awards or supporting agreements, provided the requesting investigator executes a data use agreement with NYU Langone Health. This instance of data sharing will also require separate IRB review as well as review from NYU Langone's Data Sharing Strategy Board (DSSB). Requests should be directed to: Dr. Collin Popp, collin.popp@nyulangone.org. The protocol and statistical analysis plan will be posted on Clinicaltrials.gov only as required by federal regulation or supporting awards and agreements.