A randomised controlled trial in adults with obesity to evaluate the effects of tirzepatide-induced weight loss, with and without structured exercise, on metabolic, immunological, and imaging biomarkers of systemic and brain inflammation.

TIRZEPATIDE Eligible participants will be individuals who are opportunistically recruited, having been prescribed or considering treatment with tirzepatide for weight management. The safety and appropriateness of tirzepatide treatment will have been determined by the participant’s prescribing clinician prior to study inclusion, with dosing and continuation managed as part of routine clinical care. Tirzepatide is administered as a once-weekly subcutaneous injection, typically initiated at 2.5 mg and titrated in 2.5 mg increments each month up to a maximum of 15 mg weekly, with the most common maintenance dose being 5 mg once weekly. As participants are recruited following clinical prescription, they may be on varying doses depending on their stage of dose escalation, and treatment will continue for up to 6 months in line with the study duration. Participant adherence, including current dose, missed doses, treatment changes, and any side effects, will be monitored using a standardised questionnaire during regular phone or in-person follow-up. The study duration will be 6 months. Safety blood tests will be performed at baseline and at the end of the study, and a medical assessment will be conducted as part of the screening process. Participants who discontinue tirzepatide during the study will be invited to continue participation, with all treatment changes recorded for analysis. EXERCISE INTERVENTION Following baseline assessments and commencement of tirzepatide, participants randomised to the intervention group will undertake a supervised physical activity program for 12 weeks. This program will be individualised based on each participant’s baseline activity levels and physical capacity. The goal is for participants to work up to the below physical activity targets during the supervised period: (1) At least 150 minutes of moderate-intensity aerobic physical activity per week, 55–80% peak heart rate (monitored via Fitbit), 4–6 on Borg's modified Rating of Perceived Exertion (RPE) scale, involving large muscle groups, over 3 to 5 days per week. (2) Moderate-to-high intensity resistance exercises, 10–15 repetitions of each exercise, 4–6 on Borg's RPE scale, targeting large muscle groups, over 2 to 3 days per week. Aerobic All aerobic sessions will include a 3-minute light intensity warm-up and 2-minute cool down, equivalent to an RPE of 1-3 out of 10. Aerobic exercises will be done via a treadmill, cycle ergometer, or land-based walking as appropriate. Exercise intensity will be individualised based on each participant’s baseline testing (e.g., HRpeak or peak power output) and monitored using the RPE scale and heart rate monitors (Fitbit and/or Polar devices). Resistance All strength sessions will be completed with a 5-minute cool down including static stretches and breathing. The resistance program will include 6 to 8 compound exercises focusing on major muscle groups to improve muscle strength and muscle mass such as squats, lunges, modified push-ups, etc. The dosage will include 1 to 3 sets of 8 to 15 repetitions performed at 55-70% of their 1 repetition maximum at baseline, with 1-2-minute rest between sets. The intensity and volume will progressively increase over the course of the 12-week program as tolerated. Technique will be closely monitored, and participants will be encouraged to perform the exercises with control. Participants will attend 2–3 supervised sessions per week (approximately 1 hour each) with an accredited exercise physiologist (AEP). Sessions may be delivered individually or in small groups (up to three participants), either in person or via telehealth. During the supervised phase, any prescribed home-based exercises will be supported using the Physitrack platform. Following the supervised period, participants will continue with an individualised home-based exercise program for the remainder of the study (up to 6 months). Exercise adherence and progression will be supported and monitored using Fitbit and the Physitrack platform, which will be used by the AEP to adjust exercise programs. Regular follow-up will be conducted via phone, email, or telehealth. Participants who are not meeting their prescribed exercise targets may be contacted and encouraged to attend additional supervised sessions where appropriate.