OBJECTIVE: Incretin-based obesity medication maintains weight loss by mimicking the appetite-inhibiting hormone GLP-1. Interestingly, chronic exercise may improve postprandial appetite control by increasing late postprandial secretion of endogenous GLP-1. Therefore, we investigated whether an exercise program after weight loss could increase late-phase postprandial GLP-1 secretion. METHODS: This study is an exploratory analysis of adults with obesity (n = 195) who lost 13.1 kg on a low-calorie diet and were randomized to 52 weeks of either usual activity, moderate-to-vigorous intensity exercise, the GLP-1 receptor agonist liraglutide (3.0 mg/day), or the combination. The primary endpoint was change in late-phase GLP-1 response to a 3-h liquid mixed meal test before and after diet-induced weight loss and after 1 year of intervention. RESULTS: Diet-induced weight loss did not change late-phase GLP-1 response (3%; 95% CI -4% to 10%). One year of exercise increased late-phase postprandial GLP-1 response within the group by 37% (95% CI 20% to 57%), and this increase was 25% greater (95% CI 3% to 51%, p = 0.02) compared to the usual activity group. Late-phase postprandial GLP-1 response was unchanged in both groups treated with GLP-1 receptor agonist compared to placebo. CONCLUSIONS: One year of exercise increased late-phase postprandial GLP-1 response, which may prevent increased appetite after weight loss and thereby weight regain. TRIAL REGISTRATION: EudraCT number: 2015-005585-32; ClinicalTrials.gov identifier: NCT04122716.

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