Prolonged Semaglutide Treatment Reveals Stage-Dependent Changes to Feeding Behavior and Metabolic Adaptations in Male Mice

Glucagon-like peptide 1 receptor (GLP-1R) agonists have transformed obesity treatment, but weight loss responses to these drugs vary widely. Elucidating behavioral and metabolic phenotypes throughout GLP-1R agonist treatment could identify mechanisms underlying this response spectrum. We characterized food intake, meal patterns, energy expenditure (EE), and substrate oxidation during prolonged semaglutide treatment and posttreatment recovery in obese male mice at room temperature (RT) and thermoneutral temperature (TN). Semaglutide-induced weight loss and posttreatment weight regain were similar at RT and TN. Weight loss was divided into three stages at both temperatures: rapid initial weight loss, slower gradual weight loss, and weight maintenance. Initial weight loss was marked by reduced food intake, smaller and less frequent meals, and increased lipid oxidation. Food intake gradually returned to pretreatment levels through increased meal frequency, whereas meal size remained suppressed. Lipid oxidation gradually decreased, whereas carbohydrate oxidation increased. Weight-adjusted EE remained constant and elevated in semaglutide- versus vehicle-treated mice, and locomotor activity increased throughout semaglutide treatment. Mice rapidly regained weight after treatment cessation as a result of increased food intake, meal size and frequency, carbohydrate oxidation, EE, and activity. Thus, semaglutide-induced weight loss and regain after treatment cessation involve dynamic, stage-specific changes in feeding behavior, EE, and substrate oxidation. ARTICLE HIGHLIGHTS Although many studies have demonstrated acute behavioral and metabolic effects of glucagon-like peptide 1 receptor (GLP-1R) agonists, few have assessed long-term effects of these drugs on these phenotypes. We assessed changes in various behavioral and metabolic phenotypes throughout a 21-day treatment regimen with semaglutide and posttreatment. Weight loss in response to prolonged semaglutide treatment can be divided into distinct phases, and each phase is characterized by different effects on food intake, meal patterns, energy expenditure, and substrate oxidation. Our findings suggest that differences in behavioral changes and/or metabolic adaptations may underlie the degree of weight loss responsiveness to GLP-1R agonists.