Chronic semaglutide treatment reveals stage-dependent changes to feeding behavior and metabolic adaptations in male mice

ABSTRACT Glucagon-like peptide-1 receptor (Glp1r) agonists have transformed obesity treatment, but weight loss responses to these drugs vary widely. Elucidating behavioral and metabolic phenotypes throughout Glp1r agonist treatment could identify mechanisms underlying this response spectrum. We characterized food intake, meal patterns, energy expenditure (EE), and substrate oxidation during chronic semaglutide treatment and post-treatment recovery in obese male mice at room temperature (RT) and thermoneutral temperature (TN). Semaglutide-induced weight loss and post-treatment weight regain were similar at RT and TN. Weight loss was divided into three stages at both temperatures: 1) rapid initial weight loss, 2) slower gradual weight loss, and 3) 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 pre-treatment levels through increased meal frequency, while meal size remained suppressed. Lipid oxidation gradually decreased while carbohydrate oxidation increased. Weight-adjusted EE and locomotor activity increased throughout semaglutide treatment. Mice rapidly regained weight after treatment cessation, and this was associated with increased food intake, meal size and frequency, carbohydrate oxidation, EE, and activity. These findings reveal that 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 demonstrate acute behavioral and metabolic effects of glucagon- like peptide-1 receptor (Glp1r) agonists, few have assessed chronic effects of these drugs on these phenotypes. We wanted to assess changes to various behavioral and metabolic phenotypes throughout a chronic treatment regimen with semaglutide and post-treatment. Weight loss in response to chronic 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 Glp1r agonists.