Co-agonism of GLP-1R and CTR/AMYR in the lateral dorsal tegmental nucleus produces additive effects on homeostatic and motivated feeding.

As obesity rates continue to rise globally, combination therapies are being developed for their pronounced and sustained weight loss effects. CagriSema is a fixed-ratio combination of the long-acting GLP-1R agonist semaglutide and the calcitonin (CTR)/amylin receptor (AMYR) agonist cagrilintide that shows greater efficacy for weight loss compared to GLP-1R and CTR/AMYR mono-agonists alone. However, knowledge of the neural sites capable of producing potentiated effects as a result of GLP-1R/CTR/AMY co-agonism remains incomplete. In this study, we investigate the laterodorsal tegmental nucleus (LDTg) as a central site of integration for GLP-1R and CTR/AMYR signaling, and explore the effect of co-agonism in this nucleus on feeding behavior. We first performed fluorescence in situ hybridization (FISH) to show that glp-1r- and ctr-expressing neurons comprise largely distinct populations within the LDTg, supporting a model where LDTg GLP-1R and CTR/AMYR agonists reduce feeding via engagement of distinct complementary cells in the LDTg. We also showed that co-administration of GLP-1R and CTR/AMYR agonists into the LDTg resulted in a greater suppression of food intake and reduction in body weight compared to either treatment alone. Finally, using an operant model, we found that this combinatorial treatment significantly reduced motivation to self-administer a highly palatable food reward. Overall, intra-LDTg co-agonism of GLP-1Rs and CTR/AMYRs produced a greater suppressive effect on homeostatic and motivational aspects of feeding behavior than monotherapy alone. These results highlight the LDTg as a previously undescribed central site with potential clinical relevance for the development of dual GLP-1R and CTR/AMYR pharmacotherapies to combat obesity.