Parabrachial CGRP neurons mediate incretin-induced aversion and anti-aversion, but not anorexia or weight loss.

Incretin mimetics such as the glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide cause decreased food intake, weight loss, and aversion. Here, we examined the extent to which parabrachial calcitonin gene-related peptide (CGRP) neurons contribute to these effects. Further, we assessed whether glucose-dependent insulinotropic polypeptide receptor (GIPR) agonism alters liraglutide-induced behavior and CGRP neuron activity. We found that liraglutide activates parabrachial CGRP neurons and that this is required for liraglutide-induced aversion, but not anorexia or weight loss. Additionally, treatment with a GIPR agonist (GIPRA) or the well-established anti-emetic drug ondansetron ameliorated liraglutide-induced conditioned taste avoidance (CTA) and CGRP neuron activation without affecting acute liraglutide-induced feeding suppression. Taken together, our findings demonstrate that the aversive and anorexigenic effects of liraglutide are mediated by distinct neural mechanisms that can be separably manipulated. Our findings also highlight GIPR agonism as an emerging anti-aversive approach to GLP-1RA-induced malaise while maintaining the beneficial metabolic effects.