An area postrema GLP-1R to NTS pathway dissociates semaglutide-induced satiation, nausea and reduced food motivation from satiety

Abstract The GLP-1-based anti-obesity drug semaglutide lowers bodyweight primarily by increasing satiation and satiety, whilst also reducing motivation to consume high calorie foods, and commonly causing nausea. The brainstem dorsal vagal complex (DVC) has been identified as a key mediator of these phenotypic components of semaglutide’s anorectic effect. However, which DVC neuron populations are recruited to mediate these components and whether they are dissociable, are translationally important but unresolved questions. We addressed these in mice using metabolic and behavioural phenotyping to resolve the distinct anorectic components elicited by the acute administration of semaglutide. We combined this phenotyping approach with activity-dependent genetic labelling to identify semaglutide-recruited neuron populations (‘Sema-TRAP’) and chemogenetic manipulation to interrogate their contribution to these effects. Semaglutide potentiated satiation and satiety, caused behavioural proxies of nausea, and suppressed motivation to consume high-fat, high-sugar Western diet, in a largely sex-independent manner. It activated a substantial proportion of GLP-1R-expressing neurons in the brainstem area postrema (AP), but surprisingly most semaglutide-activated neurons in the nucleus tractus solitarius (NTS) did not express GLP-1R. Chemogenetic reactivation of Sema-TRAP neurons in the NTS alone was sufficient to recapitulate the effects of semaglutide on satiation, nausea, motivation for Western diet, and bodyweight. Knockdown of GLP-1R expression in the AP prior to Sema-TRAPing prevented the recruitment of Sema-TRAP NTS neurons which elicited these effects on satiation, nausea and motivation. AP GLP-1R knockdown also abolished semaglutide’s effect on satiation and motivation, while effects on satiety and bodyweight were preserved. These data demonstrate that semaglutide suppresses eating via distinct behavioural mechanisms, at least some of which are mediated by dissociable circuits. GLP-1R populations outside the DVC, or distinct subpopulations within the non-GLP-1R NTS neurons recruited downstream of GLP-1R AP , may therefore represent therapeutic targets to tune GLP-1-based obesity drugs towards a better-tolerated effect profile.