A cross-species atlas of the dorsal vagal complex reveals neural mediators of the effects of cagrilintide on energy balance.

Amylin receptor agonists such as cagrilintide represent emerging obesity therapies. To understand mediators of cagrilintide action, we generated a transcriptomics atlas of over 530,000 cells comprising 80 neuronal cell populations across rat, mouse and macaque caudal brainstem, with spatial profiling to map distribution in the rat dorsal vagal complex (DVC). Here we show that cagrilintide regulates two conserved Calcr-expressing DVC neuronal populations. While acute cagrilintide treatment alters gene expression in area postrema Calcr/Ramp3 neurons, chemogenetic activation in rats fails to affect long-term food intake and body weight. In contrast, long-term cagrilintide treatment in rats upregulates prolactin-releasing hormone (Prlh) expression in nucleus of the solitary tract Calcr/Prlh cells that are conserved across rodents, macaques and humans. Knocking down DVC Prlh abrogates the effects of cagrilintide but not semaglutide in rats. Our study provides a cross-species spatially resolved atlas of DVC cell populations and defines Calcr/Prlh neurons as mediators of amylin receptor agonist action.