Cagrilintide's long-term weight loss effects mediated by `Prlh` upregulation in conserved `Calcr/Prlh` DVC neurons.

Effective treatments for obesity are crucial, with amylin receptor agonists like cagrilintide emerging as promising therapies. While these agents enhance satiety and improve glycemic control, the precise neural circuits and cellular mechanisms mediating their long-term effects remain incompletely understood. The dorsal vagal complex (DVC) in the brainstem is a critical hub for integrating metabolic signals and regulating energy balance, making it a key area to investigate the actions of such compounds. Unraveling cagrilintide's specific DVC targets could lead to more refined and potent anti-obesity strategies.

Researchers generated a comprehensive transcriptomics atlas of over 530,000 cells from the caudal brainstem of rat, mouse, and macaque, identifying 80 neuronal cell populations. Spatial profiling mapped these populations within the rat DVC. They then investigated the effects of acute and long-term cagrilintide treatment in rats. This included assessing gene expression changes, performing chemogenetic activation of specific DVC neuron populations, and conducting Prlh knockdown experiments in the DVC to determine its role in cagrilintide's actions. Semaglutide was used as a comparator in knockdown studies.

The study identified that cagrilintide regulates two conserved Calcr-expressing DVC neuronal populations. Acute cagrilintide treatment altered gene expression in Calcr/Ramp3 neurons in the area postrema; however, chemogenetic activation of these specific neurons in rats failed to affect long-term food intake and body weight. In contrast, long-term cagrilintide treatment in rats significantly upregulated prolactin-releasing hormone (Prlh) expression in nucleus of the solitary tract (NTS) Calcr/Prlh cells. These Calcr/Prlh cells were found to be conserved across rodents, macaques, and humans, highlighting their evolutionary importance.

Knocking down DVC Prlh expression abrogated the beneficial effects of cagrilintide on energy balance in rats, while notably, it did not impact the effects of semaglutide, suggesting a distinct mechanism. This indicates Calcr/Prlh neurons and Prlh signaling are critical mediators specific to amylin receptor agonist action.