Semaglutide effects on energy balance are mediated by Adcyap1+ neurons in the dorsal vagal complex

The use of the GLP-1R agonist semaglutide is revolutionizing the treatment of obesity, yet its mechanistic effects on energy balance remain elusive. Here, we demonstrate that reactivation of semaglutide-responsive dorsal vagal complex neurons mimics the drug's effects of reducing food intake and body weight and promoting fat utilization and conditioned taste aversion. We observe that many of the semaglutide-activated area postrema (AP) and nucleus of the solitary tract (NTS) neurons express Adcyap1 mRNA, and ablation of AP/NTS Adcyap1+ neurons largely reverses semaglutide's effects on energy balance acutely in lean mice and in subchronically treated obese mice. Semaglutide-activated AP/NTS Adcyap1+ neurons promote the loss of fat rather than lean mass, with only a modest effect on conditioned taste aversion. Furthermore, NTS Adcyap1+ neurons are engaged by GLP-1R-expressing AP neurons and are necessary for semaglutide-induced activation of several downstream satiety-related structures. Selective targeting of semaglutide-responsive Adcyap1+ neurons holds potential for improved future anti-obesity treatments.