A single dorsal vagal complex circuit mediates the aversive and anorectic responses to GLP1R agonists.

GLP-1 receptor agonists (GLP1RAs) effectively reduce feeding to treat obesity, although nausea and other aversive side effects of these drugs can limit their use. Brainstem circuits that promote satiation and that mediate the physiologic control of body weight can be distinguished from those that cause aversion. It remains unclear whether brainstem neurons contribute to the normal regulation of energy balance and whether GLP1RAs control appetite via circuits distinct from those that mediate aversive responses, however. Hence, we defined roles for AP and NTS -expressing neurons (AP and NTS neurons, respectively) in the physiologic control of body weight, the GLP1RA-dependent suppression of food intake, and the GLP1RA-mediated stimulation of aversive responses. While silencing non-aversive NTS neurons interfered with the physiologic restraint of feeding and body weight, restoring NTS neuron expression on an otherwise -null background failed to enable long-term body weight suppression by GLP1RAs. In contrast, selective expression in AP neurons restored both aversive responses and long-term body weight suppression by GLP1RAs. Thus, while non-aversive NTS neurons control physiologic feeding, aversive AP neurons mediate both the anorectic and weight loss effects of GLP1RAs, dictating the functional inseparability of these pharmacologic GLP1RA responses at a circuit level.