The long-acting GLP-1 analogue semaglutide has revolutionized the pharmacological treatment of obesity, but the brain-mediated mechanisms behind the body weight loss and its most common side effect, nausea, remain unclear. By using select delivery of a Cre-dependent viral vector encoding hM3DGq and mCherry into the dorsal vagal complex (DVC) of TRAP2 mice, we here show that neurons in the DVC that are activated by semaglutide have direct projections to a variety of brainstem and forebrain structures involved in appetite regulation and visceral malaise. CNO-mediated re-activation of DVC neurons previously engaged by semaglutide recapitulates the majority of the brain-wide activation pattern seen after injection of semaglutide itself, via direct projections. Moreover, we further show that chemogenetic activation of this neuronal ensemble is sufficient to cause long-lasting anorexia, promote fat utilization, body weight loss and nausea. Our data thus advances current knowledge on how the most efficient long-acting GLP-1R agonist exerts its action in the brain, suggesting that the acute brain-wide activations pattern upon semaglutide injection is derived from the DVC and, importantly, that chemogenetic re-activation of this DVC population mimics the effects of semaglutide itself on key aspects: Food intake, body weight, fat utilization and nausea, clearly pointing towards the DVC in driving the acute feeding and metabolic responses to semaglutide.