Semaglutide engages distinct brainstem-to-hypothalamus circuits to suppress motivated feeding and regulate ketogenesis and energy expenditure

Summary Semaglutide-induced weight loss requires neurons in the dorsal vagal complex (DVC), but how DVC-derived downstream brain circuits coordinate the drug’s effects on feeding and metabolism is unknown. We show that semaglutide suppresses fasting-induced AgRP neuron activation through DVC neurons, including Adcyap1 + neurons of the nucleus of the solitary tract ( Adcyap1 NTS ). Projection-specific optogenetic stimulation reveals that Adcyap1 NTS inputs to the arcuate nucleus and dorsomedial hypothalamus non-aversively suppress feeding during elevated motivational drive, while sparing active-phase chow intake. Adcyap1 NTS →arcuate stimulation additionally promotes food intake-independent ketogenesis and weight loss, while stimulation of the Adcyap1 NTS →DMH pathway lowers energy expenditure. Crucially, stimulation of semaglutide-responsive NTS projections to both hypothalamic regions recapitulates key effects of the corresponding Adcyap1 NTS pathways on palatable-food intake and metabolism, while also suppressing fasting-induced AgRP neuron activation, demonstrating that these pathway-specific functions are retained within neuronal circuits recruited by semaglutide. Together, our findings identify brainstem-to-hypothalamus circuit substrates through which semaglutide regulates motivated feeding and metabolic state downstream of the DVC.