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

Semaglutide's ability to induce weight loss appears to be linked to specific circuits within the brainstem and hypothalamus. Researchers identified neurons in the dorsal vagal complex (DVC) that play a key role in this process. Further investigation revealed that DVC-derived brain circuits coordinate semaglutide's effects on feeding and metabolism.

Optogenetic stimulation demonstrated that Adcyap1+ neurons in the nucleus of the solitary tract (Adcyap1NTS) of the DVC suppress fasting-induced AgRP neuron activation. Importantly, stimulating Adcyap1NTS inputs to the arcuate nucleus and dorsomedial hypothalamus led to non-aversive suppression of feeding during heightened motivational drive, while still allowing active-phase chow intake.

Conversely, stimulating the Adcyap1NTS[- ]arcuate pathway promoted ketogenesis and weight loss independent of food intake, while stimulation of the Adcyap1NTS[- ]DMH pathway decreased energy expenditure.

Interestingly, stimulating semaglutide-responsive NTS projections to both hypothalamic regions replicated the effects of their respective Adcyap1NTS pathways on palatable-food intake and metabolism. Crucially, these pathway-specific functions were retained within neuronal circuits that were recruited by semaglutide's action. In summary, the findings highlight brainstem-to-hypothalamus circuit substrates through which semaglutide regulates motivated feeding and metabolic state downstream of the DVC.