Semaglutide engages distinct brainstem-to-hypothalamus circuits to suppress motivated feeding and regulate ketogenesis and energy expenditure
- 1Institute of Neuroscience and Physiology, University of Gothenburg
Abstract
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 (Adcyap1NTS). Projection-specific optogenetic stimulation reveals that Adcyap1NTS inputs to the arcuate nucleus and dorsomedial hypothalamus non-aversively suppress feeding during elevated motivational drive, while sparing active-phase chow intake. Adcyap1NTS[->]arcuate stimulation additionally promotes food intake-independent ketogenesis and weight loss, while stimulation of the Adcyap1NTS[->]DMH pathway lowers energy expenditure. Crucially, stimulation of semaglutide-responsive NTS projections to both hypothalamic regions recapitulates key effects of the corresponding Adcyap1NTS 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.
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BibTeX
@misc{skoldheden2026semaglutide,
title = {{Semaglutide engages distinct brainstem-to-hypothalamus circuits to suppress motivated feeding and regulate ketogenesis and energy expenditure}},
author = {S. Blid Sköldheden and J. Teixidor-Deulofeu and J. Ruud and L. Engström Ruud},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.04.749561},
url = {https://www.biorxiv.org/content/10.64898/2026.09.04.749561v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Semaglutide engages distinct brainstem-to-hypothalamus circuits to suppress motivated feeding and regulate ketogenesis and energy expenditure
AU - S. Blid Sköldheden
AU - J. Teixidor-Deulofeu
AU - J. Ruud
AU - L. Engström Ruud
PY - 2026
DA - 2026/09/04
PB - bioRxiv
DO - 10.64898/2026.09.04.749561
UR - https://www.biorxiv.org/content/10.64898/2026.09.04.749561v1
AB - 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 (Adcyap1NTS). Projection-specific optogenetic stimulation reveals that Adcyap1NTS inputs to the arcuate nucleus and dorsomedial hypothalamus non-aversively suppress feeding during elevated motivational drive, while sparing active-phase chow intake. Adcyap1NTS[->]arcuate stimulation additionally promotes food intake-independent ketogenesis and weight loss, while stimulation of the Adcyap1NTS[->]DMH pathway lowers energy expenditure. Crucially, stimulation of semaglutide-responsive NTS projections to both hypothalamic regions recapitulates key effects of the corresponding Adcyap1NTS 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.
ER -