A cross-species atlas of the dorsal vagal complex reveals neural mediators of the effects of cagrilintide on energy balance
10 affiliations
- 1Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
- 2Research and Development, Novo Nordisk, Måløv, Denmark
- 3Departments of Internal Medicine, University of Michigan and Molecular and Integrative Physiology, Ann Arbor, MI, USA
- 4Pioneer Centre for SMARTbiomed, University of Copenhagen, Copenhagen, Denmark
- 5Institute of Veterinary Physiology, Vetsuisse Faculty University of Zurich, Zurich, Switzerland
- 6Department of Medicine, McGill University, Montreal, Quebec, Canada
- 7Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, USA
- 8One Health Institute, University of Zurich, Zurich, Switzerland
- 9Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark. [email protected]
- 10Pioneer Centre for SMARTbiomed, University of Copenhagen, Copenhagen, Denmark. [email protected]
Abstract
Amylin analogs, including potential anti-obesity therapies like cagrilintide, act on neurons in the brainstem dorsal vagal complex (DVC) that express calcitonin receptors (CALCR). These receptors, often combined with receptor activity-modifying proteins (RAMPs), mediate the suppression of food intake and body weight. To understand the molecular and neural mechanisms of cagrilintide action, we used single-nucleus RNA sequencing to define 89 cell populations across the rat, mouse, and non-human primate caudal brainstem. We then integrated spatial profiling to reveal neuron distribution in the rat DVC. Furthermore, we compared the acute and long-term transcriptional responses to cagrilintide across DVC neurons of rats, which exhibit strong cagrilintide responsiveness, and mice, which respond poorly to cagrilintide over the long term. We found that cagrilintide promoted long-term transcriptional changes, including increased prolactin releasing hormone ( Prlh ) expression, in the nucleus of the solitary tract (NTS) Calcr/Prlh cells in rats, but not in mice, suggesting the importance of NTS Calcr/Prlh cells for sustained weight loss. Indeed, activating rat area postrema Calcr cells briefly reduced food intake but failed to decrease food intake or body weight over the long term. Overall, these results not only provide a cross-species and spatial atlas of DVC cell populations but also define the molecular and neural mediators of acute and long-term cagrilintide action.
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BibTeX
@article{ludwig2026crossspecies,
title = {{A cross-species atlas of the dorsal vagal complex reveals neural mediators of the effects of cagrilintide on energy balance}},
author = {Mette Q. Ludwig and Bernd Coester and Desiree Gordian and Shad Hassan and Abigail J. Tomlinson and Mouhamadoul Habib Toure and Oliver P. Christensen and Greta Lommi and Anja Moltke-Prehn and Jenny M. Brown and Dylan M. Belmont-Rausch and S. Sherona Bau and Çağrı Bodur and Anika Gowda and Iris Wu and Stace Kernodle and Victoria Dong and Mike Ayensu-Mensah and Paul V. Sabatini and Jae Hoon Shin and Melissa Ann Kirigiti and Kristoffer Lihme Egerod and Christelle Le Foll and Sofia Hult Lundh and Marina Kjærgaard Gerstenberg and Thomas A. Lutz and Paul Kievit and Anna Secher and Kirsten Raun and Martin Grosvenor Myers and Tune H. Pers},
journal = {Nature Metabolism},
year = {2026},
month = jun,
doi = {10.1038/s42255-026-01539-3},
url = {https://doi.org/10.1038/s42255-026-01539-3},
note = {CC BY},
}
RIS
TY - JOUR
TI - A cross-species atlas of the dorsal vagal complex reveals neural mediators of the effects of cagrilintide on energy balance
AU - Mette Q. Ludwig
AU - Bernd Coester
AU - Desiree Gordian
AU - Shad Hassan
AU - Abigail J. Tomlinson
AU - Mouhamadoul Habib Toure
AU - Oliver P. Christensen
AU - Greta Lommi
AU - Anja Moltke-Prehn
AU - Jenny M. Brown
AU - Dylan M. Belmont-Rausch
AU - S. Sherona Bau
AU - Çağrı Bodur
AU - Anika Gowda
AU - Iris Wu
AU - Stace Kernodle
AU - Victoria Dong
AU - Mike Ayensu-Mensah
AU - Paul V. Sabatini
AU - Jae Hoon Shin
AU - Melissa Ann Kirigiti
AU - Kristoffer Lihme Egerod
AU - Christelle Le Foll
AU - Sofia Hult Lundh
AU - Marina Kjærgaard Gerstenberg
AU - Thomas A. Lutz
AU - Paul Kievit
AU - Anna Secher
AU - Kirsten Raun
AU - Martin Grosvenor Myers
AU - Tune H. Pers
PY - 2026
DA - 2026/06/08
JO - Nature Metabolism
DO - 10.1038/s42255-026-01539-3
UR - https://doi.org/10.1038/s42255-026-01539-3
AB - Amylin analogs, including potential anti-obesity therapies like cagrilintide, act on neurons in the brainstem dorsal vagal complex (DVC) that express calcitonin receptors (CALCR). These receptors, often combined with receptor activity-modifying proteins (RAMPs), mediate the suppression of food intake and body weight. To understand the molecular and neural mechanisms of cagrilintide action, we used single-nucleus RNA sequencing to define 89 cell populations across the rat, mouse, and non-human primate caudal brainstem. We then integrated spatial profiling to reveal neuron distribution in the rat DVC. Furthermore, we compared the acute and long-term transcriptional responses to cagrilintide across DVC neurons of rats, which exhibit strong cagrilintide responsiveness, and mice, which respond poorly to cagrilintide over the long term. We found that cagrilintide promoted long-term transcriptional changes, including increased prolactin releasing hormone ( Prlh ) expression, in the nucleus of the solitary tract (NTS) Calcr/Prlh cells in rats, but not in mice, suggesting the importance of NTS Calcr/Prlh cells for sustained weight loss. Indeed, activating rat area postrema Calcr cells briefly reduced food intake but failed to decrease food intake or body weight over the long term. Overall, these results not only provide a cross-species and spatial atlas of DVC cell populations but also define the molecular and neural mediators of acute and long-term cagrilintide action.
SN - 2522-5812
ER -