A genetic map of the mouse dorsal vagal complex and its role in obesity
Open accessAbstract
The brainstem dorsal vagal complex (DVC) is known to regulate energy balance and is the target of appetite-suppressing hormones, such as glucagon-like peptide 1 (GLP-1). Here we provide a comprehensive genetic map of the DVC and identify neuronal populations that control feeding. Combining bulk and single-nucleus gene expression and chromatin profiling of DVC cells, we reveal 25 neuronal populations with unique transcriptional and chromatin accessibility landscapes and peptide receptor expression profiles. GLP-1 receptor (GLP-1R) agonist administration induces gene expression alterations specific to two distinct sets of Glp1r neurons-one population in the area postrema and one in the nucleus of the solitary tract that also expresses calcitonin receptor (Calcr). Transcripts and regions of accessible chromatin near obesity-associated genetic variants are enriched in the area postrema and the nucleus of the solitary tract neurons that express Glp1r and/or Calcr, and activating several of these neuronal populations decreases feeding in rodents. Thus, DVC neuronal populations associated with obesity predisposition suppress feeding and may represent therapeutic targets for obesity.
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It is well-established that GLP-1RAs activate neurons in the area postrema and nucleus tractus solitarius and induce differential gene expression in the area postrema.
“It is well-established, however, that GLP-1RAs activate neurons in the AP and the NTS (22, 63) and induce differential gene expression in the AP (63, 107), findings relevant because of the well-established role of the AP in sensing nausea-inducing stimuli (48, 108).”
From GLP-1 and the Neurobiology of Eating Control: Recent Advances (2025) · cites this paper as [107]
GLP-1R neurons in the area postrema are a heterogeneous population, with subsets co-expressing Gfral, encoding the GDF15 receptor known to be involved in the neural circuitry for nausea, or Prlhr, encoding the receptor for prolactin-releasing peptide hormone shown to mediate satiety without aversion.
“Several sequencing studies have shown that GLP-1R neurons in the AP are a heterogeneous population, with subsets co-expressing Gfral (48, 107), encoding the GDF15 receptor known to be involved in the neural circuitry for nausea (114), or Prlhr, encoding the receptor for prolactin-releasing peptide hormone shown to mediate satiety without aversion (115).”
From GLP-1 and the Neurobiology of Eating Control: Recent Advances (2025) · cites this paper as [107]
GLP-1R neurons in both the NTS and AP exhibit substantial molecular heterogeneity, including in cell surface receptor expression.
“GLP-1R neurons in both the NTS and AP exhibit substantial molecular heterogeneity, including in cell surface receptor expression (48, 107, 118, 119).”
From GLP-1 and the Neurobiology of Eating Control: Recent Advances (2025) · cites this paper as [107]
AP and NTS GLP1R neurons are largely distinct from other DVC cell types.
“This analysis also suggests that APGLP1R and NTSGLP1R neurons are largely distinct from other DVC cell types”
From Dissociable hindbrain GLP1R circuits for satiety and aversion (2024) · cites this paper as [16]
Reanalysis of three single-cell/nucleus RNA sequencing datasets showed that AP and NTS GLP1R neurons are mixed excitatory and inhibitory populations, with a greater proportion of NTS GLP1R neurons being excitatory.
“we combined and re-analyzed three existing single cell/nucleus RNA sequencing datasets13,16,17 to determine that APGLP1R and NTSGLP1R neurons are mixed excitatory and inhibitory populations, with a greater proportion of NTSGLP1R neurons being excitatory”
From Dissociable hindbrain GLP1R circuits for satiety and aversion (2024) · cites this paper as [16]
A minority of NTS GLP1R neurons express CCK.
“Given that a minority of NTSGLP1R neurons express CCK (Extended Data Fig. 8q)16”
From Dissociable hindbrain GLP1R circuits for satiety and aversion (2024) · cites this paper as [16]
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GLP-1 physiology informs the pharmacotherapy of obesity
Drucker, D. J. (2022) · Molecular Metabolism · doi:10.1016/j.molmet.2021.101351 · Cited by 510 · see citing works
Beyond the pancreas: contrasting cardiometabolic actions of GIP and GLP1
Hammoud, R., & Drucker, D. J. (2023) · Nature Reviews Endocrinology · doi:10.1038/s41574-022-00783-3 · Cited by 244 · see citing works
Integrative neurocircuits that control metabolism and food intake
Brüning, J. C., & Fenselau, H. (2023) · Science · doi:10.1126/science.abl7398 · Cited by 214 · see citing works
Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity.
Garvey, W. T., Blüher, M., Osorto Contreras, C. K., Davies, M. J., Winning Lehmann, E., Pietiläinen, K. H., Rubino, D., Sbraccia, P., Wadden, T., Zeuthen, N., et al. (2025) · New England Journal of Medicine · doi:10.1056/nejmoa2502081 · Cited by 238 · see citing works
Incretins (GLP-1 receptor agonists and dual/triple agonists) and the liver
Newsome, P. N., & Ambery, P. (2023) · Journal of Hepatology · doi:10.1016/j.jhep.2023.07.033 · Cited by 211 · see citing works
Borner, T., Geisler, C. E., Fortin, S. M., Cosgrove, R., Alsina-Fernandez, J., Dogra, M., Doebley, S., Sanchez-Navarro, M. J., Leon, R. M., Gaisinsky, J., et al. (2021) · Diabetes · doi:10.2337/db21-0459 · Cited by 202 · see citing works
Dissociable hindbrain GLP1R circuits for satiety and aversion
Huang, K.-P., Acosta, A. A., Ghidewon, M. Y., McKnight, A. D., Almeida, M. S., Nyema, N. T., Hanchak, N. D., Patel, N., Gbenou, Y. S. K., Adriaenssens, A. E., et al. (2024) · Nature · doi:10.1038/s41586-024-07685-6 · Cited by 166 · see citing works
GLP-1 increases preingestive satiation via hypothalamic circuits in mice and humans
Kim, K. S., Park, J. S., Hwang, E., Park, M. J., Shin, H. Y., Lee, Y. H., Kim, K. M., Gautron, L., Godschall, E., Portillo, B., et al. (2024) · Science · doi:10.1126/science.adj2537 · Cited by 148 · see citing works
Cagrilintide–Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes
Davies, M. J., Bajaj, H. S., Broholm, C., Eliasen, A., Garvey, W. T., le Roux, C. W., Lingvay, I., Lyndgaard, C. B., Rosenstock, J., & Pedersen, S. D. (2025) · New England Journal of Medicine · doi:10.1056/nejmoa2502082 · Cited by 143 · see citing works
Liskiewicz, A., Khalil, A., Liskiewicz, D., Novikoff, A., Grandl, G., Maity-Kumar, G., Gutgesell, R. M., Bakhti, M., Bastidas-Ponce, A., Czarnecki, O., et al. (2023) · Nature Metabolism · doi:10.1038/s42255-023-00931-7 · Cited by 110 · see citing works
Sequential appetite suppression by oral and visceral feedback to the brainstem
Ly, T., Oh, J. Y., Sivakumar, N., Shehata, S., La Santa Medina, N., Huang, H., Liu, Z., Fang, W., Barnes, C., Dundar, N., et al. (2023) · Nature · doi:10.1038/s41586-023-06758-2 · Cited by 90 · see citing works
Obesity and the kidney: mechanistic links and therapeutic advances
Yau, K., Kuah, R., Cherney, D. Z. I., & Lam, T. K. T. (2024) · Nature Reviews Endocrinology · doi:10.1038/s41574-024-00951-7 · Cited by 91 · see citing works
Adriaenssens, A., Broichhagen, J., de Bray, A., Ast, J., Hasib, A., Jones, B., Tomas, A., Burgos, N. F., Woodward, O., Lewis, J., et al. (2023) · JCI Insight · doi:10.1172/jci.insight.164921 · Cited by 77 · see citing works
GLP-1 agonist to treat obesity and prevent cardiovascular disease: what have we achieved so far
Pedrosa, M. R., Franco, D. R., Gieremek, H. W., Vidal, C. M., Bronzeri, F., de Cassia Rocha, A., de Carvalho Cara, L. G., Fogo, S. L., & Eliaschewitz, F. G. (2022) · Current Atherosclerosis Reports · doi:10.1007/s11883-022-01062-2 · Cited by 68 · see citing works
Lutz, T. A. (2022) · Appetite · doi:10.1016/j.appet.2022.105965 · Cited by 59 · see citing works
Brain control of energy homeostasis: implications for anti-obesity pharmacotherapy
Johansen, V. B. I., Petersen, J., Lund, J., Mathiesen, C. V., Fenselau, H., & Clemmensen, C. (2025) · Cell · doi:10.1016/j.cell.2025.06.010 · Cited by 53 · see citing works
Ghidewon, M., Wald, H. S., McKnight, A. D., De Jonghe, B. C., Breen, D. M., Alhadeff, A. L., Borner, T., & Grill, H. J. (2022) · Diabetes, Obesity and Metabolism · doi:10.1111/dom.14663 · Cited by 51 · see citing works
GLP-1 receptor agonist-based therapies and cardiovascular risk: a review of mechanisms
Mullur, N., Morissette, A., Morrow, N. M., & Mulvihill, E. E. (2024) · Journal of Endocrinology · doi:10.1530/joe-24-0046 · Cited by 51 · see citing works
Samms, R. J., Sloop, K. W., Gribble, F. M., Reimann, F., & Adriaenssens, A. E. (2021) · Diabetes · doi:10.2337/dbi21-0002 · Cited by 49 · see citing works
GLP-1 and the Neurobiology of Eating Control: Recent Advances
Jones, L. A., & Brierley, D. I. (2025) · Endocrinology · doi:10.1210/endocr/bqae167 · Cited by 43 · see citing works
Reagents and models for detecting endogenous GLP1R and GIPR
Ast, J., Broichhagen, J., & Hodson, D. J. (2021) · EBioMedicine · doi:10.1016/j.ebiom.2021.103739 · Cited by 40 · see citing works
Wean, J., Kowalsky, A. H., Laker, R., Will, S., Drucker, D. J., Rhodes, C. J., & Seeley, R. J. (2025) · Molecular Metabolism · doi:10.1016/j.molmet.2024.102074 · Cited by 28 · see citing works
Self-citationBrainstem BDNF neurons are downstream of GFRAL/GLP1R signalling
Feetham, C. H., Collabolletta, V., Worth, A. A., Shoop, R., Groom, S., Harding, C., Boutagouga Boudjadja, M., Coskun, T., Emmerson, P. J., D’Agostino, G., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-54367-y · Cited by 22 · see citing works
- Authors
- Ludwig, M. Q., Cheng, W., Gordian, D., Lee, J., Paulsen, S. J., Hansen, S. N., Egerod, K. L., Barkholt, P., Rhodes, C. J., Secher, A., Knudsen, L. B., Pyke, C., Myers, M. G., & Pers, T. H.
- Affiliations
- University of Copenhagen (DK)
- University of Michigan (US)
- Novo Nordisk (Denmark) (DK)
- Gubra (Denmark) (DK)
- AstraZeneca (United States) (US)
- Corresponding author
- Pers, Tune H.
- ORCID
- Venue
- Nature Metabolism
- Published
- 2021-03-25
- Volume
- 3
- Issue
- 4
- Pages
- 530-545
- ISSN
- 2522-5812 (ISSN-L)
- PMC
- PMC12009600
- OpenAlex
- W3137550402
- Cited by
- 186
- References
- 79
- Citations by year
- 2026: 35 · 2025: 50 · 2024: 47 · 2023: 20 · 2022: 21 · 2021: 13
- FWCI
- 13.30
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Lundbeckfonden (R190 2014-3904)
- National Institute of Diabetes and Digestive and Kidney Diseases (P01DK117821, P30DK020572, P30DK036836)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Health Sciences › Nursing › Nutrition and Dietetics › Biochemical Analysis and Sensing Techniques
- Keywords
- dorsal vagal complex, obesity, genetic linkage map, neuronal populations, food intake regulation, GLP-1 receptor, area postrema, nucleus tractus solitarius, calcitonin receptor, chromatin accessibility, single-nucleus transcriptomics, energy balance, therapeutic target
- MeSH terms
- Glucagon-Like Peptide-1 Receptor, Animals, Appetite, Body Weight, Brain Stem, Cell Nucleus, Chromatin, Chromosome Mapping, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Obesity, Vagus Nerve, Gene Expression, Solitary Nucleus, Mice, Calcitonin Receptor-Like Protein
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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