Semaglutide attenuates neuroinflammation in male mice
8 affiliations
- 1Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
- 2Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- 3Research and Development, Novo Nordisk A/S, Måløv, Denmark
- 4Research and Development, Novo Nordisk A/S, Søborg, Denmark
- 5Gubra A/S, Hørsholm, Denmark
- 6Research and Development, Novo Nordisk A/S, Måløv, Denmark. [email protected]
- 7Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark. [email protected]
- 8Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected]
Abstract
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown promise in preclinical models of neurodegeneration, with emerging evidence suggesting these effects may be driven by modulation of neuroinflammation. However, the cellular mechanisms underlying GLP-1RA effects on neuroinflammation remain poorly understood. Here we show, using a mouse model of lipopolysaccharide-induced neuroinflammation, how semaglutide coordinates cellular responses to resolve neuroinflammation. We find that semaglutide in male mice prevents brain infiltration of neutrophils, excessive cytokine release, and suppresses neuroinflammation-associated transcriptional signatures specifically in microglia, endothelial cells, and a subset of pericytes. Mechanistically, we identify a subset of Glp1r-expressing neurons in the dorsal vagal complex that, upon semaglutide treatment, regulate genes involved in anti-inflammatory signaling. Semaglutide-modulated pathways overlap with inflammatory signatures found in human neurodegenerative diseases, including Alzheimer's disease, suggesting broad relevance for conditions involving neuroinflammation. Together, these findings reveal how GLP-1R signaling in male mice orchestrates resolution of neuroinflammation through coordinated multi-cellular programs.
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BibTeX
@article{rausch2026semaglutide,
title = {{Semaglutide attenuates neuroinflammation in male mice}},
author = {Dylan M. Rausch and Mette Q. Ludwig and Marie Aare Bentsen and Stine N. Hansen and Anna Secher and Dorte Holst and Jaime Moreno and Vivek Das and Kristoffer Lihme Egerod and Anne-Mette Bjerregaard and Kristoffer Niss and S. Sherona Bau and Charles Pyke and Kevin Dalgaard and Myrte Merkestein and Franziska Wichern and Charlotte Thim Hansen and Joseph Polex-Wolf and LOTTE BJERRE KNUDSEN and Tune H. Pers},
journal = {Nature Communications},
year = {2026},
month = jun,
doi = {10.1038/s41467-026-74038-4},
url = {https://doi.org/10.1038/s41467-026-74038-4},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Semaglutide attenuates neuroinflammation in male mice
AU - Dylan M. Rausch
AU - Mette Q. Ludwig
AU - Marie Aare Bentsen
AU - Stine N. Hansen
AU - Anna Secher
AU - Dorte Holst
AU - Jaime Moreno
AU - Vivek Das
AU - Kristoffer Lihme Egerod
AU - Anne-Mette Bjerregaard
AU - Kristoffer Niss
AU - S. Sherona Bau
AU - Charles Pyke
AU - Kevin Dalgaard
AU - Myrte Merkestein
AU - Franziska Wichern
AU - Charlotte Thim Hansen
AU - Joseph Polex-Wolf
AU - LOTTE BJERRE KNUDSEN
AU - Tune H. Pers
PY - 2026
DA - 2026/06/09
JO - Nature Communications
DO - 10.1038/s41467-026-74038-4
UR - https://doi.org/10.1038/s41467-026-74038-4
AB - Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown promise in preclinical models of neurodegeneration, with emerging evidence suggesting these effects may be driven by modulation of neuroinflammation. However, the cellular mechanisms underlying GLP-1RA effects on neuroinflammation remain poorly understood. Here we show, using a mouse model of lipopolysaccharide-induced neuroinflammation, how semaglutide coordinates cellular responses to resolve neuroinflammation. We find that semaglutide in male mice prevents brain infiltration of neutrophils, excessive cytokine release, and suppresses neuroinflammation-associated transcriptional signatures specifically in microglia, endothelial cells, and a subset of pericytes. Mechanistically, we identify a subset of Glp1r-expressing neurons in the dorsal vagal complex that, upon semaglutide treatment, regulate genes involved in anti-inflammatory signaling. Semaglutide-modulated pathways overlap with inflammatory signatures found in human neurodegenerative diseases, including Alzheimer's disease, suggesting broad relevance for conditions involving neuroinflammation. Together, these findings reveal how GLP-1R signaling in male mice orchestrates resolution of neuroinflammation through coordinated multi-cellular programs.
SN - 2041-1723
ER -