Regulatory T cells in the mouse hypothalamus control immune activation and ameliorate metabolic impairments in high-calorie environments
The hypothalamus in the central nervous system (CNS) has important functions in controlling systemic metabolism. A calorie-rich diet triggers CNS immune activation, impairing metabolic control and promoting obesity and Type 2 Diabetes (T2D), but the mechanisms driving hypothalamic immune activation remain unclear. Here we identify regulatory T cells (Tregs) as key modulators of hypothalamic immune responses. In mice, calorie-rich environments activate hypothalamic CD4<sup>+</sup> T cells, infiltrating macrophages and microglia while reducing hypothalamic Tregs. mRNA profiling of hypothalamic CD4<sup>+</sup> T cells reveals a Th1-like activation state, with increased Tbx21, Cxcr3 and Cd226 but decreased Ccr7 and S1pr1. Importantly, results from Treg loss-of function and gain-of-function experiments show that Tregs limit hypothalamic immune activation and reverse metabolic impairments induced by hyper-caloric feeding. Our findings thus help refine the current model of Treg-centered immune-metabolic crosstalk in the brain and may contribute to the development of precision immune modulation for obesity and diabetes.
Authors
- Matthias Tschoep (ORCID: https://orcid.org/0000-0002-4744-371X)
- Isabelle Serr (ORCID: https://orcid.org/0000-0001-9277-9055)
- Heather S. Hipp (ORCID: https://orcid.org/0000-0002-1089-3928)
- Alma N. Mohebiany (ORCID: https://orcid.org/0000-0001-9818-6867)
- Maike Becker (ORCID: https://orcid.org/0000-0001-6416-4213)
- Ari Waisman (ORCID: https://orcid.org/0000-0003-4304-8234)
- Benno Weigmann (ORCID: https://orcid.org/0000-0002-2398-0844)
- Michael W. Pfaffl (ORCID: https://orcid.org/0000-0002-3192-1019)
- Martin G. Scherm
- Tobias Bopp (ORCID: https://orcid.org/0000-0002-3232-8065)
- Alexei Nikolaev
- Markus Hippich (ORCID: https://orcid.org/0000-0001-6253-2596)
- Beata Legutko
- Sarah Dietzen
- Roland E. Kälin (ORCID: https://orcid.org/0000-0003-2680-5715)
- Carolin Daniel (ORCID: https://orcid.org/0000-0003-4698-7069)
- Fabian Hosp (ORCID: https://orcid.org/0000-0002-2884-9335)
- Bettina Haase (ORCID: https://orcid.org/0000-0002-9811-473X)
- Victoria K. Salb
- Chun‐Xia Yi (ORCID: https://orcid.org/0000-0003-1184-4615)
- Stefanie Kälin
- Matthias Mann (ORCID: https://orcid.org/0000-0003-1292-4799)
- Bianca Flachmeyer
- Daria Opaleva (ORCID: https://orcid.org/0000-0003-3947-7060)
- Verena B. Ott (ORCID: https://orcid.org/0000-0003-2203-073X)
- Stephen C. Woods
- Lucas F. Nascimento
- Markus Lauber
- Martin Krueger
- Anne H. Neubig (ORCID: https://orcid.org/0000-0003-1770-6416)
Institutions
- Johannes Kepler University of Linz (AT)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Johannes Gutenberg University Mainz (DE)
- TUM Klinikum (DE)
- Helmholtz Zentrum München (DE)
- University Medical Center of the Johannes Gutenberg University Mainz (DE)
- European Molecular Biology Laboratory (DE)
- Max Planck Institute of Biochemistry (DE)
- Amsterdam University Medical Centers (NL)
- Deutsches Diabetes-Zentrum e.V. (DE)
- German Center for Diabetes Research (DE)
- Heinrich Heine University Düsseldorf (DE)
- Technical University of Munich (DE)
- Ludwig-Maximilians-Universität München (DE)
- University of Amsterdam (NL)
- University of Cincinnati Medical Center (US)
- Leipzig University (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-20
- DOI
- https://doi.org/10.1038/s41467-025-57918-z
- Citations
- 10
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 7.97
Funders
- Eli Lilly and Company
- Alexander von Humboldt-Stiftung
- Anni Hofmann Stiftung
- European Foundation for the Study of Diabetes
- Deutsche Forschungsgemeinschaft
- Max-Planck-Gesellschaft
- Ludwig-Maximilians-Universität München
- Medizinischen Fakultät, Ludwig-Maximilians-Universität München
- Helmholtz Zentrum München