Regulatory T cells in the mouse hypothalamus control immune activation and ameliorate metabolic impairments in high-calorie environments
Abstract 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 ac...
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Nature Portfolio
2025-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-57918-z |
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| author | Maike Becker Stefanie Kälin Anne H. Neubig Michael Lauber Daria Opaleva Hannah Hipp Victoria K. Salb Verena B. Ott Beata Legutko Roland E. Kälin Markus Hippich Martin G. Scherm Lucas F. R. Nascimento Isabelle Serr Fabian Hosp Alexei Nikolaev Alma Mohebiany Martin Krueger Bianca Flachmeyer Michael W. Pfaffl Bettina Haase Chun-Xia Yi Sarah Dietzen Tobias Bopp Stephen C. Woods Ari Waisman Benno Weigmann Matthias Mann Matthias H. Tschöp Carolin Daniel |
| author_facet | Maike Becker Stefanie Kälin Anne H. Neubig Michael Lauber Daria Opaleva Hannah Hipp Victoria K. Salb Verena B. Ott Beata Legutko Roland E. Kälin Markus Hippich Martin G. Scherm Lucas F. R. Nascimento Isabelle Serr Fabian Hosp Alexei Nikolaev Alma Mohebiany Martin Krueger Bianca Flachmeyer Michael W. Pfaffl Bettina Haase Chun-Xia Yi Sarah Dietzen Tobias Bopp Stephen C. Woods Ari Waisman Benno Weigmann Matthias Mann Matthias H. Tschöp Carolin Daniel |
| author_sort | Maike Becker |
| collection | DOAJ |
| description | Abstract 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 + T cells, infiltrating macrophages and microglia while reducing hypothalamic Tregs. mRNA profiling of hypothalamic CD4 + 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. |
| format | Article |
| id | doaj-art-bebe56f823364a8fb8db6a479705ff53 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-bebe56f823364a8fb8db6a479705ff532025-08-20T02:41:33ZengNature PortfolioNature Communications2041-17232025-03-0116112310.1038/s41467-025-57918-zRegulatory T cells in the mouse hypothalamus control immune activation and ameliorate metabolic impairments in high-calorie environmentsMaike Becker0Stefanie Kälin1Anne H. Neubig2Michael Lauber3Daria Opaleva4Hannah Hipp5Victoria K. Salb6Verena B. Ott7Beata Legutko8Roland E. Kälin9Markus Hippich10Martin G. Scherm11Lucas F. R. Nascimento12Isabelle Serr13Fabian Hosp14Alexei Nikolaev15Alma Mohebiany16Martin Krueger17Bianca Flachmeyer18Michael W. Pfaffl19Bettina Haase20Chun-Xia Yi21Sarah Dietzen22Tobias Bopp23Stephen C. Woods24Ari Waisman25Benno Weigmann26Matthias Mann27Matthias H. Tschöp28Carolin Daniel29Research Unit Type 1 Diabetes Immunology, Helmholtz Diabetes Center at Helmholtz MunichGerman Center for Diabetes Research (DZD)Research Unit Type 1 Diabetes Immunology, Helmholtz Diabetes Center at Helmholtz MunichResearch Unit Type 1 Diabetes Immunology, Helmholtz Diabetes Center at Helmholtz MunichResearch Unit Type 1 Diabetes Immunology, Helmholtz Diabetes Center at Helmholtz MunichResearch Unit Type 1 Diabetes Immunology, Helmholtz Diabetes Center at Helmholtz MunichResearch Unit Type 1 Diabetes Immunology, Helmholtz Diabetes Center at Helmholtz MunichGerman Center for Diabetes Research (DZD)Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Munich and Division of Metabolic Diseases, Technische Universität MünchenDepartment of Neurosurgery, Medical Faculty, Johannes Kepler University LinzGerman Center for Diabetes Research (DZD)Research Unit Type 1 Diabetes Immunology, Helmholtz Diabetes Center at Helmholtz MunichResearch Unit Type 1 Diabetes Immunology, Helmholtz Diabetes Center at Helmholtz MunichResearch Unit Type 1 Diabetes Immunology, Helmholtz Diabetes Center at Helmholtz MunichDepartment of Proteomics and Signal Transduction, Max Planck Institute of BiochemistryInstitute for Molecular Medicine, Universitätsmedizin der Johannes-Gutenberg-UniversitätInstitute for Molecular Medicine, Universitätsmedizin der Johannes-Gutenberg-UniversitätInstitute for Anatomy, Leipzig UniversityInstitute for Anatomy, Leipzig UniversityAnimal Physiology and Immunology, Technische Universität MünchenGenomics Core Facility, EMBL European Molecular Biology LaboratoryDepartment of Endocrinology and Metabolism, Amsterdam University Medical Center, location AMC, University of AmsterdamInstitute of Immunology, Johannes Gutenberg University MainzInstitute of Immunology, Johannes Gutenberg University MainzMetabolic Diseases Institute, Department of Psychiatry and Behavioral Neuroscience, University of CincinnatiInstitute for Molecular Medicine, Universitätsmedizin der Johannes-Gutenberg-UniversitätDepartment of Medicine 1, University of Erlangen-Nuremberg, Kussmaul Campus for Medical ResearchDepartment of Proteomics and Signal Transduction, Max Planck Institute of BiochemistryGerman Center for Diabetes Research (DZD)Research Unit Type 1 Diabetes Immunology, Helmholtz Diabetes Center at Helmholtz MunichAbstract 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 + T cells, infiltrating macrophages and microglia while reducing hypothalamic Tregs. mRNA profiling of hypothalamic CD4 + 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.https://doi.org/10.1038/s41467-025-57918-z |
| spellingShingle | Maike Becker Stefanie Kälin Anne H. Neubig Michael Lauber Daria Opaleva Hannah Hipp Victoria K. Salb Verena B. Ott Beata Legutko Roland E. Kälin Markus Hippich Martin G. Scherm Lucas F. R. Nascimento Isabelle Serr Fabian Hosp Alexei Nikolaev Alma Mohebiany Martin Krueger Bianca Flachmeyer Michael W. Pfaffl Bettina Haase Chun-Xia Yi Sarah Dietzen Tobias Bopp Stephen C. Woods Ari Waisman Benno Weigmann Matthias Mann Matthias H. Tschöp Carolin Daniel Regulatory T cells in the mouse hypothalamus control immune activation and ameliorate metabolic impairments in high-calorie environments Nature Communications |
| title | Regulatory T cells in the mouse hypothalamus control immune activation and ameliorate metabolic impairments in high-calorie environments |
| title_full | Regulatory T cells in the mouse hypothalamus control immune activation and ameliorate metabolic impairments in high-calorie environments |
| title_fullStr | Regulatory T cells in the mouse hypothalamus control immune activation and ameliorate metabolic impairments in high-calorie environments |
| title_full_unstemmed | Regulatory T cells in the mouse hypothalamus control immune activation and ameliorate metabolic impairments in high-calorie environments |
| title_short | Regulatory T cells in the mouse hypothalamus control immune activation and ameliorate metabolic impairments in high-calorie environments |
| title_sort | regulatory t cells in the mouse hypothalamus control immune activation and ameliorate metabolic impairments in high calorie environments |
| url | https://doi.org/10.1038/s41467-025-57918-z |
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