Nature Communications (Mar 2025)
Regulatory T cells in the mouse hypothalamus control immune activation and ameliorate metabolic impairments in high-calorie environments
- 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
Affiliations
- Maike Becker
- Research Unit Type 1 Diabetes Immunology, Helmholtz Diabetes Center at Helmholtz Munich
- Stefanie Kälin
- German Center for Diabetes Research (DZD)
- Anne H. Neubig
- Research Unit Type 1 Diabetes Immunology, Helmholtz Diabetes Center at Helmholtz Munich
- Michael Lauber
- Research Unit Type 1 Diabetes Immunology, Helmholtz Diabetes Center at Helmholtz Munich
- Daria Opaleva
- Research Unit Type 1 Diabetes Immunology, Helmholtz Diabetes Center at Helmholtz Munich
- Hannah Hipp
- Research Unit Type 1 Diabetes Immunology, Helmholtz Diabetes Center at Helmholtz Munich
- Victoria K. Salb
- Research Unit Type 1 Diabetes Immunology, Helmholtz Diabetes Center at Helmholtz Munich
- Verena B. Ott
- German Center for Diabetes Research (DZD)
- Beata Legutko
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Munich and Division of Metabolic Diseases, Technische Universität München
- Roland E. Kälin
- Department of Neurosurgery, Medical Faculty, Johannes Kepler University Linz
- Markus Hippich
- German Center for Diabetes Research (DZD)
- Martin G. Scherm
- Research Unit Type 1 Diabetes Immunology, Helmholtz Diabetes Center at Helmholtz Munich
- Lucas F. R. Nascimento
- Research Unit Type 1 Diabetes Immunology, Helmholtz Diabetes Center at Helmholtz Munich
- Isabelle Serr
- Research Unit Type 1 Diabetes Immunology, Helmholtz Diabetes Center at Helmholtz Munich
- Fabian Hosp
- Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry
- Alexei Nikolaev
- Institute for Molecular Medicine, Universitätsmedizin der Johannes-Gutenberg-Universität
- Alma Mohebiany
- Institute for Molecular Medicine, Universitätsmedizin der Johannes-Gutenberg-Universität
- Martin Krueger
- Institute for Anatomy, Leipzig University
- Bianca Flachmeyer
- Institute for Anatomy, Leipzig University
- Michael W. Pfaffl
- Animal Physiology and Immunology, Technische Universität München
- Bettina Haase
- Genomics Core Facility, EMBL European Molecular Biology Laboratory
- Chun-Xia Yi
- Department of Endocrinology and Metabolism, Amsterdam University Medical Center, location AMC, University of Amsterdam
- Sarah Dietzen
- Institute of Immunology, Johannes Gutenberg University Mainz
- Tobias Bopp
- Institute of Immunology, Johannes Gutenberg University Mainz
- Stephen C. Woods
- Metabolic Diseases Institute, Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati
- Ari Waisman
- Institute for Molecular Medicine, Universitätsmedizin der Johannes-Gutenberg-Universität
- Benno Weigmann
- Department of Medicine 1, University of Erlangen-Nuremberg, Kussmaul Campus for Medical Research
- Matthias Mann
- Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry
- Matthias H. Tschöp
- German Center for Diabetes Research (DZD)
- Carolin Daniel
- Research Unit Type 1 Diabetes Immunology, Helmholtz Diabetes Center at Helmholtz Munich
- DOI
- https://doi.org/10.1038/s41467-025-57918-z
- Journal volume & issue
-
Vol. 16,
no. 1
pp. 1 – 23
Abstract
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.
