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 () and Carolin Daniel ()
Additional contact information
Maike Becker: Helmholtz Diabetes Center at Helmholtz Munich
Stefanie Kälin: German Center for Diabetes Research (DZD)
Anne H. Neubig: Helmholtz Diabetes Center at Helmholtz Munich
Michael Lauber: Helmholtz Diabetes Center at Helmholtz Munich
Daria Opaleva: Helmholtz Diabetes Center at Helmholtz Munich
Hannah Hipp: Helmholtz Diabetes Center at Helmholtz Munich
Victoria K. Salb: Helmholtz Diabetes Center at Helmholtz Munich
Verena B. Ott: German Center for Diabetes Research (DZD)
Beata Legutko: Technische Universität München
Roland E. Kälin: Johannes Kepler University Linz
Markus Hippich: German Center for Diabetes Research (DZD)
Martin G. Scherm: Helmholtz Diabetes Center at Helmholtz Munich
Lucas F. R. Nascimento: Helmholtz Diabetes Center at Helmholtz Munich
Isabelle Serr: Helmholtz Diabetes Center at Helmholtz Munich
Fabian Hosp: Max Planck Institute of Biochemistry
Alexei Nikolaev: Universitätsmedizin der Johannes-Gutenberg-Universität
Alma Mohebiany: Universitätsmedizin der Johannes-Gutenberg-Universität
Martin Krueger: Leipzig University
Bianca Flachmeyer: Leipzig University
Michael W. Pfaffl: Technische Universität München
Bettina Haase: EMBL European Molecular Biology Laboratory
Chun-Xia Yi: University of Amsterdam
Sarah Dietzen: Johannes Gutenberg University Mainz
Tobias Bopp: Johannes Gutenberg University Mainz
Stephen C. Woods: University of Cincinnati
Ari Waisman: Universitätsmedizin der Johannes-Gutenberg-Universität
Benno Weigmann: Kussmaul Campus for Medical Research
Matthias Mann: Max Planck Institute of Biochemistry
Matthias H. Tschöp: German Center for Diabetes Research (DZD)
Carolin Daniel: Helmholtz Diabetes Center at Helmholtz Munich

Nature Communications, 2025, vol. 16, issue 1, 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.

Date: 2025
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DOI: 10.1038/s41467-025-57918-z

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