Regulatory T cells in the mouse hypothalamus control immune activation and ameliorate metabolic impairments in high-calorie environments

Becker M, Kälin S, Neubig AH, Lauber M, Opaleva D, Hipp H, Salb VK, Ott VB, Legutko B, Kälin RE, Hippich M, Scherm MG, Nascimento LF, Serr I, Hosp F, Nikolaev A, Mohebiany A, Krueger M, Flachmeyer B, Pfaffl MW, Haase B, Yi CX, Dietzen S, Bopp T, Woods SC, Waisman A, Weigmann B, Mann M, Tschöp MH, Daniel C (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Nature Communications Nature Publishing Group: Nature Communications

Book Volume: 16

Article Number: 2744

Journal Issue: 1

DOI: 10.1038/s41467-025-57918-z

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.

Authors with CRIS profile

Benno Weigmann Medizinische Fakultät

Involved external institutions

Deutsches Zentrum für Diabetesforschung e.V. (DZD) DE Germany (DE) Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich DE Germany (DE) Technische Universität München (TUM) DE Germany (DE) Max-Planck-Institut für Biochemie / Max Planck Institute of Biochemistry DE Germany (DE) Universitätsmedizin der Johannes Gutenberg-Universität Mainz DE Germany (DE) Universität Leipzig DE Germany (DE) European Molecular Biology Laboratory (EMBL) DE Germany (DE) Amsterdam University Medical Centers (Amsterdam UMC) / Amsterdam Universitair Medische Centra NL Netherlands (NL) Johannes Gutenberg-Universität Mainz (JGU) DE Germany (DE) University of Cincinnati US United States (USA) (US)

How to cite

APA:

Becker, M., Kälin, S., Neubig, A.H., Lauber, M., Opaleva, D., Hipp, H.,... Daniel, C. (2025). Regulatory T cells in the mouse hypothalamus control immune activation and ameliorate metabolic impairments in high-calorie environments. Nature Communications, 16(1). https://doi.org/10.1038/s41467-025-57918-z

MLA:

Becker, Maike, et al. "Regulatory T cells in the mouse hypothalamus control immune activation and ameliorate metabolic impairments in high-calorie environments." Nature Communications 16.1 (2025).

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