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<p>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><i>+</i></sup> T cells, infiltrating macrophages and microglia while reducing hypothalamic Tregs. mRNA profiling of hypothalamic CD4<sup><i>+</i></sup> T cells reveals a Th1-like activation state, with increased <i>Tbx21</i>, <i>Cxcr3</i> and <i>Cd226</i> but decreased <i>Ccr7</i> and <i>S1pr1</i>. 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月20日

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  • 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

摘要

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.