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

The hypothalamus in the central nervous system (CNS) plays a key role in the control of systemic metabolism. A calorie-rich diet triggers CNS immune activation, which contributes to impairments of metabolic control, favoring obesity and Type 2 Diabetes (T2D). However, cell types and molecular processes regulating hypothalamic immune activation remain incompletely understood. Here, we report the functionally relevant presence of regulatory T cells (Tregs), key players in the control of immune and tissue homeostasis, in the hypothalamus. Exposure to calorie-rich environments triggers immune activation of hypothalamic CD4+T cells, infiltrating macrophages and microglia while decreasing the presence of hypothalamic Tregs in mice. mRNA expression profiling of hypothalamic CD4+T cells revealed a Th1-like activation state evidenced by high levels of Tbx21, Cxcr3 and Cd226 and a decrease of Ccr7 and S1pr1 expression, a profile typical for recruitment of T cells to and retention at inflammatory sites. Importantly, mechanistic Treg loss- and gain-of-function experiments in vivo, show that Foxp3+Tregs limit hypothalamic immune activation and improve metabolic impairments induced by hyper-caloric feeding. Our findings refine the current model of immuno-metabolic crosstalk in the brain in response to environmental challenges and are of relevance for the future development of immune interventions to support health in obesity and T2D. Overall design: Foxp3 GFP reporter mice were fed a high-fat high-sugar diet (HFHSD) or a standard diet (SD) for the indicated time points. Additionally, genetically obese ob/ob mice vs. BL6J mice were used. Cells from brains or hypothalami were isolated by homogenization and stained for FACS, followed by sorting of the indicated T cell subsets for purity. Bulk RNA-seq was performed.