Obesity disrupts cholesterol homeostasis to dysregulate VAT Treg subsets 2358

Abstract Description A specialized population of regulatory T cells (Tregs) resides in the visceral adipose tissue (VAT), displays a unique transcriptional profile and T cell receptor (TCR) repertoire, and plays a key role in regulating systemic metabolic balance. However, obesity leads to the loss of these cells, resulting in increased insulin sensitivity. VAT Tregs consist of distinct subsets. Here, we investigated the metabolic pathways that regulate the homeostasis, composition, and function of VAT Tregs at steady state and after high-fat diet (HFD) feeding. We discovered that cholesterol metabolism is specifically upregulated in ST2hi VAT Treg subsets. Ablating key regulators of cholesterol homeostasis (CH) in Tregs specifically reduced the accumulation of ST2hi VAT Tregs and led to increased insulin resistance. Single-cell RNA/TCR sequencing revealed a selective loss and decreased clonal expansion of ST2hi, but not other VAT Treg subsets after Treg-specific ablation of CH. Using a unique VAT Treg TCR transgenic (vTreg53) mouse model and peptides with varying affinities for the vTreg53 TCR, we found that strong TCR signaling, enhanced by CH, selectively promoted the accumulation of ST2hiVAT Tregs. However, prolonged HFD feeding disrupted VAT Treg CH and impaired ST2hi VAT Treg clonal expansion. Restoring Treg CH in obese mice rescued VAT Treg accumulation, suggesting that CH modulation could be a promising approach for Treg-targeted therapies in obesity-related metabolic diseases. Funding Sources Supported by NIH/NIDDK R01DK128061; F31DK137590; NIH/NCI 5T32CA275777. Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)