Obesity reshapes regulatory T cells in the visceral adipose tissue by disrupting cellular cholesterol homeostasis

Regulatory T cells (T regs ) accumulate in the visceral adipose tissue (VAT) to maintain systemic metabolic homeostasis but decline during obesity. Here, we explored the metabolic pathways controlling the homeostasis, composition, and function of VAT T regs under normal and high-fat diet feeding conditions. We found that cholesterol metabolism was specifically up-regulated in ST2 hi VAT T reg subsets. T reg -specific deletion of Srebf2 , the master regulator of cholesterol homeostasis, selectively reduced ST2 hi VAT T regs , increasing VAT inflammation and insulin resistance. Single-cell RNA/T cell receptor (TCR) sequencing revealed a specific loss and reduced clonal expansion of ST2 hi VAT T reg subsets after Srebf2 deletion. Srebf2 -mediated cholesterol homeostasis potentiated strong TCR signaling, which preferentially promoted ST2 hi VAT T reg accumulation. However, long-term high-fat diet feeding disrupted VAT T reg cholesterol homeostasis and impaired clonal expansion of the ST2 hi subset. Restoring T reg cholesterol homeostasis rescued VAT T reg accumulation in obese mice, suggesting that modulation of cholesterol homeostasis could be a promising strategy for T reg -targeted therapies in obesity-associated metabolic diseases.