Abstract
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.