Context-dependent roles of sex hormone signaling in controlling visceral adipose tissue Treg heterogeneity and clonal expansion.

Sex hormones are important for maintaining metabolic health. Females with low estrogen or high androgen levels exhibit an elevated risk for developing obesity-associated metabolic syndromes. Chronic low-grade inflammation in the visceral adipose tissue (VAT) is a major contributor to metabolic dysfunction during obesity. However, how sex hormones impact the VAT inflammatory environment to curtail obesity-associated pathology remain incompletely understood. Regulatory T cells (Tregs) expressing a clonally expanded T cell receptor (TCR) repertoire and high levels of the IL-33 receptor ST2 are highly enriched in male epididymal VAT (eVAT), in which they suppress tissue inflammation and protect against metabolic diseases. While TCR specificity and activation are critical for the accumulation of ST2+ eVAT Tregs in males, the factors governing Treg clonality in female ovarian VAT (oVAT) and their relevance to obesity-associated metabolic diseases remain largely unexplored. In this study, we used estrogen receptor α (ERα)-deficient mice, which exhibit impaired estrogen signaling and elevated androgen levels, to investigate the impact of sex hormone disruption on oVAT Tregs in lean and obese female mice. At steady state, ERα deficiency promoted age-dependent clonal expansion of specific ST2+ oVAT Treg subsets indirectly through modulating antigen presentation. However, combinations of obesity and ERα deficiency induced IFNγ production to deplete ST2+ oVAT Tregs, exacerbating oVAT inflammation and insulin resistance. Together, these findings reveal distinct, diet-dependent roles for sex hormones in regulating oVAT Tregs and suggest that loss of ST2+ oVAT Treg subsets during obesity may contribute to increased metabolic risk in females with disrupted sex hormone signaling.