Estrogen signaling governs the composition and clonality of VAT Tregs in female mice during obesity 3123

Abstract Description A population of regulatory T cells (Tregs) with a unique PPARγ-dependent transcriptional program and clonally expanded TCR repertoire are highly enriched in the visceral adipose tissue (VAT) of male mice and help maintain metabolic health. Curiously, VAT Tregs are lost during obesity in male, but not female mice, which enhances VAT inflammation and insulin resistance in the former. Recent studies have identified distinct VAT Treg subsets with sex-specific biases including ST2+ and CXCR3+ Tregs enriched in males and females, respectively. This raises the question as to whether and how sex hormones alter VAT Treg subset composition to mitigate VAT Treg loss during obesity in females? Utilizing flow cytometry and single cell transcriptomics, we find that, compared to wildtype mice, lean female mice lacking the estrogen receptor α (Era) show robust clonal expansion of ST2+ VAT Tregs. However, obesity led to a profound loss of clonal ST2+ Tregs and an enrichment of CXCR3+ Tregs in the VAT of Era-/-, but not wildtype, females. Similar to males, loss of ST2+ VAT Tregs in obese Era-/- females was associated with enhanced VAT inflammation and insulin resistance, which could be rescued by restoring ST2+ VAT Tregs using a PPARγ agonist pioglitazone. These data indicate that estrogen mediates sex-specific differences in the clonality and phenotypic response of VAT Tregs during obesity which has implications in the development of metabolic disease in obese, post-menopausal women. Funding Sources Supported by NIH/NIDDK R01DK128061; NIH/NIDDK F31DK137590 Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)