Estradiol Treatment Induces Both Shared and Unique Gene Regulation and Networks in Adipose Cell Types of Gonadectomized Obese XX and XY Mice

Background Obesity is driven by the pathological expansion and accumulation of adipose tissue and demonstrates sex differences. Estradiol (E2) is known to influence fat distribution and metabolism. However, a comprehensive understanding of the sex-specific effect of E2 on individual adipose cell types remains elusive. Methods We measured adiposity and utilized single-cell RNA sequencing to dissect how E2 affects the molecular processes within gonadal adipose tissue from diet-induced obese, gonadectomized mice of both sexes (XX and XY) through differential gene expression, pathway enrichment, transcription factor enrichment, intracellular and intercellular network modeling, and human disease relevance analysis. Results We found striking sex-and cell-type-specific responses to E2 treatment. Accompanying more significant fat reduction under diet-induced obesity in XX mice, adipose stem and progenitor cells (ASPCs) of XX mice exhibited a stronger transcriptomic shift in response to E2 than ASPCs in XY mice, with altered expression of genes related to stemness and lipid metabolism. E2 broadly suppressed extracellular matrix (ECM) genes in both sexes, with more pronounced downregulation of collagen, glycoprotein, and metalloproteinase-related genes in XY preadipocytes, and reduced proteoglycan genes in XX mice. Macrophages also demonstrated heightened sensitivity to E2, showing trends in decreased proportion of lipid-associated macrophages, increased perivascular-like macrophages, and downregulated inflammatory and metabolic pathways in both sexes as well as sex-specific changes in immune genes. Furthermore, we identified strengthened macrophage to ASPC communications in XX mice and differential enrichment patterns of sex-biased E2-altered genes with human metabolic diseases. Conclusions Our findings provide a cell-resolution, sex-specific understanding of E2's profound impact on gonadal adipose tissue remodeling to guide sex-specific therapeutic interventions in obesity.