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Life sciences · Journal article
Biology of Sex Differences · August 7, 2026
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This is a mechanistic transcriptomic study characterizing how chronic estradiol treatment remodels hepatic gene expression in obese mice, identifying both shared and sex-specific regulatory responses across hepatocyte subtypes. The findings suggest estradiol activates metabolically protective pathways in both sexes, with sex-specific modulation of lipid and glucose metabolism, but remain at the level of gene expression mapping and require functional validation and human evidence to support clinical application.
Single-nucleus RNA sequencing study. Gonadectomized obese female (XX) and male (XY) mice with diet-induced obesity treated chronically with estradiol. Intervention: Chronic estradiol (E2) treatment.
E2-induced transcriptional effects in hepatocyte subtypes were largely sex-concordant in both males and females, along with sex-specific E2 changes In pericentral hepatocytes, E2 concordantly reduced expression of genes involved in insulin resistance, FOXO signaling, and lipid biosynthesis In periportal hepatocytes, E2 enhanced cholesterol efflux genes and suppressed oxidative stress response genes
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These findings highlight potential sex-specific mechanisms by which estradiol modulates hepatic metabolism in obesity and suggest that sex chromosome complement influences estradiol's therapeutic effects. The identification of sex-specific regulatory pathways may inform future development of sex-tailored therapeutic strategies for metabolic dysfunction-associated fatty liver disease and related metabolic disorders.
Single-nucleus transcriptomics study mapping gene expression and regulatory networks in obese mice; mechanistic and exploratory, without clinical outcomes or direct human validation of therapeutic efficacy.
As stated by the source record.
These findings highlight potential sex-specific mechanisms by which estradiol modulates hepatic metabolism in obesity and suggest that sex chromosome complement influences estradiol's therapeutic effects. The identification of sex-specific regulatory pathways may inform future development of sex-tailored therapeutic strategies for metabolic dysfunction-associated fatty liver disease and related metabolic disorders.
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Abstract Background Obesity is a prevalent, systemic metabolic disease affecting not only various adipose depots but also the liver, where lipid accumulation results in metabolic dysfunction-associated fatty liver disease, dyslipidemia, and insulin resistance. While estradiol (E2) has been known to be hepatoprotective for glucose and lipid metabolism in females, whether E2’s effects on individual liver cell types are shared between sexes or are sex-specific with obesity remains poorly defined. Methods We performed single-nucleus RNA sequencing on liver tissue of E2-treated obese, gonadectomized male (XY) and female (XX) mice with diet-induced obesity to evaluate the sex-concordant and discordant effects of chronic E2 treatment. Differential gene expression, pathway analysis, intracellular and intercellular regulatory network modeling, and human metabolic disease/trait association analysis were conducted. Results E2-induced transcriptional effects among hepatocyte subtypes were largely sex-concordant in both males and females, along with sex-specific E2 changes. In pericentral hepatocytes, E2 concordantly reduced the expression of genes involved in insulin resistance, FOXO signaling, and lipid biosynthesis; in periportal hepatocytes, E2 treatment enhanced cholesterol efflux genes and suppressed oxidative stress response genes. XY-specific effects of E2 included additional suppression of lipid and energy metabolic pathways in pericentral hepatocytes and oxidative phosphorylation in periportal hepatocytes, while in XX mice E2 showed unique regulation of glucose and lipid utilization programs. Network analysis revealed that E2-responsive genes in hepatocyte subtypes in both sexes showed enriched transcription factors associated with estrogen receptor signaling and lipid sensing and metabolism, alongside sex-specific regulators. Intercellular signaling affected by E2 showed more changes in XY mice than in XX mice across hepatocyte subtypes. Lastly, while E2-responsive genes in hepatocyte subtypes of both sexes were enriched for human genetic signals associated with lipid profiles and coronary artery disease, we also identified sex-specific associations, such as the link of E2-downregulated genes in XY hepatocytes to body mass index in men. Conclusions Our findings revealed that chronic E2 administration remodels gene regulatory programs in individual liver cell types through both shared and sex-specific mechanisms, highlighting the importance of considering sex chromosome-dependent E2 responses when developing therapeutic strategies for obesity and associated hepatic metabolic dysfunction.
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