Mapping the hepatic regulatory landscape of estradiol in gonadectomized obese female and male mice at single-nucleus resolution
6 affiliations
- 1Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA USA
- 2Molecular, Cellular, and Integrative Physiology Interdepartmental Ph.D. Program, University of California, Los Angeles, Los Angeles, CA USA
- 3Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Vanderbilt University Medical Center, Nashville, TN USA
- 4Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, TN USA
- 5Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA USA
- 6Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, The Ohio State University, Wexner Medical Center, Columbus, OH USA
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.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s13293-026-00962-1.
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BibTeX
@article{zhao2026mapping,
title = {{Mapping the hepatic regulatory landscape of estradiol in gonadectomized obese female and male mice at single-nucleus resolution}},
author = {Yutian Zhao and Ruirui Lan and In Sook Ahn and Sophia Yu and Guanglin Zhang and Graciel Diamante and Bridget Litts and Ariel Thorson and Kelsey P. Schaefers and Xia Yang and John M. Stafford},
journal = {Biology of Sex Differences},
year = {2026},
month = aug,
doi = {10.1186/s13293-026-00962-1},
url = {https://doi.org/10.1186/s13293-026-00962-1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Mapping the hepatic regulatory landscape of estradiol in gonadectomized obese female and male mice at single-nucleus resolution
AU - Yutian Zhao
AU - Ruirui Lan
AU - In Sook Ahn
AU - Sophia Yu
AU - Guanglin Zhang
AU - Graciel Diamante
AU - Bridget Litts
AU - Ariel Thorson
AU - Kelsey P. Schaefers
AU - Xia Yang
AU - John M. Stafford
PY - 2026
DA - 2026/08/07
JO - Biology of Sex Differences
DO - 10.1186/s13293-026-00962-1
UR - https://doi.org/10.1186/s13293-026-00962-1
AB - 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. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s13293-026-00962-1.
SN - 2042-6410
ER -