Epigenetic programming of estrogen receptor in adipocytes by high-fat diet regulates obesity-induced inflammation
Rui Wu, … , Bingzhong Xue, Hang Shi
Rui Wu, … , Bingzhong Xue, Hang Shi
Published August 26, 2025
Citation Information: JCI Insight. 2025;10(19):e173423. https://doi.org/10.1172/jci.insight.173423.
View: Text | PDF
Research Article Endocrinology Metabolism

Epigenetic programming of estrogen receptor in adipocytes by high-fat diet regulates obesity-induced inflammation

Abstract

Adipose inflammation plays a key role in obesity-induced metabolic abnormalities. Epigenetic regulation, including DNA methylation, is a molecular link between environmental factors and complex diseases. Here we found that high-fat diet (HFD) feeding induced a dynamic change of DNA methylome in mouse white adipose tissue (WAT) analyzed by reduced representative bisulfite sequencing. Interestingly, DNA methylation at the promoter of estrogen receptor α (Esr1) was significantly increased by HFD, concomitant with a downregulation of Esr1 expression. HFD feeding in mice increased the expression of DNA methyltransferase 1 (Dnmt1) and Dnmt3a and binding of DNMT1 and DNMT3a to Esr1 promoter in WAT. Mice with adipocyte-specific Dnmt1 deficiency displayed increased Esr1 expression, decreased adipose inflammation, and improved insulin sensitivity upon HFD challenge; mice with adipocyte-specific Dnmt3a deficiency showed a mild metabolic phenotype. Using a modified CRISPR/RNA-guided system to specifically target DNA methylation at the Esr1 promoter in WAT, we found that reducing DNA methylation at Esr1 promoter increased Esr1 expression, decreased adipose inflammation, and improved insulin sensitivity in HFD-challenged mice. Our study demonstrated that DNA methylation at Esr1 promoter played an important role in regulating adipose inflammation, which may contribute to obesity-induced insulin resistance.

Authors

Rui Wu, Fenfen Li, Shirong Wang, Jia Jing, Xin Cui, Yifei Huang, Xucheng Zhang, Jose A. Carrillo, Zufeng Ding, Jiuzhou Song, Liqing Yu, Huidong Shi, Bingzhong Xue, Hang Shi

×

Figure 1

HFD regulates Esr1 expression via promoter DNA methylation.

Options: View larger image (or click on image) Download as PowerPoint
HFD regulates Esr1 expression via promoter DNA methylation. (A and B) Di...
(A and B) Distribution of DMRs in the genome (A) and RRBS profiling of DNA methylation levels at Esr1 promoter (B) in gWAT of male mice fed with LFD or HFD for 12 weeks. RRBS was performed in gWAT from male C57BL/6J mice fed with LFD or HFD for 12 weeks. Genomic DNA from 4 animals was pooled in each group for RRBS analysis. (C) DNA methylation levels at individual CpG sites at Esr1 promoter in gWAT of male C57BL/6J mice fed LFD or HFD for 12 weeks, n = 4/group. *P < 0.05 vs. LFD by Student’s t test. (D and E) Average DNA methylation levels at Esr1 promoter (D, n = 5/group) and Esr1 expression (E, n = 4/group) in gWAT of male C57BL/6J mice fed LFD or HFD for 12 or 24 weeks. *P < 0.05 vs. LFD by Student’s t test. (F and G) DNA methylation levels at individual CpG sites at Esr1 promoter (F) and Esr1 expression (G) in gWAT of female C57BL/6J mice fed LFD or HFD for 12 weeks, n = 5/group. *P < 0.05 vs. LFD by Student’s t test. (H) DNA methylation levels at individual CpG sites at Esr1 promoter in 3T3-L1 adipocytes treated with palmitate (C16) or stearate (C18), n = 3/group. Groups labeled with different letters are statistically different from each other as analyzed by 1-way ANOVA with Fisher’s least significant difference (LSD) post hoc test. (I) Esr1 promoter luciferase activity in 3T3-L1 adipocytes transfected with fully methylated or unmethylated constructs, n = 3. *P < 0.05 vs. all other groups as analyzed by 2-way ANOVA with Fisher’s LSD post hoc test. (J) Esr1 promoter luciferase activity in 3T3-L1 adipocytes transfected with unmethylated constructs treated with BSA, palmitate (C:16, 200 μM), or stearate (C:18, 200 μM). n = 3. *P < 0.05 vs. BSA by 2-way ANOVA with Fisher’s LSD post hoc test. All data are expressed as mean ± SEM.