Liver ERα mediates sex differences in metabolic pattern changes in response to time-restricted feeding

Haoqi Zhang; Tengteng Huang; Xianyang Jin; Siyuan Liu; Yi Yang; Luting Liu; Xuemei Jiang; Ruinan Zhang; Hui Ye; Xinyue Qi; Tongxing Song; Chao Jin; Bin Feng; Lianqiang Che; Shengyu Xu; Yan Lin; Zhengfeng Fang; Ting Luo; Yong Zhuo; De Wu; Lun Hua

doi:10.1093/lifemeta/loaf011

Liver ERα mediates sex differences in metabolic pattern changes in response to time-restricted feeding

Life Metab. 2025 Mar 25;4(4):loaf011. doi: 10.1093/lifemeta/loaf011. eCollection 2025 Aug.

Authors

Haoqi Zhang^{1

2

3}, Tengteng Huang^{1

2

3}, Xianyang Jin^{1

2

3}, Siyuan Liu^{1

2

3}, Yi Yang^{1

2

3}, Luting Liu^{1

2

3}, Xuemei Jiang^{1

2

3}, Ruinan Zhang^{1

2

3}, Hui Ye⁴, Xinyue Qi⁴, Tongxing Song⁵, Chao Jin^{1

2

3}, Bin Feng^{1

2

3}, Lianqiang Che^{1

2

3}, Shengyu Xu^{1

2

3}, Yan Lin^{1

2

3}, Zhengfeng Fang^{1

2

3}, Ting Luo⁶, Yong Zhuo^{1

2

3}, De Wu^{1

2

3}, Lun Hua^{1

2

3}

Affiliations

¹ Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, Sichuan 611130, China.
² Key Laboratory for Animal Disease-Resistant Nutrition of the Ministry of Education of China, Sichuan Agricultural University, Chengdu, Sichuan 611130, China.
³ Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan 611130, China.
⁴ School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, Singapore 637371, Singapore.
⁵ College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, Hubei 430070, China.
⁶ State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, Jiangxi 330047, China.

Abstract

Time-restricted feeding (TRF) is a dietary strategy used to prevent and treat obesity in both sexes. However, TRF affects liver metabolism differently in males and females, and the mechanisms behind these differences remain unclear. Our study reveals that during TRF, female livers are more likely to break down amino acids (AAs) to synthesize fats, while male livers significantly reduce fatty acid synthesis. The changes in the liver's AA metabolic profile after gonadectomy suggest that estrogen signaling is crucial for regulating AA metabolism in females during TRF. Additionally, we demonstrate that hepatic estrogen receptor α (ERα)-mediated AA metabolism contributes to the sex-specific effects of TRF on liver metabolism. These findings offer new insights into the molecular mechanisms of TRF and its potential clinical application for treating fatty liver and other metabolic disorders. They also emphasize the need to consider sex differences when developing nutritional and pharmacological treatments for metabolic diseases in females.

Keywords: estrogen receptor α; liver metabolism; sexual dimorphism; time-restricted feeding.