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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,B. Feng,L. Che,Shengyu Xu,Yan Lin,Z. Fang,Ting Luo,Y. Zhuo,De Wu,Lun Hua

Published 2025 in Life Metabolism

ABSTRACT

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.

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