image: Working model of liver ERα mediating differences in metabolic pattern changes between sexes in response to TRF.
Credit: 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
Time-restricted feeding (TRF) is a dietary strategy based on circadian rhythms, where food intake is restricted to a specific time window, followed by a fasting period. Previous studies have demonstrated that TRF can improve metabolic health, reducing the risk of obesity, type 2 diabetes, and other metabolic disorders. However, the role of sex differences in metabolic regulation has often been overlooked despite its significant impact.
A recent study published in Life Metabolism from Professor Wu De's team at Sichuan Agricultural University unveils how TRF impacts liver metabolism in a sex-dependent manner. The research highlights that while TRF is an emerging dietary strategy for alleviating obesity-related metabolic issues, its effects differ markedly between males and females, which is primarily driven by the liver estrogen receptor ERα.
In the study, researchers revealed that TRF promotes the breakdown of amino acids to sustain lipid synthesis in females, whereas males maintain amino acid stability and show a suppression of lipid production. This sexual dimorphism is closely linked to the action of ERα, which is significantly more abundant in the female liver (Figure 1).
To further probe the mechanism, the team employed ovariectomized mice and liver-specific Esr1 knockout models. These experiments confirmed that the absence of liver ERα in females converts their metabolic pattern from an “amino acid breakdown to support lipid synthesis” mode to a “male-like” pattern that prioritizes amino acid homeostasis and inhibits lipid accumulation. Morphological analyses also indicated that while TRF improves lipid deposition in male livers, its protective effects in females are evident only when liver ERα is disrupted (Figure 1).
The innovation of this research lies in its detailed exploration of the molecular basis behind the sex-specific responses to TRF, offering crucial insights into how estrogen signaling modulates liver metabolism. These findings not only deepen our understanding of metabolic regulation under TRF but also provide a potential basis for personalized nutritional strategies and clinical interventions targeting metabolic disorders.
Journal
Life Metabolism
Method of Research
Experimental study
Subject of Research
Animal tissue samples
Article Title
Liver ERα mediates sex differences in metabolic pattern changes in response to time-restricted feeding
Article Publication Date
25-Mar-2025