The Leucine-mTOR-Autophagy Axis in Granulosa Cells Mediates Circadian Disruption-Induced Anovulation

Dec 9, 2025International journal of biological sciences

How Light Disruption Affects Ovulation through the Leucine-MTOR Pathway

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Abstract

Continuous light exposure may disrupt ovulation, as indicated by altered estrous cycles and increased anti-Müllerian hormone (AMH) levels in female SD rats.

Female SD rats exposed to continuous light showed polycystic ovaries and disrupted estrous cycles.
A high-leucine diet was linked to anovulation and polycystic morphology in normal light conditions.
Leucine restriction alleviated the effects of induced anovulation and polycystic morphology in recovered rats.
In patients with polycystic ovary syndrome (PCOS), higher serum levels of branched-chain amino acids (BCAAs), particularly leucine, correlated with elevated AMH levels and altered hormone ratios.
Mendelian randomization analysis suggested a potential link between night shift work and increased risk of PCOS through elevated serum leucine levels.

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Ovulation disorders represent the most common cause of infertility in women. Previous studies have reported that continuous light exposure can induce anovulation. However, the underlying mechanisms remain unclear.We assessed the phenotypes of ovulation disorders by using vaginal smears, hormone levels, and ovarian morphology. Metabolomics and RNA sequencing were employed to identify key metabolites and explore potential underlying mechanisms. Additionally, we investigated the effects of a leucine-rich diet on the phenotypes of ovulation disorders and autophagy. Serum levels of branched-chain amino acids (BCAAs) in patients with polycystic ovary syndrome (PCOS) were also measured. Causality was explored by using Mendelian randomization (MR) methods based on GWAS summary data.Female SD rats subjected to continuous light exhibited disrupted estrous cycles and polycystic ovaries, as well as increased anti-Müllerian hormone (AMH) levels. Metabolic profiling revealed that leucine was a pivotal metabolite. Specifically, a high-leucine diet induced anovulation and polycystic morphology, along with reducing autophagy, in rats under normal light conditions; additionally, leucine restriction alleviated these effects in recovered rats. Moreover, the mTOR-ULK1-LC3-II/I autophagy pathway was influenced bothandby leucine. In patients with PCOS, elevated serum BCAA levels (especially leucine) were observed to be correlated with increased AMH levels, higher luteinizing hormone (LH)-to-follicle-stimulating hormone (FSH) ratios, and higher antral follicle counts. MR analysis indicated that night shift work may increase the risk of PCOS through elevated serum leucine levels.These results suggest that the disruption of the leucine-mTOR-autophagy axis in granulosa cells (GCs) mediates continuous light-induced ovulation disorders. The potential therapeutic targeting of leucine-mTOR pathways for managing PCOS should be investigated. Background: Methods: Results: Conclusions: in vivo in vitro

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The Leucine-mTOR-Autophagy Axis in Granulosa Cells Mediates Circadian Disruption-Induced Anovulation

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