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Animal Models

Agomelatine alleviates palmitic acid-induced mouse oocyte meiosis defects by restoring mitochondrial function

International Journal of Obesity volume 49, pages 1781–1791 (2025)Cite this article

Subjects

Abstract

Background/objective

Palmitic acid (PA) is known to be elevated in the follicular fluid of women with obesity, negatively affecting female fertility. However, the mechanism by which PA exposure reduces female fertility is not fully understood, and how it can be treated requires further investigation.

Methods

We first established in vivo and in vitro models of mouse oocyte maturation at high concentrations of PA and determined the effects of treatment with agomelatine (Ago) which is a melatonin receptor agonist with antioxidant properties. We assessed oocyte maturation rates, spindle morphology and chromosome morphology, oxidative stress and apoptosis levels. Lastly, we examined energy levels, mitochondrial function, and mitochondrial synthesis-related protein expression levels.

Results

Our results showed that PA exposure disrupted spindle assembly and chromosome alignment, reduced microtubule stability, and impaired the meiotic maturation of oocytes. PA also disrupted mitochondrial function, leading to decreased ATP production, elevated Reactive Oxygen Species(ROS) levels, oxidative stress, and apoptosis. Remarkably, Ago supplementation promoted oocyte quality by restoring spindle/chromosome conformation, maintaining mitochondrial function, lowering ROS levels, and inhibiting apoptosis.

Conclusions

This study establishes that Ago ameliorates metabolic stress-induced oocyte deterioration through mitochondrial functional restoration, providing mechanistic insights into obesity-associated infertility. Importantly, our study identifies a potentially favorable drug for combating obesity-induced female infertility.

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Fig. 1: Ago alleviates oocyte maturation defects in PA-treated oocytes.
Fig. 2: Ago restores the damaged spindle structure, chromosome arrangement and microtubule stability in PA-treated oocytes.
Fig. 3: Ago attenuates oxidative stress in PA-treated oocytes.
Fig. 4: Ago restores normal energy levels and mitochondrial function in PA-treated oocytes.
Fig. 5: Ago alleviates PA-induced abnormal levels of SIRT1 and PGC1α.
Fig. 6: Protective effect of Ago on PA-treated oocytes in vivo is similar to in vitro results.

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Data availability

All data generated or analysed during this study are included in this published article (and its Supplementary Information files). Detailed individual analysis will be available from the corresponding author on reasonable request.

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Acknowledgements

We thank Zhen Wang and Lei Chen (Life Science Research Core Services, Northwest A&F University, Yangling, China) for transmission electron microscopy experimental assistance. Mouse and syringe cartoon images used in figure were obtained from Scidraw.io.

Funding

This work was supported by the National Natural Science Foundation of China [grant number U24A20442]; the Key R&D and Transformation program of Qinghai Province [grant number 2023-NK-131, 2022-QY-209].

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Authors and Affiliations

  1. Key Laboratory of Livestock Biology, College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, PR China

    Ruolin Zhao, Yujie Tang, Yingbing Zhang, Jinwang Liu, Changsheng Zhong, Bozhen Ji, Weijia Song & Jianmin Su

  2. Xining Center for Animal Disease Prevention and Control, Xining, Qinghai, PR China

    Chengtu Zhang

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Contributions

RLZ and JMS conceptualized and designed the study. RLZ, YJT, YBZ and BZJ completed data collection. JWL, CSZ and WJS analysed and interpreted data. RLZ drafted the manuscript. JMS critically revised the manuscript for important intellectual content. CTZ and JMS supervised the study. All authors have read and approved the final version of the manuscript.

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Correspondence to Jianmin Su.

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The authors declare no competing interests.

Ethical approval

All animal experiments were conducted in strict accordance with the China National Guidelines for Ethical Review of Laboratory Animal Welfare (GB/T 35892-2018) and the Regulations for the Administration of Affairs Concerning Experimental Animals (2017 Revision). The experimental protocols were approved by the Animal Care and Use Committee of Northwest A&F University (Protocol number: XN-2023-1207). This study did not involve any human participants or human data.

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Zhao, R., Tang, Y., Zhang, Y. et al. Agomelatine alleviates palmitic acid-induced mouse oocyte meiosis defects by restoring mitochondrial function. Int J Obes 49, 1781–1791 (2025). https://doi.org/10.1038/s41366-025-01825-2

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