Dong Jinhui, Tong Xiaohui, Xu Jing, Pan Min, Wang Lei, Xu Fei, Wang Yajuan, Li Li, Wang Tongsheng
Department of Physiology and Pharmacology, Anhui University of Chinese Medicine, Hefei, 230012, China.
Department of Physiology and Pharmacology, Anhui University of Chinese Medicine, Hefei, 230012, China.
Eur J Pharmacol. 2024 Apr 5;968:176388. doi: 10.1016/j.ejphar.2024.176388. Epub 2024 Feb 16.
Researches have proposed that obesity might contribute to development of oligoasthenospermia. This study was performed to confirm whether obesity contributes to oligoasthenospermia as well as the underlying mechanisms in mice fed with a high fat diet (HFD). Meanwhile, the actions of metformin, a drug of well-known weight-lowering effect, on sperm quality in obese mice were investigated. Our results showed that HFD feeding reduced sperm quality and steroid hormone levels in mice, associated with disruptions in testicular histomorphology and spermatogenesis. Moreover, obesity increased sperm apoptosis. These effects could be prevented by metformin treatment in HFD-fed mice. Mechanistically, an increasement in lipid contents associated with decreased hormone-sensitive lipase (HSL) protein expression in testes in HFD-fed mice was observed, which could be improved by metformin treatment. Then, the model of TM4 mouse Sertoli cells stimulated with palmitic acid (PA) was used to investigate the potential effect of lipid retention on testicular apoptosis and sperm quality reduction. In consistent, PA exposure elevated lipid contents as well as apoptosis in TM4 cells, which could also be improved by metformin treatment. Of note, the protein expression of HSL was reduced stimulated by PA in TM4 cells, also rescued by metformin. Then, anti-apoptosis effect of metformin would be lost with the deficiency of HSL. In summary, our study propose that obesity contributes to oligoasthenospermia by increasing sperm apoptosis induced by impaired lipid hydrolysis due to HSL down-regulation, which could be prevented with metformin treatment via regulating the expression of HSL in testis in mice.
研究表明，肥胖可能导致少弱精子症的发生。本研究旨在证实肥胖是否会导致少弱精子症以及高脂饮食（HFD）喂养小鼠的潜在机制。同时，研究了具有显著减肥效果的药物二甲双胍对肥胖小鼠精子质量的影响。我们的结果表明，高脂饮食喂养会降低小鼠的精子质量和类固醇激素水平，这与睾丸组织形态学和精子发生的破坏有关。此外，肥胖会增加精子凋亡。在高脂饮食喂养的小鼠中，二甲双胍治疗可以预防这些影响。从机制上讲，观察到高脂饮食喂养的小鼠睾丸中脂质含量增加，同时激素敏感性脂肪酶（HSL）蛋白表达降低，二甲双胍治疗可以改善这种情况。然后，使用棕榈酸（PA）刺激的TM4小鼠支持细胞模型来研究脂质潴留对睾丸凋亡和精子质量降低的潜在影响。一致的是，PA暴露会提高TM4细胞中的脂质含量以及凋亡，二甲双胍治疗也可以改善这种情况。值得注意的是，PA刺激会降低TM4细胞中HSL的蛋白表达，二甲双胍也可以挽救这种情况。然后，缺乏HSL会导致二甲双胍的抗凋亡作用丧失。总之，我们的研究表明，肥胖通过增加由于HSL下调导致脂质水解受损而诱导的精子凋亡来导致少弱精子症，在小鼠中，二甲双胍可以通过调节睾丸中HSL的表达来预防这种情况。
