Palmitic acid (PA), the main component of dietary saturated fat, has been known to increase in patients with obesity, and PA‐induced lipotoxicity may contribute to obesity‐related male infertility. Melatonin has beneficial effects on reproductive processes; however, the effect and the underlying molecular mechanism of melatonin's involvement in PA‐induced cytotoxicity in the testes are poorly understood. Our findings showed that lipotoxicity was observed in mouse testes after long‐term PA treatment and that melatonin therapy restored spermatogenesis and fertility in these males. Moreover, melatonin therapy suppressed PA‐induced apoptosis by modulating apoptosis‐associated proteins such as Bcl2, Bax, C‐Caspase3, C‐Caspase12, and CHOP in type B spermatogonial stem cells. Changes in the expression of endoplasmic reticulum (ER) stress markers (p‐IRE1, p‐PERK, ATF4) and intracellular Ca²⁺ levels showed that melatonin relieved PA‐induced ER stress. Mechanistically, melatonin stimulated the expression and nuclear translocation of SIRT1 through its receptors and prevented PA‐induced ROS production and mitochondrial dysfunction via SIRT1 signaling pathway. Furthermore, melatonin promoted SIRT1‐mediated p53 deacetylation, thereby relieving G2/M arrest in response to PA‐stimulated DNA damage. Collectively, these findings indicate that melatonin protects the testes from PA‐induced lipotoxicity through the activation of SIRT1, which alleviates oxidative stress, ER stress, mitochondrial dysfunction, and DNA damage.

中文翻译：

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褪黑激素通过以 SIRT1 依赖性方式减弱氧化应激和 DNA 损伤来保护小鼠睾丸免受棕榈酸诱导的脂毒性。

已知膳食饱和脂肪的主要成分棕榈酸 (PA) 在肥胖患者中增加，PA 诱导的脂毒性可能导致肥胖相关的男性不育症。褪黑激素对生殖过程有益；然而，对褪黑激素参与 PA 诱导的睾丸细胞毒性的作用和潜在分子机制知之甚少。我们的研究结果表明，在长期 PA 治疗后，在小鼠睾丸中观察到脂毒性，并且褪黑激素治疗恢复了这些雄性的精子发生和生育能力。此外，褪黑激素治疗通过调节 B 型精原干细胞中的 Bcl2、Bax、C-Caspase3、C-Caspase12 和 CHOP 等凋亡相关蛋白来抑制 PA 诱导的细胞凋亡。²⁺水平表明褪黑激素减轻了 PA 诱导的内质网应激。从机制上讲，褪黑激素通过其受体刺激 SIRT1 的表达和核转位，并通过 SIRT1 信号通路阻止 PA 诱导的 ROS 产生和线粒体功能障碍。此外，褪黑激素促进了 SIRT1 介导的 p53 去乙酰化，从而缓解了对 PA 刺激的 DNA 损伤的 G2/M 期阻滞。总的来说，这些发现表明，褪黑激素通过激活 SIRT1 来保护睾丸免受 PA 诱导的脂毒性，从而减轻氧化应激、ER 应激、线粒体功能障碍和 DNA 损伤。