Ju Jiaxi, Wen Shuangli, Zhao Xuan, Cheng Jiyuan, Yang Hongjin, Zhu Guiming
Department of Biochemistry and Molecular Biology, School of Basic Medicine, Guizhou Medical University, Guiyang, China.
Key Laboratory of Biology and Medical Engineering, School of Biology and Engineering (School of Modern Industry for Health and Medicine), Guizhou Medical University, Guiyang, China.
Transgenic Res. 2025 Jun 22;34(1):32. doi: 10.1007/s11248-025-00448-7.
Obesity is a well-established risk factor for male infertility. Recent studies have demonstrated that endoplasmic reticulum (ER) stress is a key contributor to spermatogenic disorder associated with obesity. Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been shown to mitigate ER stress, thereby alleviating insulin resistance. However, their specific role in obesity-induced reproductive disorders remains unclear. In this study, we used the transgenic fat-1 mice (TG mice) that are capable of endogenously converting Omega-6 polyunsaturated fatty acids (n-6 PUFAs) to n-3 PUFAs. The mice were divided into four groups according to their diet: a control group (WT + ND, n = 8), a wild type high-fat diet group (WT + HFD, n = 8), a transgenic control group (TG + ND, n = 8), and a transgenic high-fat diet group (TG + HFD, n = 8). After 18 weeks of feeding, the mice were anesthetized and euthanized to examine indicators related to obesity and reproductive function. High-fat diet (HFD) induced significant obesity in WT mice, and we observed significant alteration mitophagy in the reproductive function of WT mice (P < 0.001), primarily manifested as abnormal testicular morphology, decreased sperm quantity and motility (P < 0.01), and reduced testosterone levels (P < 0.01). TG mice exhibited a significant attenuation of these pathological changes (P < 0.05). Markers of ER stress and mitophagy were significantly reduced in the testes of TG mice (P < 0.01), accompanied by an increased expression of phosphorylated AMP-activated protein kinase (AMPK) (P < 0.01), compared to WT mice. Concurrently, TG mice exhibited significantly elevated levels of mitochondrial biogenesis markers and key enzymes involved in testosterone synthesis in the testes, compared to those in WT mice (P < 0.01). Furthermore, TG mice displayed notable resistance to testicular inflammation induced by HFD compared with WT mice (P < 0.01). Our findings suggest that HFD-induced obesity is associated with impaired testicular morphology and function in mice. n-3 PUFAs may ameliorate these impairments by activating AMPK to suppress ER stress, restore mitochondrial dysfunction, and alleviate inflammation, thereby improving testicular morphology and function.
肥胖是男性不育症一个已被充分证实的风险因素。最近的研究表明，内质网（ER）应激是与肥胖相关的生精障碍的关键因素。ω-3多不饱和脂肪酸（n-3 PUFAs）已被证明可减轻内质网应激，从而缓解胰岛素抵抗。然而，它们在肥胖诱导的生殖障碍中的具体作用仍不清楚。在本研究中，我们使用了能够将ω-6多不饱和脂肪酸（n-6 PUFAs）内源性转化为n-3 PUFAs的转基因fat-1小鼠（TG小鼠）。根据饮食将小鼠分为四组：对照组（WT + ND，n = 8）、野生型高脂饮食组（WT + HFD，n = 8）、转基因对照组（TG + ND，n = 8）和转基因高脂饮食组（TG + HFD，n = 8）。喂养18周后，将小鼠麻醉并处死，以检查与肥胖和生殖功能相关的指标。高脂饮食（HFD）在WT小鼠中诱导了显著的肥胖，并且我们观察到WT小鼠生殖功能中的线粒体自噬有显著改变（P < 0.001），主要表现为睾丸形态异常、精子数量和活力下降（P < 0.01）以及睾酮水平降低（P < 0.01）。TG小鼠表现出这些病理变化的显著减轻（P < 0.05）。与WT小鼠相比，TG小鼠睾丸中内质网应激和线粒体自噬的标志物显著降低（P < 0.01），同时磷酸化AMP激活蛋白激酶（AMPK）的表达增加（P < 0.01）。同时，与WT小鼠相比，TG小鼠睾丸中线粒体生物发生标志物和参与睾酮合成的关键酶水平显著升高（P < 0.01）。此外，与WT小鼠相比，TG小鼠对HFD诱导的睾丸炎症表现出显著抗性（P < 0.01）。我们的研究结果表明，HFD诱导的肥胖与小鼠睾丸形态和功能受损有关。n-3 PUFAs可能通过激活AMPK来抑制内质网应激、恢复线粒体功能障碍并减轻炎症，从而改善睾丸形态和功能，进而减轻这些损伤。
