Abstract：
Obesity is a growing epidemic among reproductive-age men, which can cause and exacerbate male infertility by means of associated comorbidities, endocrine abnormalities, and direct effects on the fidelity and throughput of spermatogenesis. A prominent consequence of male obesity is a reduction in testosterone levels. Natural products have shown tremendous potential anti-obesity effects in metabolic diseases. This study aimed to investigate the potential of apigenin (AP) to alleviate testicular dysfunction induced by a high-fat diet (HFD) and to investigate the underlying mechanisms, focusing on endoplasmic reticulum stress (ERS) and testosterone synthesis. A murine model of obesity was established using HFD-fed mice. The effects of AP on obesity, lipid metabolism, testicular dysfunction, and ERS were assessed through various physiological, histological, and molecular techniques. Administration of AP (10 mg/kg) ameliorated HFD-induced obesity and testicular dysfunction in a mouse model, as evidenced by decreased body weight, improved lipid profiles and testicular pathology, and restored protein levels related to testosterone. Furthermore, in vitro studies demonstrated that AP relieved ERS and recovered testosterone synthesis in murine Leydig cells (TM3) treated with free fatty acids (FFAs). It was also observed that AP rescued testosterone synthesis enzymes in TM3 cells, similar to that observed with the inhibitor of the PERK pathway (GSK2606414). In addition, ChIP, qPCR, and gene silencing showed that the C/EBP homologous protein (CHOP) bound directly to the promoter region of steroidogenic STAR and negatively modulated its expression. Collectively, AP has remarkable potential to alleviate HFD-induced obesity and testicular dysfunction. Its protective effects are attributable partly to mitigating ERS and restoring testosterone synthesis in Leydig cells.
摘要：
肥胖在育龄男性中越来越流行，这可以通过相关的合并症导致和加剧男性不育，内分泌异常,并直接影响精子发生的保真度和通量。男性肥胖的一个突出后果是睾酮水平降低。天然产物在代谢性疾病中显示出巨大的潜在抗肥胖作用。本研究旨在探讨芹菜素（AP）减轻高脂饮食（HFD）引起的睾丸功能障碍的潜力，并探讨其潜在机制。关注内质网应激（ERS）和睾酮合成。使用HFD喂养的小鼠建立肥胖的鼠模型。AP对肥胖的影响，脂质代谢，睾丸功能障碍,和ERS通过各种生理评估，组织学,和分子技术。在小鼠模型中，服用AP（10mg/kg）改善了HFD诱导的肥胖和睾丸功能障碍，体重下降证明了这一点，改善血脂和睾丸病理，并恢复与睾酮相关的蛋白质水平。此外，体外研究表明，在用游离脂肪酸（FFA）处理的鼠睾丸间质细胞（TM3）中，AP缓解了ERS并恢复了睾丸激素的合成。还观察到AP拯救了TM3细胞中的睾酮合成酶，与PERK途径抑制剂(GSK2606414)观察到的相似.此外,ChIP,qPCR,基因沉默表明，C/EBP同源蛋白（CHOP）直接与类固醇STAR的启动子区结合，并负调控其表达。总的来说，AP具有减轻HFD诱导的肥胖和睾丸功能障碍的显著潜力。其保护作用部分归因于减轻ERS和恢复睾丸间质细胞中的睾酮合成。
