Department of Cellular Biology, Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University, Guangzhou, China.
Center for Reproductive Medicine, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China.
J Cell Physiol. 2020 Oct;235(10):7465-7483. doi: 10.1002/jcp.29651. Epub 2020 Mar 11.
Obesity is strongly linked to male infertility. Testicular spermatogenic cell apoptosis plays an important role in obesity-related male infertility. Pituitary adenylate cyclase-activating peptide (PACAP) has been recently shown to exhibit antiapoptotic and antidiabetic effects. However, the effects of PACAP on obesity-related male infertility remain unknown. The purpose of the current study is to explore the role of PACAP in obesity-related male infertility. Here, C57BL/6 male mice were fed with a high-fat diet to induce obesity and then treated with PACAP. PACAP treatment ameliorated obesity characteristics, including body weight, epididymal adipose weight, testes/body weight, serum lipids levels, and reproductive hormone levels in vivo. Additionally, PACAP was shown to improve the reproductive function of the obese mice, which was characterized by improved testis morphology, sperm parameters, acrosome reaction, and embryo quality after in vitro fertilization via silent information regulator 1 (Sirt1) activation and p53 deacetylation. These beneficial effects of PACAP were abolished in obese mice with testis-specific knockdown of Sirt1. The mechanism studies showed that PACAP selectively binds to the PAC1 receptor to attenuate palmitic acid-induced mouse spermatogenic cell (GC-1) apoptosis via the PKA/CREB/Sirt1/p53 pathway. However, this mechanism was inhibited in GC-1 cells lacking Sirt1. Finally, human semen studies showed that the decline in sperm quality in obese infertile men was partly due to Sirt1 downregulation and p53 acetylation. Our data suggest that PACAP could ameliorate fertility in obese male mice and may be a promising candidate drug for obesity-induced male infertility.
肥胖与男性不育密切相关。睾丸生殖细胞凋亡在肥胖相关男性不育中起重要作用。最近研究表明，垂体腺苷酸环化酶激活肽（PACAP）具有抗凋亡和抗糖尿病作用。然而，PACAP 对肥胖相关男性不育的影响尚不清楚。本研究旨在探讨 PACAP 在肥胖相关男性不育中的作用。本研究采用 C57BL/6 雄性小鼠高脂饮食诱导肥胖，然后用 PACAP 处理。PACAP 治疗改善了肥胖特征，包括体重、附睾脂肪重量、睾丸/体重比、血清脂质水平和生殖激素水平。此外，PACAP 改善了肥胖小鼠的生殖功能，表现为精子参数、顶体反应和体外受精胚胎质量的改善，这与沉默信息调节因子 1（Sirt1）激活和 p53 去乙酰化有关。在睾丸特异性敲低 Sirt1 的肥胖小鼠中，PACAP 的这些有益作用被消除。机制研究表明，PACAP 通过 PKA/CREB/Sirt1/p53 通路选择性结合 PAC1 受体，减轻棕榈酸诱导的小鼠生殖细胞（GC-1）凋亡。然而，在缺乏 Sirt1 的 GC-1 细胞中，这种机制被抑制。最后，人类精液研究表明，肥胖不育男性精子质量下降部分归因于 Sirt1 下调和 p53 乙酰化。我们的数据表明，PACAP 可改善肥胖雄性小鼠的生育能力，可能是肥胖引起男性不育的有前途的候选药物。
