Institute of Biomedicine, Department of Cellular Biology, Jinan University, Guangzhou, China.
National Engineering Research Center of Genetic Medicine, Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University, Guangzhou, China.
J Endocrinol. 2021 Mar;248(3):337-354. doi: 10.1530/JOE-20-0316.
Obesity is strongly linked to male infertility. Apoptotic inflammatory response caused by oxidative stress in testicular spermatogenic cells is one of the important causes of obesity-related male infertility. As bioactive peptide is secreted by the pituitary gland, pituitary adenylate cyclase activating polypeptide (PACAP) has a powerful triple role of anti-oxidation, anti-apoptosis, and anti-inflammation, and it is involved in the male reproduction regulation, but the specific mechanism remains unknown. The purpose of this study is to explore the role of PACAP in obesity-related male infertility. In cellular level experiments, mouse spermatocytes (GC-2) were treated with palmitate (PA) to establish an high-fat injury cell model in vitro and then treated with PACAP. In animal-level experiments, C57BL/6 male mice were fed with a high-fat diet (HFD) to induce obesity and subsequently treated with PACAP. The cell mechanism studies show that PACAP selectively binded to the PAC1 receptor to attenuate palmitic acid-induced mouse spermatogenic cell (GC-2) oxidative damage and apoptotic inflammatory response via the PKA/ERK/Nrf2 signaling axis. However, this mechanism was inhibited in GC-2 cells inhibiting the activity of Nrf2. The animal experiment studies show that 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 and sperm parameters via Keap1/Nrf2/ARE pathway. These beneficial effects of PACAP were abolished in obese mice with testes-specific knockdown of Nrf2. Our data suggested 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。睾丸生殖细胞中氧化应激引起的凋亡性炎症反应是肥胖相关男性不育的重要原因之一。作为脑垂体分泌的生物活性肽，垂体腺苷酸环化酶激活肽（PACAP）具有强大的抗氧化、抗凋亡和抗炎三重作用，参与男性生殖调控，但具体机制尚不清楚。本研究旨在探讨 PACAP 在肥胖相关男性不育中的作用。在细胞水平实验中，用棕榈酸（PA）处理小鼠精母细胞（GC-2），建立体外高脂肪损伤细胞模型，然后用 PACAP 处理。在动物水平实验中，用高脂肪饮食（HFD）喂养 C57BL/6 雄性小鼠，诱导肥胖，随后用 PACAP 处理。细胞机制研究表明，PACAP 通过 PKA/ERK/Nrf2 信号通路选择性结合 PAC1 受体，减轻棕榈酸诱导的小鼠生殖细胞（GC-2）氧化损伤和凋亡性炎症反应。然而，在抑制 Nrf2 活性的 GC-2 细胞中，这种机制被抑制。动物实验研究表明，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，通过 Keap1/Nrf2/ARE 通路改善了睾丸形态和精子参数。在睾丸特异性敲低 Nrf2 的肥胖小鼠中，PACAP 的这些有益作用被消除。我们的数据表明，PACAP 可以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。
