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Wailan Shan, Shiyin Lu, Biqian Ou, Jia Feng, Zixian Wang, Huixian Li, Xiaohua Lu, and Ma Yi

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. Pituitary adenylate cyclase activating polypeptide (PACAP) as a bioactive peptide secreted by the pituitary gland, has a powerful triple role of anti-oxidation, anti-apoptosis and anti-inflammation, and is involved in male reproduction regulation, but the specific mechanism remains unknown. The purpose of the current study is to explore the role of PACAP in obesity-related male infertility. In cell-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 then treated with PACAP. The cell mechanism studies showed that PACAP selectively binds 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 showed 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 testis-specific knockdown of Nrf2.