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Testicular spermatogenic cell apoptosis plays an important role in obesity\u2010related male infertility. Pituitary adenylate cyclase\u2010activating peptide (PACAP) has been recently shown to exhibit antiapoptotic and antidiabetic effects. However, the effects of PACAP on obesity\u2010related male infertility remain unknown. The purpose of the current study is to explore the role of PACAP in obesity\u2010related male infertility. Here, C57BL\/6 male mice were fed with a high\u2010fat diet to induce obesity and then treated with PACAP. PACAP treatment ameliorated\u00a0obesity\u00a0characteristics, 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\u2010specific knockdown of Sirt1. The mechanism studies showed that PACAP selectively binds to the PAC1 receptor to attenuate palmitic acid\u2010induced mouse spermatogenic cell (GC\u20101) apoptosis via the PKA\/CREB\/Sirt1\/p53 pathway. However, this mechanism was inhibited in GC\u20101 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\u2010induced male infertility.<\/jats:p>","DOI":"10.1002\/jcp.29651","type":"journal-article","created":{"date-parts":[[2020,3,11]],"date-time":"2020-03-11T10:21:53Z","timestamp":1583922113000},"page":"7465-7483","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["PACAP ameliorates fertility in obese male mice via PKA\/CREB pathway\u2010dependent Sirt1 activation and p53 deacetylation"],"prefix":"10.1002","volume":"235","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7701-5126","authenticated-orcid":false,"given":"Qiuxia","family":"Yan","sequence":"first","affiliation":[{"name":"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 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