Deficiency of the GnIH/GPR147 System Induces Asthenozoospermia via PI3K-Mediated Metabolic and Apoptotic Dysregulation in the Testis

Objective: Obesity-related spermatogenic dysfunction has attracted growing attention. Concurrently, GnIH has been recognized as a pivotal node bridging metabolic dysregulation and testicular dysfunction. To investigate the mechanistic contribution of GnIH/GPR147 signaling to spermatogenic dysfunction and metabolic syndrome-associated male infertility, Methods: this study will employ GEO database analysis and molecular biology techniques to examine the effects of GnIH/GPR147 signaling ablation on testicular morphology, spermatogenic function, testosterone levels, and blood-testis barrier (BTB) integrity in mice under different dietary regimens. Transcriptomic approaches were employed to elucidate the molecular mechanisms underlying GnIH/GPR147 signaling ablation-induced male reproductive disorders. Results: Results demonstrated a significant correlation between downregulated GnIH/GPR147 signaling and male reproductive disorders. Both GnIH deficiency and GPR147 ablation induced spermatogenic dysfunction and BTB impairment in mice under normal diet. These genetic manipulations exacerbated high-fat/high-sugar diet-induced spermatogenic abnormalities, including morphological sperm abnormalities and defective sperm motility. However, neither GnIH deficiency nor GPR147 ablation affected serum testosterone levels or the integrity of the BTB in high-fat/high-sugar diet-fed mice. Transcriptome analysis indicated that GPR147 knockout activates the PI3K signaling pathway, thereby inducing downstream glycolytic dysfunction, cell cycle arrest, and apoptosis, which ultimately leads to impaired spermatogenesis and compromised sperm motility. Conclusion: In summary, deficiency of the GnIH/GPR147 system induces testicular metabolic dysfunction and apoptosis via PI3K hyperactivation, leading to spermatogenic dysfunction. This study highlights the essential role of the GnIH/GPR147 gene in reproductive function, providing novel insights into the pathological mechanisms and potential therapeutic strategies for male infertility.