Dialogue between nutrition and reproduction: preliminary exploration of sperm quality response to high-fat diet in mice

Background: High-fat diets are known to affect semen quality, potentially through metabolic and cellular stress mechanisms. Objectives: This study investigates the impact of a high-fat diet on semen quality in male mice and identifies the underlying mechanisms involved. Materials and methods: Thirty male C57BL/6J mice were randomly assigned to a control diet (CD) or HFD for 12 weeks. Sperm parameters and fertility were assessed by computer-assisted sperm analysis and mating trials. Testicular oxidative stress indices, autophagy- and apoptosis-related proteins were analyzed by biochemical assays and Western blot. Mitophagy (LC3B-Grp75 co-localization), tissue morphology (H&E, TUNEL, electron microscopy) and sperm DNA damage (DNA fragmentation index, 8-hydroxy-2'-deoxyguanosine [8-OHdG]) were further evaluated. Serum lipids and testosterone were measured by enzymatic assays and ELISA. Results: HFD mice developed obesity, dyslipidemia, reduced testosterone, marked decreases in sperm count, progressive motility and normal morphology, and complete loss of fertility. Region-specific molecular alterations were observed along the reproductive tract: in epididymal caput, Beclin-1 and LC3B were upregulated and p62 downregulated, indicating enhanced autophagic flux; in cauda epididymis, pro-apoptotic markers increased and Bcl-2 decreased, consistent with augmented apoptosis; in testis, ATG5, Beclin-1, caspase-3 and Apaf-1 were elevated. HFD also increased testicular ROS and MDA, reduced SOD activity and mitochondrial membrane potential, and elevated sperm apoptosis, DNA fragmentation and 8-OHdG. Conclusion: HFD induces a pathogenic cascade-oxidative stress, disrupted autophagy/mitophagy, and mitochondrial apoptosis-that collectively impair spermatogenesis and male fertility. Therapeutic strategies targeting antioxidant defenses, autophagic flux, and mitophagy may ameliorate obesity-related reproductive dysfunction.