Establishment and characterization of an HFD-induced mouse model of obesity-associated male hypogonadism

To establish and characterize a high-fat diet (HFD)-induced mouse model of obesity-associated male hypogonadism (MOSH) with impaired sperm quality and define the minimal modeling duration. Forty 6-week-old male C57BL/6J mice were fed a standard diet or a 60% HFD for 10, 12, or 14 weeks. We analyzed body weight, adiposity, serum lipids, reproductive hormones, sperm quality, and testicular histology/ultrastructure. While 10-week HFD induced only obesity and dyslipidemia, 12- and 14-week HFD elicited a MOSH-like phenotype. These included significant hypogonadotropic hypogonadism (reduced testosterone, LH and FSH, elevated estradiol), impaired sperm quality (decreased concentration, motility and vitality), and structural testicular damage (seminiferous tubule atrophy and spermatogenic epithelial disruption). Notably, ultrastructural analysis revealed ferroptosis-like morphological features in Leydig cells. No significant differences were observed between the 12- and 14-week groups. At 12 weeks, HFD-fed animals exhibit obesity and reproductive alterations consistent with the MOSH phenotype. Although further validation is required, this model represents a promising platform for studying MOSH pathogenesis and assessing potential therapeutic interventions.