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Approximately 15% of human couples of reproductive age have impaired fertility, and the male component accounts for about half of these cases. The etiology is usually unknown, but high correlation with the increase in obesity rates is documented. In this study, we show that diet-induced and genetically obese mice display copulatory behavior comparable to controls, but the number of females impregnated by obese males is remarkably low. Screening for changes in gene expression in the male reproductive tract showed decreased Crisp4 expression in testis and epididymis of obese mice. Lack of CRISP4 in the luminal membrane of epididymal cells indicated inadequate secretion. Consistent with CRISP4 action in acrosome reaction, sperm from mice fed a high-fat diet (HFD) had decreased fertilization capacity. CRISP4 treatment of sperm from HFD mice prior to in vitro fertilization improved fertilization rate. In leptin-deficient obese and infertile mice, leptin's effect to restore CRISP4 expression and function required gonadal hormones. Our findings indicate that the obesity-induced decline in sperm motility and fertilization capacity results in part from the disruption of epididymal CRISP4 expression and secretion.