In this study we showed that decreased adiponectin/AdipoR1 signaling is implicated in obesity-induced male infertility and demonstrated for the first time that decreased adiponectin/AdipoR1 signaling involves an increase in caspase-6 activity via the AMPK-caspase-6 axis, thus resulting in suppressed spermatogenesis. This evidence concerns the gene CASP6 and obesity due to melanocortin 4 receptor deficiency.