By successfully injecting DZNep intraperitoneally in F0 mice and addressing questions at in vivo, cellular, and molecular levels, we provide an exhaustive approach for understanding the mechanisms linking the EZH2‐H3K27me3‐MANF pathway to programmed glucose metabolic dysfunction in generations following paternal obesity in this study. The gene discussed is EZH2; the disease is obesity due to melanocortin 4 receptor deficiency.