Our previous studies have found that paternal HFD exposure enhances hepatic gluconeogenesis in male offspring, while their glucose tolerance and insulin sensitivity remain largely unaffected.[21] In this study, we evaluated whether paternal obesity impacts metabolic phenotypes in the female F1 and F2 offspring, and explored the role of the EZH2‐H3K27me3 axis in this transgenerational inheritance. This evidence concerns the gene EZH2 and obesity due to melanocortin 4 receptor deficiency.