Early nutritional events may have an influence on later life health mainly through epigenetic processes.1 In our two- generation mice model, providing obese and diabetic mice with a control diet during the periconceptional/gestation/ lactation period led to a pronounced sex-specific shift from susceptibility to resistance to a high-fat diet (HFD) in the female offspring only.2,3 The aim of this study was to detect sex-specific differences in the expression of candidate genes and epigenetic marks and machinery in the liver of both sexes and both generations. As a key organ for lipid processing and detoxification, liver plays a major role in conditions of chronic lipid oversupply. According to the sex, female (F) or male (M), the generation, first (F1) or second (F2), and diet types, CD or HFD, mice were divided into eight groups (F-F1-CD, F-F1-HFD, M-F1-CD, M-F1-HFD, F-F2-CD, F-F2-HFD, M-F2-CD and M-F2-HFD). Body weight, blood glucose level and blood cholesterol levels were measured. Liver morphology was identified by hematoxylin–eosin staining and oil red O staining. Hepatosteatosis was found to be more common in all HFD groups with adaptation of the liver phenotype in F2 females but not in males, in parallel with obesity and cholesterol levels.4 Global DNA methyla- tion and histone modifications were investigated by LUMA and Western blot analysis, respectively. Interestingly, although no significant difference was found within groups, global DNA methylation level was significantly negatively correlated to steatosis percentage. Using RT-qPCR, sexual dimorphism was observed for the gene expression of 12 genes encoding enzymes of the epigenetic machinery. These marks may help us to understand the sex-specific epigenetic mechanisms of the underlying sex-specific responses to HFD and improve the early life nutritional environment in a sex-specific manner. The author(s) declare that they have no competing interests.