AIMS: This study aimed to analyze differences in sensitivity to hepatic lipid metabolism at different ages, through DNA methylation, using an experimental rat model of high-fructose corn syrup (HFCS) intake. MAIN METHODS: The experimental was divided into three periods: childhood and adolescence (postnatal day (PD) 21-60), young adulthood (PD61-100), and adulthood (PD101-140). Rats in the different age groups were assigned to receive either water (C: control group) or 20% HFCS solution (H: HFCS-fed group). We measured hepatic mRNA levels of peroxisome proliferator-activated receptor alpha (Ppara), carnitine palmitoyltransferase 1A (Cpt1a), fatty acid synthase (Fasn), and peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (Pgc1a) using real-time PCR. Additionally, we examined the DNA methylation levels of Ppara, Cpt1a, Fasn, and Pgc1a using pyrosequencing. KEY FINDINGS: Gene expressions of Cpt1a and Ppara in childhood and adolescence were significantly lower in the H group than in the C group. Conversely, Fasn and Pgc1a expressions were significantly higher in the H group than in the C group. Additionally, there was hypermethylation of Cpt1a and Ppara and hypomethylation of Fasn and Pgc1a in the H groups of childhood and adolescence. However, only one gene expression and methylation change was observed in young adulthood and adulthood groups. We found that HFCS intake in rats had stronger lipid metabolic effects in childhood and adolescence than in other generations, and that its mechanism involved epigenetic regulation. SIGNIFICANCE: We anticipate that these research findings will be a breakthrough for elucidating the varying effects of growth stage in the future.