Early-life exposure to high-fat diet may predispose rats to gender-specific hepatic fat accumulation by programming Pepck expression

Phosphoenolpyruvate carboxykinase (PEPCK) produces phosphoenolpyruvate during glyceroneogenesis. We previously demonstrated that a high-fat diet during pregnancy induced Pepck mRNA expression in neonatal rat pups, which is characterized by histone modifications in specific regions of the gene (Strakovsky RS, Zhang X, Zhou D, Pan YX. Gestational high fat diet programs hepatic phosphoenolpyruvate carboxykinase gene expression and histone modification in neonatal offspring rats. The Journal of Physiology 2011;589:2707-17). In the present study, we investigated whether these alterations persistent in adult offspring. Dams were fed either control or high-fat diet throughout gestation and lactation. Offspring were placed on control diet after weaning, generating C/C and HF/C groups. Liver was collected at 12 weeks of age. Hepatic nicotinamide adenine dinucleotide (reduced) (NADH) level was increased in both genders, but fat accumulation occurred only in liver of female offspring in HF/C group. This was accompanied by a significant increase of Pepck and fatty acid synthase (Fasn) mRNA expression in only female liver. The induction of Pepck gene expression in females was associated with increased dimethylated histone H3 lysine 4 level in multiple regions of the gene. Meanwhile, acetylated histone H3 and trimethylated histone H3 lysine 4 were induced at a specific coding region in HF/C, accompanied by decreased trimethylated histone H3 lysine 9 level at the promoter of female offspring. In conclusion, maternal high-fat diet programs Pepck expression through histone modifications in adult female offspring. Persistent Pepck induction in females may contribute to increased triglyceride synthesis, together with induced Fasn expression and NADH levels, which may lead to increased fat deposition in a gender-specific manner.