Maternal high‐fat diet increases rat hepatic interleukin‐4 (IL‐4) mRNA expression and is associated with decreased DNA methylation in male offspring

DNA methylation and histone modification are two influential contributors to transcriptional regulation in response to environmental stress, including maternal overnutrition. We observed that a maternal high‐fat (HF) diet in rats caused an inflammatory response in livers of male offspring rats, as measured by the induction of Interleukin‐4 (IL‐4), an anti‐inflammatory cytokine, and this was accompanied by a decreased number of liver inflammatory foci in HF offspring. Methylated DNA immunoprecipitation (MeDIP) results indicated that livers of HF offspring had hypomethylation of specific regions on the IL‐4 gene compared to Control. Methylation‐specific PCR (MSP) confirmed the hypomethylation in the downstream +6 kb region in the HF group, which was significantly correlated with the increased expression of the IL‐4 gene. Moreover, chromatin immunoprecipitation showed an upregulation of acetylation of histone H4 at the same region. The mRNA expression of transcription factor, CEBP/beta was, significantly increased in the HF group compared to Control, and transcriptional factor binding analysis of the selected region within IL‐4 showed strong CEBP/beta binding. In conclusion, maternal HF diet induced hepatic IL‐4 gene expression in male offspring, potentially by decreasing DNA methylation of specific regions as well as through chromatin remodeling.