Maternal high-fat diet activates hepatic interleukin-4 in rat male offspring accompanied by increased eosinophil infiltration.

Abstract

Interleukin-4 (IL-4) is activated as an immune response during infection or tissue injury. Epigenetic programming of maternal high-fat (HF) diet has long-term effects in the offspring. In the present study, we investigated the epigenetic regulation of IL-4 in a maternal HF diet model in the liver of adult offspring. Timed-pregnant Sprague-Dawley rats were fed either control (C) or HF diet throughout gestation and lactation. Offspring were placed on a control diet after weaning, generating C/C and HF/C groups. The liver was collected at 12 wk of age, followed by histological and molecular analysis to investigate the maternal programming effects on IL-4 by HF diet. Maternal HF diet significantly induced mRNA expression and protein level of IL-4 and promoted hypomethylation of Il4 compared with the control group. Methylation-selective PCR (MSP) confirmed that maternal HF diet increased RNA polymerase II, acetylation of histone H4, and dimethylation of histone 3 lysine 4 at the +6 kb region of Il4. Moreover, the rat eosinophil marker Siglec-F was increased and colocalized with IL-4 in the liver. In conclusion, our study indicated that IL-4 was increased in liver cells in response to maternal HF diet. This coincides with DNA hypomethylation in combination with chromatin remodeling at the +6 kb region of the 3' downstream region as well as an induced immune cell infiltration, especially eosinophil infiltration, in the liver of offspring.NEW & NOTEWORTHY The present study identifies that maternal high-fat-diet-induced IL-4 upregulation is associated with DNA hypomethylation at the +6 kb region of the 3' downstream region of the gene. Furthermore, our results confirm that the induced Il4 expression in the liver of male offspring corresponds to the induced immune cell, especially eosinophil, infiltration.