Maternal and Post-weaning High-Fat Diets Produce Distinct DNA Methylation Patterns in Hepatic Metabolic Pathways within Specific Genomic Contexts.

Moody Moody,Wang Wang,Jung Jung,Pan Pan,Chen Chen

doi:10.3390/ijms20133229

Abstract

Calorie-dense high-fat diets (HF) are associated with detrimental health outcomes, including obesity, cardiovascular disease, and diabetes. Both pre- and post-natal HF diets have been hypothesized to negatively impact long-term metabolic health via epigenetic mechanisms. To understand how the timing of HF diet intake impacts DNA methylation and metabolism, male Sprague–Dawley rats were exposed to either maternal HF (MHF) or post-weaning HF diet (PHF). At post-natal week 12, PHF rats had similar body weights but greater hepatic lipid accumulation compared to the MHF rats. Genome-wide DNA methylation was evaluated, and analysis revealed 1744 differentially methylation regions (DMRs) between the groups with the majority of the DMR located outside of gene-coding regions. Within differentially methylated genes (DMGs), intragenic DNA methylation closer to the transcription start site was associated with lower gene expression, whereas DNA methylation further downstream was positively correlated with gene expression. The insulin and phosphatidylinositol (PI) signaling pathways were enriched with 25 DMRs that were associated with 20 DMGs, including PI3 kinase (Pi3k), pyruvate kinase (Pklr), and phosphodiesterase 3 (Pde3). Together, these results suggest that the timing of HF diet intake determines DNA methylation and gene expression patterns in hepatic metabolic pathways that target specific genomic contexts.

Highlights

High-fat (HF) diet intake during both the pre-natal and post-natal periods has adverse effects on metabolic health, including higher body weight, reduced insulin sensitivity, systemic inflammation, and dysregulation of hypothalamic satiety cues [1,2]
To assess the potential differential effects of HF exposure at different developmental stages, male rats were exposed to HF diet either during gestation and lactation or after weaning (Figure 1a)
Food efficiency was lower in post-weaning HF diet (PHF) compared to both control-fed animals (CON) and maternal HF (MHF) (Figure S1)

Summary

Introduction

High-fat (HF) diet intake during both the pre-natal and post-natal periods has adverse effects on metabolic health, including higher body weight, reduced insulin sensitivity, systemic inflammation, and dysregulation of hypothalamic satiety cues [1,2]. De novo DNA methylation is established in the perinatal period while environmental factors during the post-natal period can interfere with the maintenance of such methylation patterns [9,10,11]. Given these differences between perinatal and post-natal epigenetic processes, it is important to understand how each exposure window impacts metabolism and gives rise to a unique methylome. MeDIP-seq offers a more cost-effective option, and integration of Methylation-sensitive Restriction Enzyme digestion followed by sequencing (MRE-seq) compensates for the limitations of MeDIP-seq by having single-base resolution and extensive coverage at regions with low CpG densities. MRE-seq is confined by the sequence-specificity of existing restriction enzymes, but integrating MRE-seq with MeDIP-seq can improve coverage and resolution of genome-wide methylation and proves to be a viable way of assessing methylation in large samples [15]

Methods

Results

Discussion

Conclusion