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A Maternal High-Fat Diet Induces DNA Methylation Changes That Contribute to Glucose Intolerance in Offspring

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A Maternal High-Fat Diet Induces DNA Methylation Changes That Contribute to Glucose Intolerance in Offspring

Qian Zhang et al. Front Endocrinol (Lausanne).

Abstract

Scope: Overnutrition in utero is a critical contributor to the susceptibility of diabetes by programming, although the exact mechanism is not clear. In this paper, we aimed to study the long-term effect of a maternal high-fat (HF) diet on offspring through epigenetic modifications. Procedures: Five-week-old female C57BL6/J mice were fed a HF diet or control diet for 4 weeks before mating and throughout gestation and lactation. At postnatal week 3, pups continued to consume a HF or switched to a control diet for 5 weeks, resulting in four groups of offspring differing by their maternal and postweaning diets. Results: The maternal HF diet combined with the offspring HF diet caused hyperglycemia and insulin resistance in male pups. Even after changing to the control diet, male pups exposed to the maternal HF diet still exhibited hyperglycemia and glucose intolerance. The livers of pups exposed to a maternal HF diet had a hypermethylated insulin receptor substrate 2 (Irs2) gene and a hypomethylated mitogen-activated protein kinase kinase 4 (Map2k4) gene. Correspondingly, the expression of the Irs2 gene decreased and that of Map2k4 increased in pups exposed to a maternal HF diet. Conclusion: Maternal overnutrition programs long-term epigenetic modifications, namely, Irs2 and Map2k4 gene methylation in the offspring liver, which in turn predisposes the offspring to diabetes later in life.

Keywords: DNA methylation; MAPK; epigenetics; insulin receptor substrate; maternal high fat diet.

Figures

Figure 1
Figure 1
Timeline of animal experiment. CON-CON: control diet mother-post-weaning control diet; CON-HF, control diet mother-post-weaning high-fat diet; HF-CON, high-fat diet mother-post-weaning control diet; HF-HF, high-fat diet mother-post-weaning high-fat diet.
Figure 2
Figure 2
The effect of maternal high-fat diet on metabolic variables of male mice offspring. (A) body weight at weaning; (B) fasting blood glucose; (C) oral glucose tolerance test (OGTT); (D) area under curve (AUC) in OGTT; (E) plasma insulin; (F) HOMA-IR. **P < 0.01 offspring diet effect; #P < 0.05; ##P < 0.01 maternal diet effect. Values are mean ± SEM (n = 10). CON-CON: control diet mother-post-weaning control diet; CON-HF, control diet mother-post-weaning high-fat diet; HF-CON, high-fat diet mother-post-weaning control diet; HF-HF, high-fat diet mother-post-weaning high-fat diet.
Figure 3
Figure 3
Differentially methylated promoters between HF-CON group and CON-CON group. (A) CpG density of differentially methylated promoters. (B) Chromosomal distribution of differentially methylated promoters. Red: differentially hypermethylated promoters; Green, differentially hypomethylated promoters. Classification of all promoters with high (HCP), intermediated (ICP), and low (LCP) CpG content.
Figure 4
Figure 4
Top 5 significant GO term of differentially methylated genes in each classification. Red, molecular function (MF); Green, cellular component (CC); Blue, biological process (BP).
Figure 5
Figure 5
Top 25 significant KEGG pathways of differentially methylated genes.
Figure 6
Figure 6
Validation of methylation array using bisulphite sequencing. (A) Schematic diagram of bisulphite sequencing results on 30 CpG sites on Irs2 and 7 CpG on Map2k4. Open circles indicate unmethylated CpGs, and closed circles indicate methylated CpGs. Methylation ratio of Irs2 (B) and Map2k4 (C) in different groups. Relative gene expression of Irs2 (D) and Map2k4 (E) in different groups. **P < 0.01 offspring diet effect; ##P < 0.01 maternal diet effect. Values are mean ± SEM (n = 10). CON-CON, control diet mother-postweaning control diet; CON-HF, control diet mother-postweaning high-fat diet; HF-CON, high-fat diet mother-postweaning control diet; HF-HF, high-fat diet mother-postweaning high-fat diet.
Figure 7
Figure 7
Epigenetic mechanism of high-fat diet in utero and adult on offspring. In utero expose to high-fat diet modify Irs2 and Map2k4 gene methylation and gene expression in offspring, led glucose intolerance, and insulin resistance.

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References

    1. Locke AE, Kahali B, Berndt SI, Justice AE, Pers TH, Day FR, et al. . Genetic studies of body mass index yield new insights for obesity biology. Nature. (2015) 518:197–206. 10.1038/nature14177 - DOI - PMC - PubMed
    1. Raciti GA, Longo M, Parrillo L, Ciccarelli M, Mirra P, Ungaro P, et al. . Understanding type 2 diabetes: from genetics to epigenetics. Acta Diabetol. (2015) 52:821–7. 10.1007/s00592-015-0741-0 - DOI - PubMed
    1. Cheng Z, Zheng L, Almeida FA. Epigenetic reprogramming in metabolic disorders: nutritional factors and beyond. J Nutr Biochem. (2018) 54:1–10. 10.1016/j.jnutbio.2017.10.004 - DOI - PMC - PubMed
    1. van Dijk SJ, Tellam RL, Morrison JL, Muhlhausler BS, Molloy PL. Recent developments on the role of epigenetics in obesity and metabolic disease. Clin Epigenetics. (2015) 7:66. 10.1186/s13148-015-0101-5 - DOI - PMC - PubMed
    1. Barker DJ. Maternal nutrition, fetal nutrition, and disease in later life. Nutrition. (1997) 13:807–13. 10.1016/S0899-9007(97)00193-7 - DOI - PubMed
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