Epigenetic origins of metabolic disease: The impact of the maternal condition to the offspring epigenome and later health consequences

Rhianna C. Laker; Mary E. Wlodek; Jessica J. Connelly; Zhen Yan

doi:10.1016/j.fshw.2013.03.002

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Research Article | Open Access

Epigenetic origins of metabolic disease: The impact of the maternal condition to the offspring epigenome and later health consequences

Rhianna C. Laker^{^a^,^b}(), Mary E. Wlodek^{^c}, Jessica J. Connelly^{^a^,^b}, Zhen Yan^{^a^,^b}()

Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA

Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA

Department of Physiology, The University of Melbourne, Royal Parade, Parkville, VIC 3010, Australia

Peer review under responsibility of Beijing Academy of Food Sciences.

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Abstract

It has long been established that an adverse maternal condition impacts on the developing fetus and predisposes the offspring to develop metabolic and cardiovascular disease in later life. However, the underlying mechanisms that are initiated during development and contribute to the disease predisposition are understudied. Recently, epigenetic reprogramming in early life has emerged as a promising candidate that could cause altered DNA transcription and gene expression into adulthood and contribute to disease susceptibility. This review will focus on the impact of maternal high fat diet to the offspring in early life and the adult health consequences. We will then discuss the current literature supporting a role for epigenetic modification, such as DNA methylation and histone modifications, as a key mechanism underlying developmental programming.

Keywords

Epigenetics Developmental programming Metabolic disease Maternal high-fat diet DNA methylation Histone modifications

References

[1]

D.J. Barker, C. Osmond, J. Golding, et al., Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease, British Medical Journal 298 (1989) 564–567.

Citation	Experimental model	Offspring tissue and age	Gene and epigenetic modification	Gene expression and potenial health outcomes
Burdge et al. [99]	9% protein diet throughout pregnancy in Wistar rats.	F1 and F2 male offspring liver at 80 d of age.	Glucocorticoid receptor and PPARα promoter regions hypomethylated.	Trend (P < 0.1) for higher mRNA of GR and PPARα and downstream targets acyl-CoA oxidase and phosphoenolpyruvate carboxykinase (PEPCK; P < 0.5). Predicts increased gluconeogenesis, metabolic dysfunction and transgenerational transmission.
Burdge et al. [100]	25% increase in dietary energy at conception through to F3 generation in Wistar rats.	F1, F2 and F3 female offspring liver at 70 d of age.	PEPCK CpG site specific hyper- and hypomethylation in experimental groups.	PEPCK mRNA was higher in experimental group and inversely related to methylation level of CpGs in promoter
Gemma et al. [101]	Small and large for gestational age humans.	Umbilical cord DNA at birth.	Positive correlation between maternal BMI and PGC-1α promoter methylation.	No association between offspring characteristics and methylation status.
Brøns et al. [70]	Healthy young men of low birth weight (LBW) with or without 5 d high fat diet.	Young adult males skeletal muscle.	PGC-1α hypermethylated in LBW with control diet only.	LBW men showed insulin resistance and decreased PGC-1α and oxidative phosphorylation gene expression following 5 days high fat diet. PGC-1α methylation did not correlate with mRNA expression.
Hoile et al. [123]	Female Wistar rats fed low (3%) or high (21%) diet content of butter or fish oil (FO).	Male and female offspring liver at 77 d of age.	Hypermethylation of Fads2 with high dietary content of butter or FO with FO higher than butter.	Fads2 mRNA correlated negatively with Fads2 promoter methylation levels. Predict contributes to regulation of PUFA synthesis in adulthood.
Lillycrop et al. [81]	50% Protein restricted diet thoughout pregnancy in Wistar rats.	Offspring liver at 34 d of age.	Glucocorticoid receptor promoter hypomethylated. Histone H3 and H4 acetylation increased.	Increased GR gene expression. Predict contributes to metabolic phenotype.
Raychaudhuri et al. [108]	50% food restriction from mid gestation to weaning in Sprague Dawley rats.	Female offspring skeletal muscle at 2 and 450 d of age.	GLUT4 histone modifications causing co-repressor formation. No change in DNA methylation.	Reduced GLUT4 protein and gene expression in adulthood of female offspring.
Zheng et al. [109]	50% food restriction throughout gestation in Sprague Dawley rats.	Female offspring skeletal muscle at 38 d of age.	C/EBPβ promoter region hyperacetylation of histones H3 and H4.	Increased gene and protein expression of transcription factor C/EBPβ, involved in energy metabolism.
Park et al. [78]	Intrauterine growth restriction in Sprague Dawley rats at day 18 of pregnancy.	Male offspring pancreatic islets at fetal (21 d gestation), 2 weeks and 6 months of age.	Pdx1 histone H3 and H4 hypermethylation and hypoacetylation with age. Extensive DNA methylation at CpG sites in the proximal promoter.	Reduced Pdx1 gene expression in islets likely contributing to impaired β-cell development and function and development of diabetes in adulthood.