Omega-3 fatty acids in the early origins of metabolic syndrome

Abstract

The role of omega-3 long chain polyunsaturated fatty acids (n-3 LCPUFA), in particular docosahexaenoic acid (DHA) in decreasing fat deposition, fat cell formation and improving insulin sensitivity in vitro and in adult animals had led to suggestions that increasing the supply of these fatty acids before birth could improve later metabolic health outcomes in the child. However, few studies had explored the role of DHA in programming of obesity and type 2 diabetes, and the results had been inconsistent. Furthermore, the mechanisms through which exposure to an increased supply of DHA during development impacted on later health outcomes in the infant were also unclear. While studies in animal models had highlighted the importance of epigenetics in the link between intrauterine nutrition and the subsequent risk of obesity and insulin resistance in the offspring, the role of whether epigenetics in the prenatal programming of obesity in humans was unknown. In addition, while there was evidence that placental alterations played a critical role in developmental programming, few studies had explored the effect of DHA on placental gene expression/function. The central aim of this thesis was to determine the effect of a specific nutritional intervention (maternal DHA supplementation) on (1) markers of metabolic health (BMI, percent body fat, insulin sensitivity) in the children at 5 years of age and (2) global and gene-specific DNA methylation profiles in children at birth and at 5 years of age. I also aimed to determine the effect of DHA on placental proliferation and gene expression in vitro. This thesis studied children born to women who participated in a large randomised controlled trial of n-3 LCPUFA supplementation in pregnancy, the DOMInO trial, at birth and 5 years of age. Insulin sensitivity in these children was estimated from the HOMA-IR index at 5 years of age. DNA was obtained from blood samples of the DOMInO children collected at birth (n=1012) and at 5 years of age (n=715) for the assessment of global and genome-wide methylation. A human placenta first trimester cell line (HTR8/SVneo) was treated with a DHA-rich emulsion in order to determine effects of DHA on placental proliferation and gene expression. Maternal DHA supplementation was associated with a reduced insulin sensitivity (increased HOMA-IR index) and increased fasting insulin concentrations in the children at 5 years of age, particularly in males. There were also small but significant differences in methylation of 44 genomic regions at birth and 30 at 5 years of age, and more differentially methylated regions (DMRs) in males compared to females at both time points. DHA treatment increased proliferation rate of HTR8/SVneo cells, and 96 genes were differentially expressed between DHA and no treatment groups. Overall, the results of this thesis provide evidence that maternal DHA supplementation may reduce insulin sensitivity in the children, although whether this translates into differences in the incidence of type 2 diabetes later in life remains to be determined. I also demonstrated that DHA has small but significant effects on DNA methylation of specific genomic regions, and significantly altered proliferation and gene expression of a placental cell line in vitro, which suggests that both epigenetic and placental modifications may be involved in mediating the effects of increased DHA exposure before birth on health outcomes in the child.