DNA methylation in blood from neonatal screening cards and the association with BMI and insulin sensitivity in early childhood.

BACKGROUND/OBJECTIVES: There is increasing evidence that metabolic diseases originate in early life, and epigenetic changes have been implicated as key drivers of this early life programming. This led to the hypothesis that epigenetic marks present at birth may predict an individual's future risk of obesity and type 2 diabetes. In this study, we assessed whether epigenetic marks in blood of newborn children were associated with body mass index (BMI) and insulin sensitivity later in childhood. SUBJECTS/METHODS: DNA methylation was measured in neonatal blood spot samples of 438 children using the Illumina Infinium 450 k BeadChip. Associations were assessed between DNA methylation at birth and BMI z-scores, body fat mass, fasting plasma glucose, insulin and homeostatic model assessment of insulin resistance (HOMA-IR) at age 5 years, as well as birth weight, maternal BMI and smoking status. RESULTS: No individual methylation sites at birth were associated with obesity or insulin sensitivity measures at 5 years. DNA methylation in 69 genomic regions at birth was associated with BMI z-scores at age 5 years, and in 63 regions with HOMA-IR. The methylation changes were generally small (<5%), except for a region near the non-coding RNA nc886 (VTRNA2-1) where a clear link between methylation status at birth and BMI in childhood was observed (P=0.001). Associations were also found between DNA methylation, maternal smoking and birth weight. CONCLUSIONS: We identified a number of DNA methylation regions at birth that were associated with obesity or insulin sensitivity measurements in childhood. These findings support the mounting evidence on the role of epigenetics in programming of metabolic health. Whether many of these small changes in DNA methylation are causally related to the health outcomes, and of clinical relevance, remains to be determined, but the nc886 region represents a promising obesity risk marker that warrants further investigation.

Epigenetics and DOHaD: from basics to birth and beyond.

Developmental origins of health and disease (DOHaD) is the study of how the early life environment can impact the risk of chronic diseases from childhood to adulthood and the mechanisms involved. Epigenetic modifications such as DNA methylation, histone modifications and non-coding RNAs are involved in mediating how early life environment impacts later health. This review is a summary of the Epigenetics and DOHaD workshop held at the 2016 DOHaD Society of Australia and New Zealand Conference. Our extensive knowledge of how the early life environment impacts later risk for chronic disease would not have been possible without animal models. In this review we highlight some animal model examples that demonstrate how an adverse early life exposure results in epigenetic and gene expression changes that may contribute to increased risk of chronic disease later in life. Type 2 diabetes and cardiovascular disease are chronic diseases with an increasing incidence due to the increased number of children and adults that are obese. Epigenetic changes such as DNA methylation have been shown to be associated with metabolic health measures and potentially predict future metabolic health status. Although more difficult to elucidate in humans, recent studies suggest that DNA methylation may be one of the epigenetic mechanisms that mediates the effects of early life exposures on later life risk of obesity and obesity related diseases. Finally, we discuss the role of the microbiome and how it is a new player in developmental programming and mediating early life exposures on later risk of chronic disease.

Epigenetics and human obesity.

BACKGROUND: Recent technological advances in epigenome profiling have led to an increasing number of studies investigating the role of the epigenome in obesity. There is also evidence that environmental exposures during early life can induce persistent alterations in the epigenome, which may lead to an increased risk of obesity later in life. METHOD: This paper provides a systematic review of studies investigating the association between obesity and either global, site-specific or genome-wide methylation of DNA. Studies on the impact of pre- and postnatal interventions on methylation and obesity are also reviewed. We discuss outstanding questions, and introduce EpiSCOPE, a multidisciplinary research program aimed at increasing the understanding of epigenetic changes in emergence of obesity. RESULTS: An electronic search for relevant articles, published between September 2008 and September 2013 was performed. From the 319 articles identified, 46 studies were included and reviewed. The studies provided no consistent evidence for a relationship between global methylation and obesity. The studies did identify multiple obesity-associated differentially methylated sites, mainly in blood cells. Extensive, but small, alterations in methylation at specific sites were observed in weight loss intervention studies, and several associations between methylation marks at birth and later life obesity were found. CONCLUSIONS: Overall, significant progress has been made in the field of epigenetics and obesity and the first potential epigenetic markers for obesity that could be detected at birth have been identified. Eventually this may help in predicting an individual's obesity risk at a young age and opens possibilities for introducing targeted prevention strategies. It has also become clear that several epigenetic marks are modifiable, by changing the exposure in utero, but also by lifestyle changes in adult life, which implies that there is the potential for interventions to be introduced in postnatal life to modify unfavourable epigenomic profiles.

Effect of a high monounsaturated fatty acids diet and a Mediterranean diet on serum lipids and insulin sensitivity in adults with mild abdominal obesity.

BACKGROUND AND AIMS: Diets high in monounsaturated fatty acids (MUFA) such as a Mediterranean diet may reduce the risk of cardiovascular diseases by improving insulin sensitivity and serum lipids. Besides being high in MUFA, a Mediterranean diet also contains abundant plant foods, moderate wine and low amounts of meat and dairy products, which may also play a role. We compared the effects of a high MUFA-diet with a diet high in saturated fatty acids (SFA) and the additional effect of a Mediterranean diet on insulin sensitivity and serum lipids. METHODS AND RESULTS: A randomized parallel controlled-feeding trial was performed, in 60 non-diabetics (40-65 y) with mild abdominal obesity. After a two week run-in diet high in SFA (19 energy-%), subjects were allocated to a high MUFA-diet (20 energy-%), a Mediterranean diet (MUFA 21 energy-%), or the high SFA-diet, for eight weeks. The high MUFA and the Mediterranean diet did not affect fasting insulin concentrations. The high MUFA-diet reduced total cholesterol (-0.41 mmol/L, 95% CI -0.74, -0.09) and LDL-cholesterol (-0.38 mmol/L, 95% CI -0.65, -0.11) compared with the high SFA-diet, but not triglyceride concentrations. The Mediterranean diet increased HDL-cholesterol concentrations (+0.09 mmol/L, 95% CI 0.0, 0.18) and reduced the ratio of total cholesterol/HDL-cholesterol (-0.39, 95% CI -0.62, -0.16) compared with the high MUFA-diet. CONCLUSION: Replacing a high SFA-diet with a high MUFA or a Mediterranean diet did not affect insulin sensitivity, but improved serum lipids. The Mediterranean diet was most effective, it reduced total and LDL-cholesterol, and also increased HDL-cholesterol and reduced total cholesterol/HDL-cholesterol ratio.

Synergistic QTL interactions between Rf-1 and Rf-3 increase renal damage susceptibility in double congenic rats.

The FHH (fawn-hooded hypertensive) rat is a model of hypertension-associated chronic kidney damage. Five interacting quantitative trait loci (QTLs), named Rf-1-Rf-5, determine the high renal susceptibility. The aim of the present study was to investigate a possible interaction between Rf-1 and Rf-3. Differences in renal susceptibility between ACI (August x Copenhagen Irish) controls, Rf-1A and Rf-3 single congenics, and Rf-1A+3 double congenic rats were assessed using four different treatments: two-kidney control (2K), 2K plus N(omega)-nitro-L-arginine methyl ester (L-NAME)-induced hypertension (2K+L-NAME), unilateral nephrectomy (UNX), and UNX plus L-NAME-induced hypertension (UNX+L-NAME). Proteinuria (UPV) and systolic blood pressure (SBP) were assessed after 6, 12, and 18 weeks, while the incidence of glomerulosclerosis (%FGS) was determined at the end of the experiment. In a separate experiment, renal autoregulation was assessed in 13-15-week old 2K rats of all four strains. Compared to ACI rats, small increases in renal susceptibility were found in Rf-1A and Rf-3 single congenics following 2K+L-NAME, UNX, and UNX+L-NAME treatments. However, in the Rf-1A+3 double congenics, a major increase in renal susceptibility was found with all four treatments. Both Rf-1A and Rf-1A+3 congenic rats had an impaired renal autoregulation. In contrast, the Rf-3 had a normal autoregulation, similar to that of the ACI rat. These findings indicate that Rf-1 and Rf-3 alone slightly increase the susceptibility to the development of renal damage. However, a synergistic interaction between these two QTLs markedly enhances renal susceptibility. In contrast to the Rf-1 region, the Rf-3 region does not carry genes influencing renal autoregulation.