Review articleEpigenetic programming, early life nutrition and the risk of metabolic disease
Graphical abstract
Introduction
The role of epigenetic mechanisms, which involve heritable changes in gene expression that do not involve a change in DNA sequence, are increasingly recognised in the aetiology and progression of human disease. These mechanisms may influence gene expression during both intrauterine and early postnatal developmental periods, predisposing individuals to an obesogenic phenotype that persists throughout adulthood, leading to long term negative metabolic effects and health outcomes. These epigenetic changes could be driven by a host of environmental and lifestyle conditions, including diet and exercise, and may have profound effects on placental development and neurogenesis of hypothalamic body-weight regulation pathways. Likewise, epigenetic changes may be implicated in chronic disease such as diabetes and atherosclerosis, thus explaining the unrelenting progression and accelerated rates of their associated microvascular and macrovascular complications. Recent epidemiological and experimental animal studies demonstrate the importance of early intervention in diabetes, resulting in decreased incidence of future complications despite subsequent poor glycaemic control, suggesting a metabolic memory effect [88]. Furthermore, altered DNA methylation patterns between healthy and non-symptomatic diseased individuals have been retrospectively observed supporting the utility of possible future prognostic epigenetic analyses in healthcare [4]. Moreover, the discovery of an atherosclerotic-specific DNA methylation profile highlights the potential for future therapeutic interventions, which are highly target specific [172]. However, further investigation into the human epigenome is desperately needed to provide significant insight and better understanding of the nature of the molecular mechanisms that underlie these interactions.
Section snippets
Metabolism and memory
The alarming rise of obesity with its associated medical burdens represents a major global public health issue that underpins the importance of elucidating the molecular mechanisms of metabolic disorders [88]. The effects of chronic hyperglycaemia in both type 1 and type 2 diabetes mellitus are strongly associated with the development of macrovascular and microvascular complications including blindness, amputations, heart attacks and strokes, kidney failure and premature mortality [85], [33],
Gestational programming and the Barker hypothesis
The phenomenon of ‘metabolic memory’ is not restricted to short and medium term periods of hyperglycaemia observed in the diabetic patient, but may also have significant consequences in the developing uterine environment, leading to more persistent and long term metabolic effects. Clinical findings from as early as the 1980s showed an increased risk of several chronic health conditions, including diabetes and CVD, in low birth weight individuals, indicating that in utero environment may
High fat diet and the Barker hypothesis
However, metabolic developmental programming is not restricted to undernutrition since recent studies have also implicated maternal low protein and high fat diet (HFD) as drivers shaping future offspring health [156]. The outcomes of maternal HFD in experimental rodent and non-human primate models include poor fetal growth and adverse metabolic events with predisposition to metabolic disease including liver dysfunction, thyroid dysregulation, insulin resistance, high blood pressure and
Gestational diabetes and the Barker hypothesis
Another notable example of the Barker hypothesis is demonstrated by gestational diabetes mellitus (GDM), defined as any degree of glucose intolerance with onset or first recognition during pregnancy [6]. This condition is becoming more common because of increasing levels of obesity, and is present in 3–17% of all pregnancies, depending on the population studied and diagnostic criteria applied [12], [76]. Apart from increased perinatal morbidity and mortality, intrauterine hyperglycaemia is
Assisted reproductive technology induced epigenetic instability
While the fetal, childhood, and adult metabolic perturbations may permanently alter long-term health outcomes, the mammalian epigenome is most plastic in the early stage of embryonic development when parent-specific genome wide reprogramming occurs [110], [130]. In the human preimplantation embryo, paternal genome demethylation and global reprogramming characterizes the early events of fertilization [145]. As increasing numbers of children are being conceived by assisted reproductive technology
Hypothalamus as a central regulator of obesity
Complex polygenic human metabolic disease represented by T2DM is poorly characterized by current monogenic animal models which rely on single gene mutations such as leptin deficiency [92]. Instead, a polygenic animal model where simple dietary modification leads to the development of metabolic syndrome is found in Psammomys obesus (Israeli sand rat) and is useful for studying nutrient restriction and models of obesity [139], [159]. The metabolic changes of high calorie consumption in humans
DNA methylation in human disease
One of the best characterized epigenetic marks is DNA methylation, which is implicated to regulate gene expression and genomic stability, and is influenced by environmental and external factors [80]. Genomic methylation has regulatory roles in a broad range of biological processes including genomic imprinting, cellular differentiation and inflammation [16]. DNA methylation at promotor regions is often inversely correlated with gene expression, whereas in gene bodies and intergenic loci it may
Epigenetic pharmacology
The inherent and potential reversibility of epigenetic mechanisms provides a unique opportunity for therapeutic targeting of human disease. Mutations in genes encoding histone and DNA demethylases as well as chromatin regulating and modifying enzymes are present in the majority of human cancers, resulting in drastically altered DNA and histone methylation patterns [169], [83], [50]. Furthermore, the dysregulation of epigenetic events is emerging as a key factor driving the pathological sequelae
Clinical implications
Although T2DM has long been known to progress despite glucose-lowering treatment [154], in one study nearly 90% of obese individuals with T2DM who underwent bariatric surgery in the 1980's retained normal blood glucose levels after 10 years [124]. A randomized study comparing gastric banding with intensive medical therapy for T2DM showed that the phenomenon of diabetes remission was directly related to the degree of weight loss rather than modality of treatment and was achieved in 73% and 13%
Conclusion
Increasing clinical and experimental evidence indicates that epigenetic processes may underlie the aetiology of chronic disease such as diabetes and atherosclerosis. It is becoming progressively conceivable that aberrant alterations in DNA methylation may occur as soon as a few hours in certain metabolic milieus and persist for much longer, particularly with continued insults. This may explain the pathogenesis of diabetes and its subsequent effects on multiple organs and tissues leading to
Conflict of interest
The authors declared they do not have anything to disclose regarding conflict of interest with respect to this manuscript.
Financial support
The authors acknowledge grant and fellowship support from the National Health and Medical Research Council (NHMRC, 0526681, 1048377 and 1113188). This work was supported in part by the Royal College of Pathologists of Australasia Pathology for Medical Schools Scholarship. Supported in part by the Victorian Government's Operational Infrastructure Support Program.
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