Intrauterine programming of obesity and type 2 diabetes

Abstract

The type 2 diabetes epidemic and one of its predisposing factors, obesity, are major influences on global health and economic burden. It is accepted that genetics and the current environment contribute to this epidemic; however, in the last two decades, both human and animal studies have consolidated considerable evidence supporting the 'developmental programming' of these conditions, specifically by the intrauterine environment. Here, we review the various in utero exposures that are linked to offspring obesity and diabetes in later life, including epidemiological insights gained from natural historical events, such as the Dutch Hunger Winter, the Chinese famine and the more recent Quebec Ice Storm. We also describe the effects of gestational exposure to endocrine disruptors, maternal infection and smoking to the fetus in relation to metabolic programming. Causal evidence from animal studies, motivated by human observations, is also discussed, as well as some of the proposed underlying molecular mechanisms for developmental programming of obesity and type 2 diabetes, including epigenetics (e.g. DNA methylation and histone modifications) and microRNA interactions. Finally, we examine the effects of non-pharmacological interventions, such as improving maternal dietary habits and/or increasing physical activity, on the offspring epigenome and metabolic outcomes.

Keywords: Developmental programming; Epigenetic variation; Intrauterine programming; Life course development; Maternal exposures; MicroRNAs; Obesity; Paternal exposures; Review; Type 2 diabetes.

Fig. 1

DNA methylation dynamics during human development. Male (blue line) and female (red line) embryos follow different DNA methylation patterns, from the birth of the parent through to zygote production (conception) and blastocyst implantation. Imprinted genes (dashed black line) do not undergo demethylation post-fertilisation and, hence, reflect parental-allele-specific methylation. PGC, primordial germ cells. Adapted from [125], with permission from Elsevier. This figure is available as part of a downloadable slideset

Fig. 2

A complex interplay between in utero environment, genetics, epigenetic marks and phenotype. (a) The fetus is exposed to various maternal exposures in utero, some of which are potentially detrimental, leading to activation of transcriptional regulators (via receptors) and of downstream genes. (b) Genetic differences also influence transcription factor binding and regulation of downstream gene expression (mRNA shown as ‘——AAA’). Transcription factor binding can lead to recruitment of epigenetic modifiers, reprogramming epigenetic marks at gene-regulatory elements. Variation in these epigenetic marks (e.g. DNA methylation, shown as grey shading of circles) often correlate with specific phenotypes at birth. (c) During postnatal life, individuals are continually exposed to environmental exposures that further modulate gene expression and phenotype. Differential epigenetic reprogramming in utero can affect the transcriptional response of cells to these new exposures, leading to different adult phenotypes. In the illustrated example, epigenetic remodelling of metabolism/nutrition genes during in utero development can lead to adult obesity. (d) A model showing how an initial exposure can alter the phenotype, leading to susceptibility to disease in response to a second environmental exposure. Solid lines indicate the order of events leading to phenotype B, while the dashed lines indicate the potential, but unproven, role for epigenetic variation in contributing to the phenotypes. The illustrations in (a–c) are based on decades of research showing that epigenetic marks can mediate the effect of exogenous signals on gene expression and phenotype. Nevertheless, showing causality is often difficult in humans and, in some cases, epigenetic differences may only correlate with exposure and outcome, but not necessarily contribute to phenotype. Longitudinal studies that make use of samples collected before disease onset are essential to tease out these causal/passenger questions. TF, transcription factor. This figure is available as part of a downloadable slideset