Minireview: Epigenetic Programming of Diabetes and Obesity: Animal Models

Abstract

A growing body of evidence suggests that the intrauterine (IU) environment has a significant and lasting effect on the long-term health of the growing fetus and the development of metabolic disease in later life as put forth in the fetal origins of disease hypothesis. Metabolic diseases have been associated with alterations in the epigenome that occur without changes in the DNA sequence, such as cytosine methylation of DNA, histone posttranslational modifications, and micro-RNA. Animal models of epigenetic modifications secondary to an altered IU milieu are an invaluable tool to study the mechanisms that determine the development of metabolic diseases, such as diabetes and obesity. Rodent and nonlitter bearing animals are good models for the study of disease, because they have similar embryology, anatomy, and physiology to humans. Thus, it is feasible to monitor and modify the IU environment of animal models in order to gain insight into the molecular basis of human metabolic disease pathogenesis. In this review, the database of PubMed was searched for articles published between 1999 and 2011. Key words included epigenetic modifications, IU growth retardation, small for gestational age, animal models, metabolic disease, and obesity. The inclusion criteria used to select studies included animal models of epigenetic modifications during fetal and neonatal development associated with adult metabolic syndrome. Experimental manipulations included: changes in the nutritional status of the pregnant female (calorie-restricted, high-fat, or low-protein diets during pregnancy), as well as the father; interference with placenta function, or uterine blood flow, environmental toxin exposure during pregnancy, as well as dietary modifications during the neonatal (lactation) as well as pubertal period. This review article is focused solely on studies in animal models that demonstrate epigenetic changes that are correlated with manifestation of metabolic disease, including diabetes and/or obesity.

Offspring DNA methylation of the aryl-hydrocarbon receptor repressor gene is associated with maternal BMI, gestational age, and birth weight

“…Animals with IUGR are not only at risk for developing central obesity and Type II diabetes mellitus 37 but also have distinct DNA methylation profiles. 38 We are currently following infants into early childhood and will be able to test the hypothesis that AHRR gene DNA methylation in humans is associated with long-term metabolic health and obesity in the future.…”

Dietary factors, epigenetic modifications and obesity outcomes: Progresses and perspectives

“…There are several epidemiological and animal studies linking suboptimal early nutrition and poor growth in utero with increased risk of hypercholesterolemia, hypertension, type 2 diabetes and obesity in adulthood (Martin-Gronert and Ozanne, 2010;Seki et al, 2012). In relation to the multiple mechanisms implicated, it is clear that epigenetics plays a clue role.…”

Exposure of neonatal rats to maternal cafeteria feeding during suckling alters hepatic gene expression and DNA methylation in the insulin signalling pathway

“…There is good evidence from animal models of undernutrition during foetal life that maternal diet can alter the epigenome, particularly DNA methylation, and this may establish changes in gene expression that permanently modify tissue structure or reset the responses to dietary and age-related challenges that occur later in life (Sinclair et al 2007;Lillycrop et al 2007;Bogdarina et al 2010). Exposure to high-fat diets has been shown to alter DNA methylation and histone marks in rodents, non-human primates and primates, with the brain being particularly sensitive to dietary influences (Seki et al 2012;Carlin et al 2013;Langie et al 2013;Jacobsen et al 2012). The theory that epigenetic marks are solely vulnerable to nutritional programming in foetal life is now discounted as the epigenome responds to dietary cues at all life stages.…”