Epigenetics in Human Obesity and Type 2 Diabetes

Abstract

Epigenetic mechanisms control gene activity and the development of an organism. The epigenome includes DNA methylation, histone modifications, and RNA-mediated processes, and disruption of this balance may cause several pathologies and contribute to obesity and type 2 diabetes (T2D). This Review summarizes epigenetic signatures obtained from human tissues of relevance for metabolism-i.e., adipose tissue, skeletal muscle, pancreatic islets, liver, and blood-in relation to obesity and T2D. Although this research field is still young, these comprehensive data support not only a role for epigenetics in disease development, but also epigenetic alterations as a response to disease. Genetic predisposition, as well as aging, contribute to epigenetic variability, and several environmental factors, including exercise and diet, further interact with the human epigenome. The reversible nature of epigenetic modifications holds promise for future therapeutic strategies in obesity and T2D.

Keywords: DNA methylation; aging; diet; epigenetics; exercise; histone modifications; obesity; physical activity; prediction; type 2 diabetes.

Figure 1

Obesity Is Associated with Differential DNA Methylation and Increased Epigenetic Variability The figure illustrates tissues and genes with observed alterations in DNA methylation due to obesity and related phenotypes (BMI, waist circumference), some of which are also associated with gene expression. Alterations in DNA methylation are more often a result of obesity than the opposite. GBP, gastric by-pass.

Figure 2

Type 2 Diabetes Is Associated with Differential DNA Methylation in Human Tissues The figure illustrates tissues and genes with observed alterations in DNA methylation in subjects with type 2 diabetes compared with non-diabetic controls. Some of these genes also show differential gene expression and have been shown to functionally affect diabetes-related phenotypes such as insulin secretion. DNA methylation of the genes indicated in blood has been associated with future risk of type 2 diabetes in prospective cohorts.

Figure 3

Different Diets and Nutrients Are Associated with Differential DNA Methylation in Human Tissues Including Adipose Tissue, Skeletal Muscle, and Pancreatic Islets The figure illustrates tissues and genes with observed alterations in DNA methylation in response to human diet interventions (overfeeding either polyunsaturated fatty acids [PUFAs] or saturated fatty acids [SFAs] for 7 weeks; 5-day high-fat overfeeding; or 36-h fasting), as well as human pancreatic islets cultured in either 1 M palmitate or 16.7 mM glucose versus control for 48 h. Some of these genes also show differential expression, and the diets and nutrients further affect metabolism and clinical phenotypes.

Figure 4

Illustration of How the Environment Affects Three Generations at a Time At time of conception, the environment influences the parents, including the spermatozoa methylome and the in utero environment and eventually has the possibility to affect both the fetus and its reproductive cells. Evidence for transgenerational epigenetic inheritance in humans, which requires four generations or more, is still sparse.

Figure 5

Interactions between the Environment, the Epigenome, and Obesity and Type 2 Diabetes Several genetic and non-genetic factors contribute to the development of obesity and type 2 diabetes. The same factors, e.g., exercise, genetic predisposition, diet, intrauterine environment, and aging, are also known to influence the human epigenome. Furthermore, the epigenome may both contribute to disease and interact with and respond to various physiological conditions of heterogeneous diseases.