Epigenetic reprogramming in metabolic disorders: nutritional factors and beyond

Abstract

Environmental factors (e.g., malnutrition and physical inactivity) contribute largely to metabolic disorders including obesity, type 2 diabetes, cardiometabolic disease and nonalcoholic fatty liver diseases. The abnormalities in metabolic activity and pathways have been increasingly associated with altered DNA methylation, histone modification and noncoding RNAs, whereas lifestyle interventions targeting diet and physical activity can reverse the epigenetic and metabolic changes. Here we review recent evidence primarily from human studies that links DNA methylation reprogramming to metabolic derangements or improvements, with a focus on cross-tissue (e.g., the liver, skeletal muscle, pancreas, adipose tissue and blood samples) epigenetic markers, mechanistic mediators of the epigenetic reprogramming, and the potential of using epigenetic traits to predict disease risk and intervention response. The challenges in epigenetic studies addressing the mechanisms of metabolic diseases and future directions are also discussed and prospected.

Keywords: DNA methylation; Epigenetic marker; Intervention; Metabolic disorders; Reprogramming.

Figure 1

The potential pathways that link the identified mediators to altered DNA methylation in metabolic disorders. Obesity due to sedentary lifestyle and energy overconsumption (e.g., HFD) is characterized by elevated fatty acids (FA), glucose, pro-inflammatory cytokines (TNFa, IL-1b), insulin resistance (or reduced insulin sensitivity), and resultant hyperglycemia (increased blood glucose). DNMT1 and DNMT3 were shown to account for DNA methylation reprogramming induced by FA, TNFa, and IL-1b in certain genes such as PPARGC1A and ADIPOC. However, it is largely unknown whether this represents a common mechanism for altered DNA methylation in other genes. In fact, TNFα induces DNMT3B in the regulation of skeletal muscle DNA methylation, whereas TNFα induces DNMT1 in adipose DNA methylation reprogramming, suggestive of a tissue-dependent selective induction of DNMTs by TNFα. Insulin and glucose alters DNA methylation of DAPK3 but not PPARGC1A in the muscle; whether and how DNMT1 or DNMT3 is involved and what accounts for the gene- or locus-specific DNA methylation reprogramming remains unknown. Genetic variant in TET2 is associated with altered PPARGC1A DNA methylation in fatty liver disease, and studies are need to examine whether TET2 SNP is related to dysregulated FA, pro-inflammatory cytokines, insulin signaling, and glucose. Longitudinal studies and MR analysis suggest that adiposity may cause DNA methylation reprogramming (e.g., in ABCG1 and HIF3A), while DNA methylation profiles (e.g., in PPARGC1A and NFATC2IP) can also predict adiposity. Maternal obesity confers epigenetic impacts on metabolic disease risk in the offspring, but maternal exercise may normalize DNA methylation (e.g., PPARGC1A hypermethylation) in the offspring. To this end, weigh loss intervention through exercise, diets or bariatric surgery have been shown to reverse the dysregulation of DNA methylation in subjects with metabolic disorders.