Understanding Dietary Intervention-Mediated Epigenetic Modifications in Metabolic Diseases

Abstract

The global prevalence of metabolic disorders, such as obesity, diabetes and fatty liver disease, is dramatically increasing. Both genetic and environmental factors are well-known contributors to the development of these diseases and therefore, the study of epigenetics can provide additional mechanistic insight. Dietary interventions, including caloric restriction, intermittent fasting or time-restricted feeding, have shown promising improvements in patients' overall metabolic profiles (i.e., reduced body weight, improved glucose homeostasis), and an increasing number of studies have associated these beneficial effects with epigenetic alterations. In this article, we review epigenetic changes involved in both metabolic diseases and dietary interventions in primary metabolic tissues (i.e., adipose, liver, and pancreas) in hopes of elucidating potential biomarkers and therapeutic targets for disease prevention and treatment.

Keywords: DNA methylation; caloric restriction; dietary interventions; histone modification; intermittent fasting; non-alcoholic fatty liver disease; obesity; type 2 diabetes.

FIGURE 1

Classification of dietary interventions. Dietary interventions can be broadly categorized according to varied meal timing (fasting interventions) and meal content (nutritional interventions). Fasting interventions can be further subdivided into periodic fasting (PF) on a monthly basis and intermittent fasting (IF) on a weekly (5:2, 2:1, 1:1 IF) or daily (TRF) basis. ADF, alternate-day fasting; EODF, every-other-day fasting.

FIGURE 2

Description of the epigenetic change and its transcriptional modulators and markers in DNA methylation, histone methylation, and histone acetylation. Simplified diagrams show the forward and reverse reactions to each epigenetic mechanism.

FIGURE 3

Epigenetic changes of adipose tissue in metabolic disease and dietary intervention. Adipose tissue in metabolic disease (i.e., obesity) predominantly consists of white adipocytes and presents with increased lipid content, inflammation and insulin resistance. Adipose tissue in dietary intervention is interspersed with both white and beige adipocytes and presents with reduced lipid content and inflammation as well as increased insulin sensitivity and thermogenesis. These physiological differences in adipose can be explained by epigenetic changes involving DNA methylation, histone methylation and histone and non-histone acetylation.

FIGURE 4

Epigenetic changes of liver in metabolic disease and dietary intervention. Liver in metabolic disease (i.e., NAFLD/NASH) presents with increased lipid content, inflammation, insulin resistance and fibrosis. The liver in dietary intervention has reduced lipid content and improved insulin sensitivity. These physiological differences of the liver can be explained by epigenetic changes involving DNA methylation, histone methylation and histone and non-histone acetylation.

FIGURE 5

Epigenetic changes of pancreas in metabolic disease and dietary intervention. In metabolic disease (i.e., T2D), the initial proliferation of pancreatic β-cells increase insulin secretion, but eventual β-cell failure leads to hypoinsulinemia and hyperglycemia. In dietary intervention, pancreatic β-cells are preserved through reduced inflammation and oxidative stress and present with increased function (i.e., GSIS) and regeneration. These physiological differences in the pancreas can be explained by epigenetic changes involving DNA methylation, histone methylation and histone and non-histone acetylation.

FIGURE 6

Epigenetic modulation by dietary intervention-induced ketogenesis and gut microbial metabolites. Dietary interventions stimulate ketone body production such as β-hydroxybutyrate, which can modulate gene expression through histone modification (bhb) and inhibition of histone deacetylases (HDACs). Dietary interventions also modulate the gut microbiota, through the release of short-chain fatty acids (SCFA) acetate and butyrate which inhibit HDACs, and folate which provides methyl donors for DNA methyltransferase (DNMT) activity.