Interestingly, a study comparing transcriptomic changes by IF (i.e., ADF) and over-expression in mice concluded that despite functional similarities such as improved insulin sensitivity, gain-of-function does not mimic nor boost the metabolic effects of IF (Boutant et al., 2016). diabetesTGTriglycerideTRFTime-restricted feedingVLDLVery-low-density lipoproteinWATWhite adipose tissue Open in a separate window Overnutrition, especially of highly processed foods (Hall et al., 2019), accompanied by erratic diurnal eating patterns, constitute the major environmental contributors to the epidemic state of metabolic diseases today. As such, switching to a regular, nutritious diet can promote processes of maturation and restoration, and protect against the development of chronic metabolic disorders (Di Francesco et al., 2018). Since the applicability of pharmacological interventions in the treatment of metabolic disorders is limited by issues regarding off-target effects, patient compliance and tolerability, as well as lack of sufficiency in disease management (Longo and Panda, 2016); dietary interventions have become a promising, low-risk alternative or supplementary form of therapy. By adjusting meal timing and/or content, dietary interventions have shown continued success in reducing risk factors, inducing beneficial pleiotropic effects and ameliorating disease states (Longo and Panda, 2016). These dietary interventions involve limiting food intake of entire (i.e., fasting interventions) or selected nutrient compositions (i.e., nutritional interventions), without disturbing energy balance or inducing malnutrition. Specifically, fasting interventions can be categorized into intermittent fasting (IF) and periodic fasting (PF), where food intake is limited either on a daily/weekly basis or on a monthly basis, respectively (Anton et al., 2018; Yong-Quan Ng et al., 2019; Figure 1). IF cycles typically last 24 h and are separated by one or more days, whereas PF cycles last two or more days and are separated by at least a week (Longo and Mattson, 2014). Different forms of IF vary in their timing of meals and include the daily time-restricted feeding (TRF), and the weekly 5:2, 2:1, or 1:1 IF regimens. Moreover, nutritional interventions vary in their meal content and include caloric restriction (CR), dietary restriction (DR), ketogenic diet (KD), and fasting-mimicking diet (FMD). Open in a separate window 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. Dietary interventions, such as CR and IF, extend lifespan and healthspan in various animal models, including yeast (Lin et al., 2000, 2002; Wu et al., 2013), worms (Wei et al., 2008; Honjoh et al., 2009; Uno et al., 2013), fruit flies (Grandison et al., 2009; Catterson et al., 2018; Villanueva et al., 2019), rodents (Goodrick et al., 1982; Hatori et al., 2012; Chaix et al., 2014; Rusli et al., 2017; Mitchell et al., 2019), and monkeys (Bodkin et al., 2003; Colman et al., 2009; Mattison et al., 2017). Studies done in humans also demonstrate beneficial effects of dietary intervention, specifically regarding overall metabolic improvements in body weight and fat mass (Heilbronn et al., 2005; Johnson et WF 11899A al., 2007; Varady et al., 2009; Harvie et al., 2011; Klempel et al., 2013; Varady et al., 2013; WF 11899A Redman et al., 2018; Anton et al., 2019; Ravussin et al., 2019; Stekovic et al., 2019; Wilkinson et al., 2020), circulating triglyceride (TG) and cholesterol levels (Johnson et al., 2007; Varady et al., 2009; Harvie et al., 2011; Klempel et al., 2013; Varady et al., 2013; Stekovic et al., 2019; Wilkinson et al., 2020), insulin sensitivity and glucose homeostasis (Halberg et al., 2005; Harvie et al., 2011; Sutton et al., 2018; Jamshed et al., 2019), and oxidative stress and inflammation (Johnson et al., 2007; Meydani et al., 2011; Redman et al., 2018; Sutton et al., 2018; Stekovic et al., 2019). Notably, the metabolic benefits of dietary interventions are not completely dependent on WF 11899A total caloric intake. For SVIL instance, the 2 2:1 IF regimen in mice provides comparable metabolic outcomes against obesity and associated metabolic dysfunctions, despite no difference in caloric intake (i.e., isocaloric) in comparison to (i.e., normal feeding) (Kim K.H. et al., 2017; Kim R.Y. et al., 2019; Kim Y.H. et al., 2019). These benefits conferred by dietary interventions involve cellular adaptations within various metabolic tissues, which are mediated by epigenetic modifications. Due to the plasticity of epigenetic factors, environmental changes, such as dietary interventions, which WF 11899A alter food intake and composition, have a significant impact on the epigenome. In this article, we will first review epigenetic changes in metabolic disease with a particular emphasis on adipose tissues, liver, and pancreas. We will primarily focus on DNA methylation and post-translational histone modifications (Figure 2), with the exception of non-coding RNAs reviewed elsewhere (Deiuliis, 2016; Green et.