**Abstract**

Dietary intervention is one of the most important approaches for the treatment of metabolic diseases such as diabetes mellitus. Fasting and caloric restriction have profound effects on systemic metabolism. The energy source-producing organs, such as the liver, and peripheral tissues rewire their metabolism to meet the energy demands of the whole body. Glycogenolysis, fatty acid oxidation, and ketone body production are characteristic metabolic changes that occur during fasting and caloric restriction. These metabolic changes are regulated by various signaling cascades including PPARα and FGF21. Moderate fasting and caloric restriction have also been implicated in extending the lifespan in a variety of organisms from nematodes to vertebrates. Intensive research has unveiled several regulatory mechanisms of longevity including metabolic regulators such as mTOR and sirtuins. The epigenome has been attracting attention as a mechanism underlying metabolic diseases and longevity. The epigenome is the concept that involves covalent modifications of DNA, histones, and RNA, which are mediated by the action of epigenetic enzymes. The activity of these enzymes is regulated by energy states, i.e. metabolites including ketone bodies and intermediates of various metabolic pathways. Thus, energy states are recorded in cells as an epigenetic memory, which may cause future onset of metabolic diseases and affect lifespan.

**Keywords:** Fasting, caloric restriction, diabetes mellitus, obesity, glycolysis, the TCA cycle, fatty acid oxidation, ketone body, PPARα, FGF21, insulin, glucagon, longevity, metabolites, and epigenome

## **1. Introduction**

For the treatment of diabetes mellitus, dietary intervention is one of the most important basic approaches along with exercise therapy. Since dietary guidance for diabetes is often based on limiting caloric intake, it is important to understand the effects of fasting and caloric restriction on systemic metabolism. Furthermore, the effects of the Mediterranean diet and the pros and cons of carbohydrate-restricted diets have recently attracted attention, and it is now widely recognized that the proportion of certain nutrients in the diet and the order in which they are eaten can affect nutrient absorption and systemic metabolism. In countries where excessive food supply has caused obesity and the associated diseases, many people have adopted fasting and caloric restriction for weight control. Academic studies have shown that moderate caloric restriction has a positive effect on those diseases and

contributes to longevity through anti-aging effects and prevention of age-related diseases. However, given that excessive fasting or caloric restriction can lead to malnutrition, it is important to accurately understand the effects on systemic metabolism.

During fasting, carbohydrates, fats, and proteins are utilized as energy sources in many organs. However, since the brain cannot directly utilize fatty acids derived from lipolysis, the insight into energy metabolism in the brain is essential to understand the systemic metabolism during fasting. In the early stages of fasting, glucose is provided to the brain by glycogenolysis (**Figure 1A**). In the case of prolonged fasting, gluconeogenesis is activated in the liver to produce glucose from pyruvate and lactate, as well as from glycerol produced by lipolysis and from amino acids produced by proteolysis (**Figure 1B**) [1]. When fasting is further prolonged, glucose is supplied by renal gluconeogenesis, and ketone bodies produced by fatty acid oxidation (or β-oxidation), and acetate are used as energy sources for the brain and skeletal muscles (**Figure 1A**) [2, 3]. Thus, brain activity is maintained by glucose and ketone bodies from the multiple sources. Of note, most of gluconeogenesis takes place in the liver and to a lesser extent in the proximal tubules of the kidney, and ketone bodies are mainly produced in the liver.

It has long been known that fasting and caloric restriction are associated with an extended lifespan in many organisms. Longevity is regulated by several factors such as mechanistic target of rapamycin (mTOR), sirtuins (SIRTs), AMP-activated protein kinase (AMPK), forkhead box protein O (FOXO), and growth hormone (GH)/insulin-like growth factor-1 (IGF-1), but the mechanism by which these factors extend lifespan in humans is not yet fully understood. One possible hypothesis is that fasting and caloric restriction are memorized in the epigenome of cells. More specifically, metabolites produced during fasting serve as inhibitors or substrates of epigenetic enzymes. For example, ketone bodies mainly inhibit class I histone deacetylases (HDACs) to promote histone acetylation. In addition, acetyl-CoA, produced by fatty acid oxidation, and α-ketoglutarate (α-KG, also known as 2-oxoglutarate), an intermediate metabolite of the tricarboxylic acid (TCA) cycle (also known as the citric acid cycle or the Krebs cycle), are substrates for histone acetyltransferases and epigenetic demethylases, respectively. Thus, the states of energy metabolism, including fasting, are recorded in cells as epigenomic memories, which may cause the development of future diseases.

#### **Figure 1.**

*The brain energy sources under the fasting condition. A. Energy sources for the brain, B. Energy sources for gluconeogenesis.*
