Metabolic Responses to Energy-Depleted Conditions

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.