title: Ketone body metabolism and sleep homeostasis in mice.
abstract: A link has been established between energy metabolism and sleep homeostasis. The ketone bodies acetoacetate and β-hydroxybutyrate, generated from the breakdown of fatty acids, are major metabolic fuels for the brain under conditions of low glucose availability. Ketogenesis is modulated by the activity of peroxisome proliferator-activated receptor alpha (PPARα), and treatment with a PPAR activator has been shown to induce a marked increase in plasma acetoacetate and decreased β-hydroxybutyrate in mice, accompanied by increased slow-wave activity during non-rapid eye movement (NREM) sleep. The present study investigated the role of ketone bodies in sleep regulation. Six-hour sleep deprivation increased plasma ketone bodies and their ratio (acetoacetate/β-hydroxybutyrate) in 10-week-old male mice. Moreover, sleep deprivation increased mRNA expression of ketogenic genes such as PPARα and 3-hydroxy-3-methylglutarate-CoA synthase 2 in the brain and decreased ketolytic enzymes such as succinyl-CoA: 3-oxoacid CoA transferase. In addition, central injection of acetoacetate, but not β-hydroxybutyrate, markedly increased slow-wave activity during NREM sleep and suppressed glutamate release. Central metabolism of ketone bodies, especially acetoacetate, appears to play a role in the regulation of sleep homeostasis.
authors.affiliation: Department of Integrative Physiology, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Chikahisa
authors.affiliation: Department of Integrative Physiology, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Shimizu
authors.affiliation: Department of Integrative Physiology, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Shiuchi
authors.affiliation: Department of Integrative Physiology, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan. Electronic address: sei@tokushima-u.ac.jp.
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Séi
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000378:metabolism; D000090:Acetoacetates / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000503:physiopathology; D005508:Food Deprivation / Q000502:physiology; D015870:Gene Expression / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology*; D007657:Ketone Bodies / Q000378:metabolism*; D008099:Liver / Q000503:physiopathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D047493:PPAR alpha / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012890:Sleep / Q000502:physiology*; D012892:Sleep Deprivation / Q000503:physiopathology*; D012894:Sleep Stages / Q000502:physiology
chemical_list: D000090:Acetoacetates; D007657:Ketone Bodies; D047493:PPAR alpha; D012333:RNA, Messenger; D018698:Glutamic Acid; C016635:acetoacetic acid; D020155:3-Hydroxybutyric Acid
keywords: Ketone bodies; PPARα; Sleep; Slow-wave activity