A link has been established between energy metabolism and sleep homeostasis. The ketone bodies acetoacetate and beta-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 (PPAR alpha), and treatment with a PPAR activator has been shown to induce a marked increase in plasma acetoacetate and decreased beta-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/beta-hydroxybutyrate) in 10-week-old male mice. Moreover, sleep deprivation increased mRNA expression of ketogenic genes such as PPAR alpha 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 beta-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. (C) 2013 Elsevier Ltd. All rights reserved.
