title: The nuclear receptor REV-ERBα is required for the daily balance of carbohydrate and lipid metabolism.
abstract: Mutations of clock genes can lead to diabetes and obesity. REV-ERBα, a nuclear receptor involved in the circadian clockwork, has been shown to control lipid metabolism. To gain insight into the role of REV-ERBα in energy homeostasis in vivo, we explored daily metabolism of carbohydrates and lipids in chow-fed, unfed, or high-fat-fed Rev-erbα(-/-) mice and their wild-type littermates. Chow-fed Rev-erbα(-/-) mice displayed increased adiposity (2.5-fold) and mild hyperglycemia (∼10%) without insulin resistance. Indirect calorimetry indicates that chow-fed Rev-erbα(-/-) mice utilize more fatty acids during daytime. A 24-h nonfeeding period in Rev-erbα(-/-) animals favors further fatty acid mobilization at the expense of glycogen utilization and gluconeogenesis, without triggering hypoglycemia and hypothermia. High-fat feeding in Rev-erbα(-/-) mice amplified metabolic disturbances, including expression of lipogenic factors. Lipoprotein lipase (Lpl) gene, critical in lipid utilization/storage, is triggered in liver at night and constitutively up-regulated (∼2-fold) in muscle and adipose tissue of Rev-erbα(-/-) mice. We show that CLOCK, up-regulated (2-fold) at night in Rev-erbα(-/-) mice, can transactivate Lpl. Thus, overexpression of Lpl facilitates muscle fatty acid utilization and contributes to fat overload. This study demonstrates the importance of clock-driven Lpl expression in energy balance and highlights circadian disruption as a potential cause for the metabolic syndrome.
authors.affiliation: Department of Neurobiology of Rhythms, Institute of Cellular and Integrative Neurosciences, University of Strasbourg, Strasbourg, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Delezie
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Dumont
authors.forename: Hugues
authors.initials: H
authors.lastname: Dardente
authors.forename: Hugues
authors.initials: H
authors.lastname: Oudart
authors.forename: Aline
authors.initials: A
authors.lastname: Gréchez-Cassiau
authors.forename: Paul
authors.initials: P
authors.lastname: Klosen
authors.forename: Michèle
authors.initials: M
authors.lastname: Teboul
authors.forename: Franck
authors.initials: F
authors.lastname: Delaunay
authors.forename: Paul
authors.initials: P
authors.lastname: Pévet
authors.forename: Etienne
authors.initials: E
authors.lastname: Challet
mesh_terms: D000818:Animals; D056926:CLOCK Proteins / Q000502:physiology*; D050260:Carbohydrate Metabolism / Q000502:physiology*; D002940:Circadian Rhythm / Q000502:physiology; D059305:Diet, High-Fat; D004734:Energy Metabolism / Q000502:physiology*; D005260:Female; D005943:Gluconeogenesis / Q000502:physiology; D006706:Homeostasis / Q000502:physiology; D007333:Insulin Resistance / Q000502:physiology; D050356:Lipid Metabolism / Q000502:physiology*; D008071:Lipoprotein Lipase / Q000378:metabolism; D008112:Liver Glycogen / Q000378:metabolism; D008297:Male; D051379:Mice; D009043:Motor Activity; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000172:deficiency / Q000502:physiology*
chemical_list: D008112:Liver Glycogen; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D056926:CLOCK Proteins; D008071:Lipoprotein Lipase