title: Reciprocal regulation of carbon monoxide metabolism and the circadian clock.
abstract: Circadian clocks are cell-autonomous oscillators regulating daily rhythms in a wide range of physiological, metabolic and behavioral processes. Feedback of metabolic signals, such as redox state, NAD+/NADH and AMP/ADP ratios, or heme, modulate circadian rhythms and thereby optimize energy utilization across the 24-h cycle. We show that rhythmic heme degradation, which generates the signaling molecule carbon monoxide (CO), is required for normal circadian rhythms as well as circadian metabolic outputs. CO suppresses circadian transcription by attenuating CLOCK-BMAL1 binding to target promoters. Pharmacological inhibition or genetic depletion of CO-producing heme oxygenases abrogates normal daily cycles in mammalian cells and Drosophila. In mouse hepatocytes, suppression of CO production leads to a global upregulation of CLOCK-BMAL1-dependent circadian gene expression and dysregulated glucose metabolism. Together, our findings show that CO metabolism is an important link between the basic circadian-clock machinery, metabolism and behavior.
authors.affiliation: Laboratory of Chronobiology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Roman
authors.initials: R
authors.lastname: Klemz
authors.affiliation: Laboratory of Chronobiology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Reischl
authors.affiliation: Laboratory of Chronobiology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wallach
authors.affiliation: Institute of Pharmacology, Center for Cardiovascular Research CCR, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Witte
authors.affiliation: Laboratory of Chronobiology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Karsten
authors.initials: K
authors.lastname: Jürchott
authors.affiliation: Laboratory of Chronobiology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Klemz
authors.affiliation: Laboratory of Chronobiology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Veronika
authors.initials: V
authors.lastname: Lang
authors.affiliation: Bernhard-Nocht-Institut, Hamburg, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Lorenzen
authors.affiliation: Institute of Pharmacology, Center for Cardiovascular Research CCR, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Knauer
authors.affiliation: Institute of Pharmacology, Center for Cardiovascular Research CCR, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Steffi
authors.initials: S
authors.lastname: Heidenreich
authors.affiliation: Department of Cell and Developmental Biology, University College London, London, UK.
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.affiliation: Division of Biochemistry, Department of Biology, University of Fribourg, Fribourg, Switzerland.
authors.forename: Jürgen A
authors.initials: JA
authors.lastname: Ripperger
authors.affiliation: Institute of Pharmacology, Center for Cardiovascular Research CCR, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schupp
authors.affiliation: Department of Cell and Developmental Biology, University College London, London, UK.
authors.forename: Ralf
authors.initials: R
authors.lastname: Stanewsky
authors.affiliation: Laboratory of Chronobiology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Achim
authors.initials: A
authors.lastname: Kramer
mesh_terms: D056930:ARNTL Transcription Factors / Q000378:metabolism; D000818:Animals; D056926:CLOCK Proteins / Q000378:metabolism; D002248:Carbon Monoxide / Q000378:metabolism*; D045744:Cell Line, Tumor; D057906:Circadian Clocks; D004331:Drosophila melanogaster; D005947:Glucose / Q000378:metabolism; D006418:Heme / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000502:physiology; D006706:Homeostasis; D006801:Humans; D008297:Male; D053858:Metabolic Networks and Pathways; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity; D011485:Protein Binding; D014158:Transcription, Genetic; D015533:Transcriptional Activation
chemical_list: D056930:ARNTL Transcription Factors; C538960:BMAL1 protein, human; D006418:Heme; D002248:Carbon Monoxide; D006419:Heme Oxygenase (Decyclizing); D056926:CLOCK Proteins; C538943:CLOCK protein, human; D005947:Glucose