Principles for circadian orchestration of metabolic pathways.
Circadian rhythms govern multiple aspects of animal metabolism. Transcriptome-, proteome- and metabolome-wide measurements have revealed widespread circadian rhythms in metabolism governed by a cellular genetic oscillator, the circadian core clock. However, it remains unclear if and under which conditions transcriptional rhythms cause rhythms in particular metabolites and metabolic fluxes. Here, we analyzed the circadian orchestration of metabolic pathways by direct measurement of enzyme activities, analysis of transcriptome data, and developing a theoretical method called circadian response analysis. Contrary to a common assumption, we found that pronounced rhythms in metabolic pathways are often favored by separation rather than alignment in the times of peak activity of key enzymes. This property holds true for a set of metabolic pathway motifs (e.g., linear chains and branching points) and also under the conditions of fast kinetics typical for metabolic reactions. By circadian response analysis of pathway motifs, we determined exact timing separation constraints on rhythmic enzyme activities that allow for substantial rhythms in pathway flux and metabolite concentrations. Direct measurements of circadian enzyme activities in mouse skeletal muscle confirmed that such timing separation occurs in vivo.
Institute for Theoretical Biology, Charité-Universitätsmedizin Berlin, 10115 Berlin, Germany.|Laboratory of Chronobiology, Institute for Medical Immunology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.|Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158-2330.
Kevin
K
Thurley
Laboratory of Chronobiology, Institute for Medical Immunology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
Christopher
C
Herbst
Institute for Theoretical Biology, Charité-Universitätsmedizin Berlin, 10115 Berlin, Germany.
Felix
F
Wesener
Laboratory of Chronobiology, Institute for Medical Immunology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
Barbara
B
Koller
Laboratory of Chronobiology, Institute for Medical Immunology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
Thomas
T
Wallach
Laboratory of Chronobiology, Institute for Medical Immunology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
Bert
B
Maier
Laboratory of Chronobiology, Institute for Medical Immunology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
Achim
A
Kramer
Institute for Theoretical Biology, Charité-Universitätsmedizin Berlin, 10115 Berlin, Germany; westermark@fbn-dummerstorf.de.
Pål O
0000-0002-6637-2566
PO
Westermark
D000465:Algorithms; D000818:Animals; D057906:Circadian Clocks / Q000235:genetics*; D002940:Circadian Rhythm / Q000235:genetics*; D004798:Enzymes / Q000235:genetics / Q000378:metabolism; D063990:Gene Ontology; D006801:Humans; D007700:Kinetics; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism; D020543:Proteome / Q000235:genetics / Q000378:metabolism; D051381:Rats; D059467:Transcriptome
D004798:Enzymes; D020543:Proteome
circadian rhythms; glucose metabolism; metabolic response analysis; mouse skeletal muscle