title: The Pentose Phosphate Pathway Regulates the Circadian Clock.
abstract: The circadian clock is a ubiquitous timekeeping system that organizes the behavior and physiology of organisms over the day and night. Current models rely on transcriptional networks that coordinate circadian gene expression of thousands of transcripts. However, recent studies have uncovered phylogenetically conserved redox rhythms that can occur independently of transcriptional cycles. Here we identify the pentose phosphate pathway (PPP), a critical source of the redox cofactor NADPH, as an important regulator of redox and transcriptional oscillations. Our results show that genetic and pharmacological inhibition of the PPP prolongs the period of circadian rhythms in human cells, mouse tissues, and fruit flies. These metabolic manipulations also cause a remodeling of circadian gene expression programs that involves the circadian transcription factors BMAL1 and CLOCK, and the redox-sensitive transcription factor NRF2. Thus, the PPP regulates circadian rhythms via NADPH metabolism, suggesting a pivotal role for NADPH availability in circadian timekeeping.
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Rey
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Utham K
authors.initials: UK
authors.lastname: Valekunja
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Feeney
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Lisa
authors.initials: L
authors.lastname: Wulund
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Nikolay B
authors.initials: NB
authors.lastname: Milev
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Stangherlin
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Ansel-Bollepalli
authors.affiliation: Metabolomics Unit, Institute for Molecular Medicine Finland (FIMM), 00290 Helsinki, Finland.
authors.forename: Vidya
authors.initials: V
authors.lastname: Velagapudi
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: John S
authors.initials: JS
authors.lastname: O'Neill
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK. Electronic address: areddy@cantab.net.
authors.forename: Akhilesh B
authors.initials: AB
authors.lastname: Reddy
mesh_terms: D000818:Animals; D001483:Base Sequence; D001522:Behavior, Animal; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D057906:Circadian Clocks / Q000235:genetics; D004331:Drosophila melanogaster / Q000502:physiology; D005786:Gene Expression Regulation; D006801:Humans; D008322:Mammals / Q000502:physiology; D009249:NADP / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009928:Organ Specificity / Q000235:genetics; D010084:Oxidation-Reduction; D010427:Pentose Phosphate Pathway / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D051267:NF-E2-Related Factor 2; D009249:NADP; D056926:CLOCK Proteins