title: Acute inhibition of casein kinase 1δ/ε rapidly delays peripheral clock gene rhythms.
abstract: Circadian rhythms are generated through a transcription-translation feedback loop involving clock genes and the casein kinases CSNK1D and CSNK1E. In this study, we investigated the effects of the casein kinase inhibitor PF-670462 (50 mg/kg) on rhythmic expression of clock genes in the liver, pancreas and suprachiasmatic nucleus (SCN) as well as plasma corticosterone, melatonin and running behaviour in rats and compared them to the responses to a 4 h extension of the light phase. PF-670462 acutely phase delayed the rhythmic transcription of Bmal1, Per1, Per2 and Nr1d1 in both liver and pancreas by 4.5 ± 1.3 and 4.5 ± 1.2 h, respectively, 1 day after administration. In the SCN, the rhythm of Nr1d1 and Dbp mRNA expression was delayed by 4.2 and 4 h, respectively. Despite these changes, the time of peak plasma melatonin secretion was not delayed, although the plasma corticosterone rhythm and onset of wheel-running activity were delayed by 2.1 and 1.1 h, respectively. These changes are in contrast to the effects of the 4 h light extension, which resulted in delays in peak expression of the clock genes of less than 1 h and no change in the melatonin or corticosterone rhythms. The ability of the casein kinase inhibitor to bring about large phase shifts in the rhythms of major metabolic target tissues may lead to new drugs being developed to rapidly phase adjust circadian rhythms to alleviate the metabolic impact of shift work.
authors.affiliation: Robinson Research Institute, School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, SA, 5005, Australia, david.kennaway@adelaide.edu.au.
authors.forename: D J
authors.initials: DJ
authors.lastname: Kennaway
authors.forename: T J
authors.initials: TJ
authors.lastname: Varcoe
authors.forename: A
authors.initials: A
authors.lastname: Voultsios
authors.forename: M D
authors.initials: MD
authors.lastname: Salkeld
authors.forename: L
authors.initials: L
authors.lastname: Rattanatray
authors.forename: M J
authors.initials: MJ
authors.lastname: Boden
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics; D000818:Animals; D048149:Casein Kinase 1 epsilon / Q000037:antagonists & inhibitors*; D048148:Casein Kinase Idelta / Q000037:antagonists & inhibitors*; D057906:Circadian Clocks / Q000235:genetics*; D002940:Circadian Rhythm / Q000235:genetics; D003345:Corticosterone / Q000097:blood; D004268:DNA-Binding Proteins / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects*; D008099:Liver / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000235:genetics; D010179:Pancreas / Q000378:metabolism; D056950:Period Circadian Proteins / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology*; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013493:Suprachiasmatic Nucleus / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics
chemical_list: D056930:ARNTL Transcription Factors; C000598703:Arntl protein, rat; C485975:DBP protein, rat; D004268:DNA-Binding Proteins; C498263:Nr1d1 protein, rat; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; C539024:Per1 protein, rat; C513311:Per2 protein, rat; D056950:Period Circadian Proteins; D011743:Pyrimidines; D014157:Transcription Factors; C522839:PF-670462; D048149:Casein Kinase 1 epsilon; D048148:Casein Kinase Idelta; D003345:Corticosterone