Oral Presentation The Annual Scientific Meeting of the Endocrine Society of Australia and the Society for Reproductive Biology 2014

Acute inhibition of casein kinase 1δ/ε rapidly resets central and peripheral clock gene rhythms (#194)

Michael J Boden 1 , Tamara J Varcoe 1 , Athena Voultsios 1 , Mark D Salkeld 1 , Leewen Rattanatray 1 , David J Kennaway 1
  1. Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia

Circadian rhythms regulate changes in energy metabolism and behaviour that occur across 24 hours. These rhythms are generated through interlocked transcription/translation feedback loops involving clock genes and their protein products and disruption of these rhythms leads to impaired metabolic function. Key to maintaining this 24 hour cycle is the phosphorylation of the Period proteins by casein kinase 1δ/ε. The effects of the casein kinase inhibitor PF-670462 (50mg/kg) on the rhythmic expression of clock and other genes in the liver, pancreas and the suprachiasmatic nucleus of the brain were assessed in rats (5wks, n=5 per group/time point) and compared to the responses to a 4-hour extension of the light phase. The changes in plasma corticosterone, melatonin and running behaviour were also evaluated.

PF-670462 acutely phase delayed the rhythmic transcription of Bmal1, Per1, Per2 and Nr1d1 in both liver and pancreas by 4.5 ± 1.3 hours and 4.5 ± 1.2 hours respectively 1 day after administration. In the suprachiasmatic nucleus, the rhythm of Nr1d1 and Dbp mRNA expression was delayed by 4.2 and 4 hours respectively. Liver expression of Pfkfb2 and Pck1 mRNA was delayed by 1.9 and 0.9 hours respectively, coinciding with a 2.1 hour delay in peak corticosterone secretion. Peak melatonin secretion was unchanged, while the onset of wheel running activity was delayed by 1.1 hours. These changes are in contrast to the effects of a 4-hour extension of the light phase, which delayed the peak expression of the clock genes by less than 1 hour, with no change in the corticosterone rhythm. The ability to drive large phase shifts in major metabolic tissues through inhibition of casein kinase 1δ/ε highlights a pathway to rapidly adjust circadian rhythms. By developing new drugs targeting these kinases, it may be possible to alleviate the metabolic disruption induced by shift work.