Four days of simulated shift work reduces insulin sensitivity in humans.

AIM: The aim of this study was to investigate the effects of 4 consecutive simulated night shifts on glucose homeostasis, mitochondrial function and central and peripheral rhythmicities compared with a simulated day shift schedule. METHODS: Seventeen healthy adults (8M:9F) matched for sleep, physical activity and dietary/fat intake participated in this study (night shift work n = 9; day shift work n = 8). Glucose tolerance and insulin sensitivity before and after 4 nights of shift work were measured by an intravenous glucose tolerance test and a hyperinsulinaemic euglycaemic clamp respectively. Muscles biopsies were obtained to determine insulin signalling and mitochondrial function. Central and peripheral rhythmicities were assessed by measuring salivary melatonin and expression of circadian genes from hair samples respectively. RESULTS: Fasting plasma glucose increased (4.4 ± 0.1 vs. 4.6 ± 0.1 mmol L-1 ; P = .001) and insulin sensitivity decreased (25 ± 7%, P < .05) following the night shift, with no changes following the day shift. Night shift work had no effect on skeletal muscle protein expression (PGC1α, UCP3, TFAM and mitochondria Complex II-V) or insulin-stimulated pAkt Ser473, pTBC1D4Ser318 and pTBC1D4Thr642. Importantly, the metabolic changes after simulated night shifts occurred despite no changes in the timing of melatonin rhythmicity or hair follicle cell clock gene expression across the wake period (Per3, Per1, Nr1d1 and Nr1d2). CONCLUSION: Only 4 days of simulated night shift work in healthy adults is sufficient to reduce insulin sensitivity which would be expected to increase the risk of T2D.

Acute inhibition of casein kinase 1δ/ε rapidly delays peripheral clock gene rhythms.

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.

Circadian regulation of reproduction: from gamete to offspring.

Few challenges are more critical to the survival of a species than reproduction. To ensure reproductive success, myriad aspects of physiology and behaviour need to be tightly orchestrated within the animal, as well as timed appropriately with the external environment. This is accomplished through an endogenous circadian timing system generated at the cellular level through a series of interlocked transcription/translation feedback loops, leading to the overt expression of circadian rhythms. These expression patterns are found throughout the body, and are intimately interwoven with both the timing and function of the reproductive process. In this review we highlight the many aspects of reproductive physiology in which circadian rhythms are known to play a role, including regulation of the estrus cycle, the LH surge and ovulation, the production and maturation of sperm and the timing of insemination and fertilisation. We will also describe roles for circadian rhythms in support of the preimplantation embryo in the oviduct, implantation/placentation, as well as the control of parturition and early postnatal life. There are several key differences in physiology between humans and the model systems used for the study of circadian disruption, and these challenges to interpretation will be discussed as part of this review.