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Abstract:
Human and animal studies demonstrate that short sleep or poor sleep quality, e.g. in night shift workers, promote the
development of obesity and diabetes. Effects of sleep disruption on glucose homeostasis and liver physiology are well
documented. However, changes in adipokine levels after sleep disruption suggest that adipocytes might be another
important peripheral target of sleep. Circadian clocks regulate metabolic homeostasis and clock disruption can result in
obesity and the metabolic syndrome. The finding that sleep and clock disruption have very similar metabolic effects
prompted us to ask whether the circadian clock machinery may mediate the metabolic consequences of sleep disruption.
To test this we analyzed energy homeostasis and adipocyte transcriptome regulation in a mouse model of shift work, in
which we prevented mice from sleeping during the first six hours of their normal inactive phase for five consecutive days
(timed sleep restriction – TSR). We compared the effects of TSR between wild-type and Per1/2 double mutant mice with the
prediction that the absence of a circadian clock in Per1/2 mutants would result in a blunted metabolic response to TSR. In
wild-types, TSR induces significant transcriptional reprogramming of white adipose tissue, suggestive of increased
lipogenesis, together with increased secretion of the adipokine leptin and increased food intake, hallmarks of obesity and
associated leptin resistance. Some of these changes persist for at least one week after the end of TSR, indicating that even
short episodes of sleep disruption can induce prolonged physiological impairments. In contrast, Per1/2 deficient mice show
blunted effects of TSR on food intake, leptin levels and adipose transcription. We conclude that the absence of a functional
clock in Per1/2 double mutants protects these mice from TSR-induced metabolic reprogramming, suggesting a role of the
circadian timing system in regulating the physiological effects of sleep disruption.
