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.
Highlights
The prevalence of obesity has dramatically increased in most industrialized countries within the last decades [1]
Acute disruption of diurnal activity patterns has been described in other mouse models of shift work [22,41,42] and both the acute and prolonged effects of activity we describe are reminiscent of what has been observed in human shift workers [43], indicating that our Timed sleep restriction (TSR) procedure mimics human shift work conditions
We show that five days of timed sleep restriction (TSR) resulted in alterations of food intake, body weight homeostasis and plasma leptin, glucose, and triglyceride levels in wild-type mice
Summary
The prevalence of obesity has dramatically increased in most industrialized countries within the last decades [1]. Circulating levels of metabolically relevant hormones such as leptin and ghrelin are altered and prediabetic changes in glucose homeostasis are observed (reviewed in [13,16]). The blood levels of several adipokine hormones correlate with sleep duration [17], suggesting that (white) adipose tissue may be an important peripheral target of sleep loss [18]. In line with this idea, sleep loss or poor sleep quality can lead to dyslipidemia and increased abdominal fat accumulation in humans [7,11,19,20]. The effects of sleep disruption on adipocyte function remain largely unknown
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