Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
PLoS One. 2012;7(12):e52983. doi: 10.1371/journal.pone.0052983. Epub 2012 Dec 28.
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.
人体和动物研究表明，睡眠不足或睡眠质量差（例如，夜班工作者）会促进肥胖和糖尿病的发展。睡眠中断对葡萄糖稳态和肝脏生理学的影响已有充分的记录。然而，睡眠中断后脂联素水平的变化表明脂肪细胞可能是睡眠的另一个重要外周靶标。生物钟调节代谢稳态，时钟中断会导致肥胖和代谢综合征。发现睡眠和时钟中断具有非常相似的代谢效应促使我们提出一个问题，即生物钟机制是否可能介导睡眠中断的代谢后果。为了验证这一点，我们在轮班工作的小鼠模型中分析了能量稳态和脂肪细胞转录组的调节，在该模型中，我们在连续五天的正常非活动期的前六个小时阻止小鼠睡眠（定时睡眠限制 TSR）。我们比较了 TSR 在野生型和 Per1/2 双突变小鼠中的作用，预测 Per1/2 突变体中没有生物钟会导致 TSR 引起的代谢反应减弱。在野生型中，TSR 诱导白色脂肪组织的显著转录重编程，提示脂肪生成增加，同时伴随着脂联素的分泌增加和食物摄入增加，这是肥胖和相关瘦素抵抗的标志。其中一些变化至少在 TSR 结束后持续一周，表明即使是短暂的睡眠中断也会引起长期的生理损伤。相比之下，Per1/2 缺陷小鼠对 TSR 引起的食物摄入、瘦素水平和脂肪转录的影响较小。我们得出的结论是，Per1/2 双突变体中功能性时钟的缺失保护了这些小鼠免受 TSR 引起的代谢重编程，表明生物钟系统在调节睡眠中断的生理效应方面发挥作用。
