Medical Research: What is the background for this study? What are the main findings?
Dr. Cedernaes: Previous studies have demonstrated that experimental sleep loss and simulated shift work (i.e. misalignment of circadian rhythms) reduces energy expenditure and insulin sensitivity, providing links to why sleep loss may increase the risk of e.g. type-2 diabetes and obesity. Such phenotypes have also been observed in animals in which clock genes are ablated. Clock genes regulate the circadian rhythms of all cells and variants in these have also been associated with increased risk of obesity, insulin resistance and type-2 diabetes in humans. Almost no study has however investigated whether overnight wakefulness – mimicking a situation which recurrently occurs in shift work – can affect the expression of such clock genes in metabolically important tissues, i.e. adipose tissue and skeletal muscle, in humans. Such gene expression changes may both acutely and more long-term be regulated by changes in methylation, i.e. an epigenetic change, which have been found in blood of e.g. shift workers and in e.g. adipose tissue of type-2 diabetic subjects. However, whether sleep loss can lead to epigenetic changes has been unknown, and therefore also whether this could affect genes important for metabolism, such as the core clock genes which are essential for orchestrating and synchronizing downstream metabolic processes according to our circadian rhythms.
With this background in mind, I and associate professor Christian Benedict set out to conduct a study to investigate how one night of sleep loss altered gene transcription and methylation of core clock genes in adipose tissue and skeletal muscle, and whether this would be reflected at the systemic level by an impaired glucose tolerance test in healthy young individuals.
For the study, we had 15 participants undergo two almost 2-day long sessions in our lab, with the first night of each session serving as a baseline or habituation night, with a normal sleep period. On the second night, in random order, participants slept a full night (8.5 hours) in one session, and were kept awake the entire night while being bed-restricted in the other of two sessions. After each of these conditions, we took biopsies in the fasting condition from the subcutaneous adipose tissue and the skeletal muscle.
In collaboration with researchers from the Karolinska Institute, Gothenburg University and the German Institute of Human Nutrition, we were able to observe transcriptional repression of clock genes in the muscle, but not in the adipose tissue following sleep loss compared with normal sleep. Instead, we found methylation of regulatory elements of clock genes to be increased in the adipose tissue but not the skeletal muscle following sleep loss compared with normal sleep. Finally, we observed that participants had an impaired glucose tolerance test when they had been kept awake as compared with their response after sleep.
Medical Research: What should clinicians and patients take away from your report?
Dr. Cedernaes: Our study provides evidence for a potential new link as to why sleep loss may impair metabolism in humans. Our findings support the notion that sleep loss can have a negative impact on tissues that are key for maintaining glucose homeostasis, by altering how the circadian clocks in these tissues function.
Chronic “social jet-lag”, where one maintains different sleep-wake times on weekends compared with workdays, has been linked to an increased risk of obesity and type-2 diabetes. Given our results, even such more subtle sleep-wake differences may involve changes to expression and regulation of core clock genes in peripheral tissues, as deviations/perturbations of these from normal levels may promote insulin resistance in humans.
As even one night of sleep loss can alter peripheral tissues’ clock gene expression and gene regulation, and since animal models show that clock gene disruptions are detrimental to metabolic integrity, it may not be surprising that repeated exposure to overnight wakefulness as in shift work can have serious metabolic consequences over time. If certain important epigenetic changes following sleep loss (for example around clock genes) are not reset as quickly as they arise (say after a full night of recovery sleep), this could provide an explanation for why shift work and prolonged periods of sleep loss could have more long-lasting consequences, which it may take some time to fully recover from. Importantly, our findings of elevated post-glucose tolerance test glucose levels after one night of sleep loss show that even the most recent sleep history of patients should be critically assessed when evaluating patients’ metabolic health status.
Medical Research: What recommendations do you have for future research as a result of this study?
Dr. Cedernaes: Even though we used a within-subject design, in which subjects serve as their own controls, our findings need to be replicated in larger samples, and also studied in women, older subjects and individuals already suffering from metabolic conditions (such as type-2 diabetes and obesity). It will also be important to examine how long-lasting epigenetic changes due to sleep loss may be.
Jonathan Cedernaes M.D., Ph.D. (2015). Overnight Sleep Loss Can Have Long Term Metabolic Consequences