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Q&A with Jonathan Cedernaes, PhD, Uppsala University

Bild Jonathan

Just one night of wakefulness can lead to alterations in epigenetic and transcriptional profile of core circadian clock genes in key metabolic tissues, which could explain why shift workers are at an increased risk of metabolic morbidities, according to a new study published in the Journal of Clinical Endocrinology & Metabolism.

Researchers led by Jonathan Cedernaes, MD, PhD, of Uppsala University in Uppsala, Sweden conclude that just one night of lost sleep results in hypermethylation of regulatory regions of key clock genes. These effects are tissue specific, and were observed to occur in adipose tissue, but not in skeletal muscle. Gene expression differences were observed for the investigated clock genes in skeletal muscle, but not in adipose tissue. They go on to note that shift work is associated with many of the same phenotypes observed in transgenic animal models in which the circadian clock is disrupted.

Endocrine News spoke with Cedernaes about his team’s study and its possible implications, as well as the future of looking at how sleep, or lack thereof, impacts the endocrine system.

EN: People are tending to get less and less sleep in modern society, for a variety of reasons. Do you see this pattern of less sleep as correlating with the rising numbers of diabetes and obesity?

JC: If you look over the past couple of decades, there is research to suggest that the increased prevalence in type 2 diabetes and obesity has paralleled an increase in the number of people who get insufficient sleep. Numerous epidemiological studies have also found associations between insufficient sleep and an increased risk of such metabolic pathologies, suggesting that chronic sleep loss could be an important contributor to the rise in these diseases. This is furthermore supported by experimental studies that have found sleep loss or misaligned sleep to increase insulin resistance, which is linked to type 2 diabetes. Experimental sleep loss, even for just a couple of days, can also cause people to gain weight, and humans seem to have an increased preference for snacks when they are sleep-deprived, which might have to do with an increased activation of reward centers in the brain, which has also been demonstrated in sleep-deprived vs. well-rested subjects. Altogether, there is a lot of evidence suggesting an association between the reduced average sleep duration and the increase in type 2 diabetes and obesity. A lot of the factors contributing to these changes (declined sleep and increased obesity/type 2 diabetes) are of course shared, such as increased working hours or increased time sitting and watching TV or playing computer games. These take away time for physical activity and/or sleep.

EN: Can you give me some background on your study “Acute Sleep Loss Induces Tissue-Specific Epigenetic and Transcriptional Alterations to Circadian Clock Genes in Men”? What made you look at acute sleep loss and how it affects the endocrine system?

JC: I have always been interested in physiology and how the body and its tissues respond to acute stressors, such as sleep loss. Skeletal muscle and adipose tissue are two of the biggest organs of the body, and two of the most important from a metabolic perspective. When I had the idea for the study, there was virtually no single study on how either of these organs were affected by sleep loss, which seemed surprising, and like an important gap to fill, given that there was a lot of evidence highlighting the fact that sleep loss is associated with insulin resistance – a condition that to a great extent depends on how the muscle and adipose tissue function. Another important reason for doing the study was that there was evidence from animal studies that “jet lag” (acute circadian misalignment) could cause the different biological “clocks” in different tissues to be shifted to various extents. Such “misalignment” or desynchrony among tissue clocks could be an important reason for why metabolic processes are no longer synchronized after for example sleep loss, and thereby could contribute to insulin resistance or endocrine disruptions as observed by others following experimental sleep loss. At the time I was also helping out with a different project where I took biopsies, so by learning that technique in that study, I was able to apply it to the study we ended up doing. I am also interested in genetics, and at the time that I had the idea for the study, a study came out showing that acute exercise could lead to epigenetic changes. But no one had investigated whether the same could occur following acute sleep loss, i.e. another stressor, and an intriguing question was whether such effects would then be different for different tissues.

EN: The people in modern society seem to think they don’t need sleep, or that it’s not as important as eating well or exercising regularly. Do you think that’s starting to turn around now? What’s the best way for people to make sure they sleep well?

JC: In certain areas of society, I think it is changing, in other areas perhaps not so much, but it’s also difficult to go back to a society in which most of us went to bed at 10pm-12am – a lot of us are simply living in a 24/7 society and most of us want to be able to maintain at least certain aspects of it, which means that others will have to work at inconvenient hours to maintain those services. It also becomes more difficult in a more global world I think, where everyone’s connected to everyone – virtually (no pun intended) obliterating the important function that earth’s different time zones normally serve. But with an increased understanding – especially at the societal level – of all the negative effects that sleep loss or mistimed sleep can lead to, I think that we will start seeing a general improvement in people’s reported sleep habits. It’s important to teach about the importance of sleep in schools – not the least because kids really need their sleep. The importance of sleep for general health and well-being was something that was almost completely ignored when I quite recently attended medical school, but it has changed since then, and may of course already have been highlighted in other countries/cities.

The comparison to exercise is also interesting, as proper sleep turns out to be just as important as exercise, even more important from a lot of perspectives. Both impact the cardiovascular system, both are linked to brain health and neurogenesis, and both are important regulators of metabolic homeostasis, including insulin sensitivity and weight regulation. There are also studies showing that even modest improvements in sleep duration can lead to substantial improvements in both e.g. metabolic (insulin sensitivity) and cardiovascular health (lower blood pressure).

I think that the comparison of sleep with exercise is one way to emphasize the importance of sleep – to see it as your daily rest, which is a time of “rest exercise” for the body and brain; a period when a lot of very important processes need to occur to restore your body and mind to their greatest potential. There’s been a lot of hype about eating well and performing daily exercise, but all of these factors are intimately linked to one another, which is why it is important to try to optimize all three. Just as time is set aside for exercise, time should be set aside each day for proper rest and sleep, realizing that this can improve many aspects of general well-being. Sometimes that means that one will need to skip an occasion for exercise, to instead try to pay back some of the sleep that has been lost e.g. during the working week.

EN: What kinds of implications do you think this study will or should have on clinical practice and/or health policy?

JC: A lot of research, including our recent results, demonstrate the importance of sleep for general and metabolic well-being. It is important for physicians as well as patients to carefully consider sleep habits and ways to improve them, as this can have ramifications for so many aspects of a person’s health. The effects of insufficient sleep can be said to reverberate throughout the body and mind, and considering the impact that just one or several nights of lost sleep can have on just your metabolism, this emphasizes the significance of trying to achieve good sleep habits in the long run.

Our study was a model of acute shift work, a work form that is very common today, and – depending on how our society and globalization develops – may become even more common. It is important for policy makers to recognize that all of these people are at increased risk of developing numerous diseases, of which some are type-2 diabetes and obesity. Shift workers not only misalign their circadian clocks – our study results suggest this occurs differentially across tissues – and related to this, shift workers often suffer from insufficient sleep. It would be great to try to further minimize the need for shift work, and where not possible, I think that even more careful monitoring than today of shift workers’ health is needed. It will be great if we can also come up with and implement standardized screening methods (perhaps including particular biomarkers in blood) that can be run when a person is considering to carry out shift work.

EN: Your research points to a mechanism for sleep’s effects on the metabolic process, which seems to be novel in this particular field of sleep and the endocrine system. Can you speak more to that?

JC: As pointed out earlier, almost no earlier study had examined the role that key metabolic tissues play for the metabolic effects associated with sleep loss, such as impaired glucose tolerance or weight gain. While blood can serve as a proxy for some of these effects, blood cells include immune cells, and studies show that there are a lot of effects that do not correlate with changes in blood. This requires analyses of the involved tissues, i.e. through biopsies of e.g. skeletal muscle. We studied both gene expression and the regulation thereof, i.e. gene methylation, which is an epigenetic phenomenon. Since epigenetic changes can be long-lasting, as they may determine to what extent a gene is expressed or not over longer time scales, we were interested in studying whether acute sleep loss altered the epigenetic status of clock genes. The reason we chose these genes is because they are so heavily involved in regulating metabolic processes across tissues, and epigenetic changes to these clock genes could be an additional mechanism by which sleep loss disrupts metabolism. We also showed there were changes in gene expression, and that the changes in both gene expression and methylation were different across the two studied tissues (skeletal muscle and subcutaneous fat), potentially indicating that there occurs some circadian desynchrony across metabolic tissues after sleep loss. This may be a further explanation why metabolic integrity is disrupted after sleep loss – metabolic processes across tissues may suddenly start running on “different clocks” and as such start interfering with one another.

It is worthwhile to point out that it of course is important to establish what changes occur in blood as well, as this is a much more accessible for routine sampling in e.g. primary healthcare, samples of which can be acquired almost anywhere, and studies on blood have already generated important insight into molecular changes as well as potential biomarkers, for effects of sleep loss.

EN: One of the limitations you point out is that methylation of clock genes was measured under fasting conditions, but that shift workers would probably be eating during the night. Can you speak more to that? What influenced that decision?

JC: We chose to study our participants under fasting conditions for several reasons: First of all, participants fast when they sleep, and introducing meals when participants are awake (during the night), could confound our results as they would only be in a fasting condition in the sleep condition (unless we had provided them food via a catheter). Another reason is that based on animal studies, food intake entrains the circadian clocks which we aimed to study, and could therefore have confounded our study results even further. With this in mind, it is very reasonable to assume that our results would have been very different if we had chosen to study participants that had the opportunity to eat during the night. But by studying participants in the fasting condition, we aimed to isolate the effect of sleep vs sleep loss, and if participants had only been studied after a morning meal, we would not have known what effects to attribute to the meal vs. sleep loss.

The point about shift workers eating during the night is a very important one. Studies suggest it is a greater challenge for the body to eat during the night (when it is expecting the individual to be sleeping), and this seems to be a contributing factor for why shift workers are at increased risk of e.g. weight gain, type-2 diabetes and hypertension. For these reasons, it is also important to conduct further studies to examine how our results would differ if the body is challenged by food intake during the night.

EN: It seems like there is much more to be studied when it comes to sleep and the endocrine system. What kinds of things are you working on now? What kinds of studies will we/should we see in the future?

JC: We are attempting to characterize what the overall changes are at the genomic level in these tissues following overnight wakefulness. We are also currently examining additional circulating molecular factors that have been linked to endocrine disruptions in other conditions, such as insulin resistance, and to what extent they are affected by sleep disruptions.

I think the current wealth of data gathered by personal “smart” devices will provide a great insight into our sleep habits. There have already been some very exciting studies that have come out of this field, which is especially exciting when longitudinal data of sleep and activity are combined with repeated tests of metabolic and cognitive health. These devices are becoming less and less obtrusive and more affordable, and can already measure factors such as glucose concentrations over longer time periods. I therefore think that we will start seeing more and more of these studies, which is also great because the greater number of individuals that are studied means that we will be able to characterize and observe the whole spectrum of individual responses to e.g. sleep loss. This will allow us to reconcile earlier contradicting study outcomes, which in smaller studies likely in part stem from the simple reason that people from various environments and genetic backgrounds are studied, under study conditions that are almost never exactly the same across studies.

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