There is an increasing amount of research on how a lack of sleep impacts endocrine system from increasing obesity to contributing to diabetes. Johnathan Cedernaes, PhD, discusses his research on this subject and what it means for the sleepless patients as well as the clinicians who treat them.
Three years ago, Endocrine News ran a story about how sleep loss affects endocrine health, how this increasing lack of sleep correlates with rising obesity and diabetes numbers, and what endocrinologists are working to do to help people get the sleep they need in this fast-paced modern world.
The following year, a study appeared in The Journal of Clinical Endocrinology & Metabolism that showed acute sleep loss – just one night of wakefulness — can lead to alterations in epigenetic and transcriptional profiles of core circadian clock genes in key metabolic tissues, providing a glimpse at some of the pathways linking sleep loss to metabolic changes. The study, by Jonathan Cedernaes, PhD, of Uppsala University in Uppsala, Sweden, et al., concluded that just one night of lost sleep results in hypermethylation of regulatory regions of key clock genes. These effects were 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.
Late last year, Cedernaes and his team published a follow-up in Science Advances that investigates what the possible downstream effects can be on tissue-specific metabolism, since acute sleep loss had different effects on adipose tissue and skeletal muscle. “To gain a more complete picture of how sleep loss adversely may affect metabolism, and whether epigenetic and gene expression changes in these tissues may translate to other tissue-specific molecular levels, we were also interested in investigating concurrent changes to protein and metabolite levels,” Cedernaes says.
We have indeed reached a point where a large set of elegant studies have proven that sleep is important for endocrine health.
Endocrine News caught up with Cedernaes to talk about this current study and its implications not just for people who experience bouts of sleep loss, but what it means for the physicians treating these patients.
Endocrine News: Tell me about the impetus of this study. It seems the healthcare community is paying more and more attention to sleep and endocrine health, but this seems like a novel approach to looking at how sleep loss affects the body. What made you want to look at sleep loss’s effects at the genomic level?
Jonathan Cedernaes: We have indeed reached a point where a large set of elegant studies have proven that sleep is important for endocrine health. However, we know much less about what the underlying mechanisms are. Both skeletal muscle and adipose tissue serve as key metabolic tissues, for instance for handling most of glucose uptake after a meal, and as our long-term energy depot in the case of adipose tissue. They are furthermore increasingly recognized as endocrine organs, as they are able to secrete endocrine factors, known as myokines (from skeletal muscle) and adipokines (from adipose tissue). Additionally, these tissues interact and contribute by separate functions to overall metabolism. Even though we have indirect evidence that these tissues are impacted by sleep loss, e.g. by evidence for impaired insulin sensitivity and alterations in levels of myokines and adipokines, few studies have investigated what happens in the actual tissues themselves. More specifically, at the most fundamental level, the function of these tissues is determined at the genetic level, which itself is controlled by genetic mechanisms such as the circadian clock, and also, inter-relatedly, by epigenetic marks that determine whether genes are turned on or off at specific times of the sleep/wake cycle. Our previous work had suggested that these mechanisms could be altered by acute sleep loss, and that this occurred differently between skeletal muscle and adipose tissue, so we wanted to investigate what the possible downstream effects could be on tissue-specific metabolism.
EN: An interesting phrase that stuck out to me was how sleep loss alters “metabolic memory.” Can you speak a little more to that?
Jonathan Cedernaes: Traditionally, there was the notion that regulation of gene expression occurred through epigenetic mechanisms that were more or less hard-wired from birth, or that may be altered in extreme conditions such as cancer cells, to achieve unrestrained cell growth. An increasing number of studies, especially during the last decade, have however shown that the epigenetic state that controls gene expression can be altered by environmental changes, such as diet, physical exercise, or stress. Since epigenetic changes control gene expression and may persist in an altered state after an initial stressor, alterations to the epigenetic landscape are thought to be able to serve as a memory, which we in the context of metabolic regulation could talk about as a “metabolic memory.” We previously provided the first direct evidence that sleep loss could in and of itself result in epigenetic modifications in humans, and epidemiological data also supports the notion that e.g. shiftwork can lead to epigenetic changes. These include changes to the methylation of DNA, which is one of the mechanisms that determines to which extent certain genes are turned on or off. This is also the type of epigenetic modification that we studied in our present study.
What was really intriguing was that we found that after one night of sleep loss, there were changes to the DNA methylation levels of over 150 genes, and we saw this specifically occur in adipose tissue, compared with after a night of normal sleep in the same participants. Several of these genes have been linked to metabolic regulation and have been found to be altered in metabolic pathologies such as obesity and type 2 diabetes. Epigenetic modifications that have been identified in these conditions have been proposed to serve as a sort of metabolic memory that could be involved in disease pathogenesis by maintaining long-term changes in how genes along key metabolic pathways are expressed. Given that sleep loss is known to adversely impact body weight, body composition, and metabolic homeostasis, it is therefore intriguing to speculate that the type of epigenetic changes we found could be causally involved in the adverse effects linked to disrupted sleep and circadian rhythms.
EN: Tell me about the study and the results themselves. I noticed that you used samples from young men. Was there a reason for that? Do you plan on further studies using samples from women, older men, etc.?
JC: Given that we set out to perform a fairly large set of analyses, each of which is quite expensive, and also are sensitive to inter-individual variation, we wanted to have a sample that was as homogenous as possible, across as many parameters as possible (because, as opposed to studies in mice, which are often inbred and therefore not only genetically identical, we humans will as a general rule always differ on parameters ranging from preferences in diet to childhood environment, which can impact the epigenetic landscape). Studies do continue to demonstrate that the response to sleep loss is modulated by a variety of inter-individual factors, such as age, and even across the menstrual cycle. It will therefore be important to investigate whether our findings translate to older individuals, women across different ages and menstrual phases, individuals of other ethnicities, and whether e.g. dietary and exercise habits can impact the extent to which sleep loss can lead to the tissue-specific responses that we observed in the limited number of individuals we were able to study.
EN: It’s interesting that you were able to see these drastic changes after just one night of sleep loss. That doesn’t seem to bode well for people who suffer from chronic sleep loss. Can you speak more to that?
JC: Since we only studied acute changes, we cannot speak to the long-term implications of our findings. It should however be noted that longitudinal data from numerous studies indicate that chronic sleep loss is associated with a greater risk of obesity, metabolic syndrome, type 2 diabetes and a reduced muscle or lean mass (which occurs with aging after around the year 30, known as sarcopenia). It should also be noted that these associations are just associations, and there are numerous lifestyles that we also know act preventatively to decrease the risk of these conditions, such as a healthy diet and regular physical activity. Thus, while the risk of these conditions increases overall for people who suffer from chronic sleep disruptions, lifestyle choices can at least to some extent counteract these risks.
EN: Since it appears even acute sleep loss can reprogram DNA methylation, is that reversible if someone is able to “correct” their sleeping habits? I see that you wrote it remains to be determined. I was just wondering if you had an opinion.
JC: This is a very interesting question that we would definitely want to see more research on. There are more and more studies coming out that show that properly timed recovery sleep can negate adverse metabolic effects of recurrent sleep loss and disrupted circadian rhythms. This has now for instance been shown for certain metabolic changes, including insulin sensitivity. The results are somewhat mixed, likely because of different study designs, chosen analytical timepoints, and whether or not the recovery sleep due to its timing results in circadian misalignment. Given these observations, it is most likely that also these effects at the DNA methylation can be reversible with enough time for recovery. Furthermore, most if not all people have experienced nights without sleep and still don’t exhibit overt long-term adverse metabolic effects due to this. The issue is of course that a lot of people are suffering from long-term sleep loss, so it will also be interesting to see whether there is a compounding or more persistent effect of such more chronic stressors, and to determine how long recovery should be depending on the duration and extent of chronic sleep loss or circadian disruption as in long-term shiftwork.
For shiftwork, we have data suggesting that long-term shiftwork leads to cognitive impairments, but that these effects are no longer detectable after a couple of years of quitting shiftwork. On the other hand, for epigenetic changes, there is this interesting field of studying biological age depending on DNA methylation of a certain set of epigenetic markers. Research in that field suggests that sleep loss accelerates biological aging at least of blood tissue. Well-controlled experimental studies have also found catching up on weekends may not be enough if you are not getting enough sleep during the week, at least if you want to be at your optimal health. And if you are changing sleep timing from week to weekend, it seems it can actually compound the effects of sleep loss experienced throughout say a “regular” work week. At the same time, thinking back specifically to epigenetic changes, it seems that interventions such as calorie restriction can attenuate the age-associated epigenetic drift (at least in other organisms). This was recently shown in rhesus monkeys, again suggesting that lifestyle interventions can counteract adverse changes to the epigenetic landscape that may occur as a result of sleep loss, and which may interact with the aging process.
EN: Can you talk a little more about the implications of this study? Chronic sleep loss and shift work aren’t always easy things to correct, especially today. What should physicians take away from this and be telling their patients?
JC: One implication that isn’t necessarily specific to our study, but just from the field in general, is that sleep – as well as its timing – is important to take into account when evaluating a patient. We and others have now together gathered very strong evidence to show that insulin sensitivity is adversely impacted by both acute and chronic sleep loss as well as by circadian disruption (as experienced by shift workers). For a clinician, it is also relevant that sleep is important for so many other aspects of a patient’s cognitive and somatic health (such as cardiovascular health and memory functions).
One important message is that clinicians should always consider and inquire about their patients’ sleep habits. This is important for properly being able to evaluate their patient’s current health status, when interpreting parameters such as insulin sensitivity, blood pressure and immune status, but also for evaluating their long-term health risks, especially in people who already are at greater risk of impaired metabolic state, such as patients suffering from type 2 diabetes. It’s important to think of sleep as one out of several key lifestyle factors that influence long term health. This means that if an individual has to carry out shiftwork and to some extent suffer from chronic sleep loss over limited time periods, physicians should try to encourage individuals to make as many other healthy lifestyle choices as possible, such as getting daily physical exercise and adopting a healthy diet.
A final but another very important note, is related to the fact that physicians also are highly involved in educating the next generation of medical doctors. It is important to encourage physicians to promote education and consideration about the importance of sleep and circadian biology throughout medical school, especially as students today often get very limited information about how sleep and circadian rhythms can modulate mental and somatic health.
EN: Last time we spoke, you talked about smart devices giving insight into our sleeping habits. What kind of data have you seen from these devices since then?
JC: Everything from activity trackers to social media are increasingly being used in research to actively and passively (e.g. over Twitter) track people’s sleeping habits. There’s even been an entire paper published on the current President’s tweeting habits in a very reputable journal. The great things about apps is that there’s been this mutual exchange: some have been designed to help people, e.g. to cope with jetlag prior to, during and immediately after traveling over multiple time zones, but at the same time, these apps have enabled the collection of users’ data to for example track their sleeping habits. This has also allowed for really interesting interventions. In one study, researchers found that by restricting the time when participants ate during the day, participants were able to lose weight more effectively, reduce their “metabolic social jetlag” and improve in subjective sleep satisfaction and energy level.
It is important to encourage physicians to promote education and consideration about the importance of sleep and circadian biology throughout medical school, especially as students today often get very limited information about how sleep and circadian rhythms can modulate mental and somatic health.
Another study has been able to use several thousand subjects’ data to reveal how sleep differs between sexes and across the lifespan in humans. While sleep researchers don’t encourage late social media use, the data is out there and continues to grow. For instance, Twitter data has been used to show how sleep habits of American citizens varies between working days and weekends and has also been able to reflect changes in mood that occur across the day and night. This data has also revealed “seasonal effects,” most of which appeared not to be based on seasonal differences in dusk and dawn timing, but rather on social structures, such as when the school holiday occurs. The findings in this case were that social jet lag as assessed by Twitter activity is lower during the summer, perhaps because parents don’t have to set the alarm clocks early or school days. This finding of socially induced jet lag – social jet lag – reinforces the notion that we still in many instances can improve work and school schedules, to reduce circadian misalignment and sleep debt that is accrued during the week’s work and school days.