Effects of Sleep Deprivation on the Human Metabolome

The negative effects of sleep deprivation on brain activity and performance in cognitive tasks have been studied for generations. However, loss of sleep also has a significant impact on the manifestation of various diseases and metabolic disorders (obesity, diabetes) and cardiovascular disease. This is why for this assignment I have picked a paper that focuses on the effect of acute sleep deprivation on metabolomic profiles of patients (Davies et. al. 2014).

The study used untargeted and targeted liquid chromatography (LC)/MS metabolomics to examine the effect of acute sleep deprivation on plasma metabolite rhythms. Characterization of plasma metabolites has revealed that lipid and acylcarnitine levels were significantly increased during acute sleep deprivation. Overall, 27 metabolites (tryptophan, serotonin, taurine, 8 acylcarnitines, 13 glycerophospholipids, and 3 sphingolipids) were increased after 24 hours of wakefulness. The levels of all metabolites changed during the 24 h wake/sleep cycle and clear daily rhythms were observed in most cases. Moreover, these rhythms were less apparent after 24 hours of wakefulness, which speaks to the significance of sleep for metabolic processes.

The significance of this study is enhanced by the fact that this is the first study focused on characterization of the 24 h rhythms of metabolic processes during the wake/sleep cycle and the changes occuring during the wakefulness period. There have been previous studies which used transcriptomic data to show that rhythmic gene expression may be affected by sleep deprivation or sleep restriction. However, metabolic profiling studies are best used for the purpose of characterising changes in specific molecular phenotypes associated with sleep deprivation (rather than inferring the changes in the metabolome from the transcriptome).

Participants

For the purpose of this study, twelve healthy young males were selected and monitored in carefully controlled laboratory conditions. The controlled variables included environmental light, sleep, meals, and posture during a 24-h wake/sleep cycle, followed by 24 h of wakefulness.

Method

The present study uses liquid chromatography-mass spectrometry (LC-MS) to ascertain the concentrations of plasma metabolites and link the changes in these concentration to the wake/sleep cycle rhythms.

As suggested in the name, LC-MS combines the physical separation of molecules using liquid chromatography with the mass analysis capabilities of mass spectrometry (MS). The coupling of the two technologies provides higher accuracy in identification of structural identity of the individual components with high molecular specificity and detection sensitivity.

In the first step (liquid chromatography) solubilized compounds are passed through a column packed with a stationary phase. The needed molecules in the mobile phase (which have the affinity for the stationary phase) get stuck on the solid stationary phase, while other molecules pass through the column freely. This effectively separates out the needed compounds based on their weight and affinity. LC is usually used the separate large non-volatile molecules such as proteins.

However, the accuracy of this separation is not high enough for some purposes (for example for identifying isomers). This is where the next step, mass spectrometry, comes in.

The sample passes into the vacuum chamber of the mass spectrometer. In simple terms, a mass spectrum measures the masses of molecules within a sample. Mass spectrometry allows to provide structural identity the the individual components of the product that has already been filtered using LC.

There is also a modification of LC, which is called HPLC (high performance liquid chromatography). The idea behind this method is using a higher pressure ranging from 50-350 bar to separate out the molecules.

Findings

An unexpected result of this study is that in comparison with the number of ions and metabolites showing time-of-day rhythms (basically significant changes in expression of these metabolites during the day), fewer ions/metabolites were significantly changed when comparing the normal wake/sleep cycle to the 24 h during sleep deprivation (only 27 metabolites out of 171 were significantly different between the sleep and sleep-deprivation periods). All of these metabolites were increased during the sleep deprivation phase of the experiment, so it is possible that sleep has an inhibitory effect on synthesis of these metabolites.

One of the metabolites which has shown increased levels after a 24 h wakefulness period is serotonin. This is an important finding because serotonin is known to be involved in both sleep cycle regulation and depression. Low levels of serotonin and reduced serotonergic neurotransmission are strongly associated with major depressive disorder, so if sleep deprivation over a short period of time (24 h) has shown to increase serotonin levels, this might provide a new avenue of clinical research.

The amino acid tryptophan, which is vital for the formation of serotonin and melatonin, has shown significantly increased levels during acute sleep deprivation. This is in line with previous studies, which have indicated that tryptophan is an effective cure for major depressive disorder.

It may be possible that the antidepressive effect of acute sleep deprivation is linked to the increased circulating levels of tryptophan, serotonin, taurine, and melatonin, and this subject deserves further investigation.

Limitations

The protocol described in the study allows identification of only metabolites that show increase or decrease in levels after a short period of time (less than 24 h) and do not show the changes in levels which occur over longer periods of sleep deprivation (longer than 24 h) or during repeated sleep deprivation (chronic partial sleep deprivation).

Future applications

Sleep deprivation has been previously shown to have an antidepressant effect. In line with this, the authors observed increased levels if serotonin, tryptophan and taurine after 24 hours of wakefulness. Therefore, the results of this study may have potential application in diagnostics and treatment of major depressive disorder, and perhaps even a series of related conditions, such as depressive disorders (seasonal affective disorder, bipolar disorder, psychotic depression, postpartum depression).

In general, the metabolomics approach presented in the paper is a step toward understanding the metabolic pathways involved in regulation of the sleep/wake cycle. Determination of the impact of factors such as sleep on the metabolome could lead to future metabolic profiling-based studies aimed at identification of biomarkers of disease and drug effects.

Conclusion

The study has presented a n implementation of a method for identification of plasma metabolites that were significantly altered during acute sleep deprivation. It has been shown that 27 metabolites (mainly lipids and acylcarnitines, serotonin, tryptophan, and taurine) were increased during sleep deprivation.

This study has provided me with some insight into why I might be able to not sleep for short periods of time, such as a 24h period investigated in the study. I myself do not know anyone who tried treatment of major depressive disorder using sleep deprivation, and the fact the people I do know that have it have told me that during the acute phase of MDD they tend to fall asleep for long periods of time and in generally sleep no less than 12 hours. It may be possible that this is in fact directly link to the cause for their disorder, and it is possible that the method suggested in this paper would help them.

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