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Metabolomic Study Profiles Daily Metabolite Variations, Changes During Sleep Deprivation

NEW YORK (GenomeWeb) – Most plasma metabolites follow a daily rhythm in their expression levels that is muted by sleep deprivation, according to a metabolomic study appearing in the Proceedings of the National Academy of Sciences today.

Researchers led by the University of Surrey's Debra Skene collected plasma samples from a dozen healthy research participants and examined their metabolite levels during a normal sleep-wake cycle and during 24 hours of wakefulness.

Based on their liquid chromatography/mass spectrometry characterization of the plasma metabolites, the researchers found that while most metabolites had reduced amplitudes of their daily rhythm during 24 hours of wakefulness, the levels of metabolites like acylcarnitines, serotonin, tryptophan, and taurine increased during sleep deprivation.

"Determining the full impact of exogenous factors such as sleep on the metabolome will be crucial for the future metabolic profiling-based identification of biomarkers of disease and drug effects," Skene and her colleagues wrote in their paper.

There is, the researchers noted, a link between the circadian clock and metabolism, and disrupted circadian rhythms and sleep deprivation have been linked to metabolic disorders such as obesity, diabetes, and cardiovascular disease. Meanwhile, acute sleep deprivation has been found to have an anti-depressive effect.

Skene and her colleagues drew plasma samples every two hours from their cohort of 12 healthy male participants during both a day of a normal sleep-wake cycle and then during 24 hours of wakefulness.

Using an untargeted LC/MS metabolomics approach, Skene and her colleagues identified 367 metabolite features for each sample. A principal components analysis of the data showed time-of-day variation for these features that fit to a cosine curve for the first day. For the second sleep deprivation day, the researchers noted, the metabolites followed the same pattern, but there was a 14 percent reduction in consignor amplitude.

Those 367 metabolites, they added, included acylcarnitines, amino acids, and cortisol, among others. Eight of the 14 acylcarnitines identified, the researchers said, were present at different levels between sleep and sleep deprivation.

Meanwhile, a targeted approach using the Biocrates AbsoluteIDQ p180 kit, which identifies and quantifies some 180 metabolites from a variety of compound classes also indicated time-of-day variation in the metabolome that fit to a cosine curve. For this set of metabolites, they noted a 24 percent reduction in consignor amplitude between sleep and sleep deprivation.

Of these 171 metabolites, 27 were significantly different between the sleep and sleep deprivation periods and not during the wake conditions. These metabolites, which included serotonin, taurine, tryptophan, and a number of acylcarnitines, among others, were present at increased levels.

Skene and her colleagues speculated that sleep might have an inhibitory effect on the synthesis of these metabolites or a stimulatory effect on their degradation.

Serotonin, the researchers noted, is known to be involved in the regulation of the sleep-wake cycle. They further suggested that the increased levels of serotonin during a night's sleep deprivation could be the mechanism through which acute sleep deprivation has its antidepressive effect.

Tryptophan, taurine, and melatonin, they added, were also increased during sleep deprivation, and they, too, are linked to depression, its treatment, or the serotonin pathway.

"Whether the antidepressive effect of acute sleep deprivation is linked to the increased circulating levels of tryptophan, serotonin, taurine, and melatonin deserves further study," Skene and her colleagues said.

Additionally, nine acylcarnitines had increased levels during sleep deprivation as compared to during sleep. Eight of those were medium- or long-chain saturated acylcarnitines, a finding which the researchers said supported the notion that the carnitine system and fatty acid oxidation play a role in regulating sleep and wakefulness.

As most plasma metabolite levels varied over the course of the day, the researchers said that such oscillations should be taken into account when studying and treating disease.

"Our results show that if we want to develop a diagnostic test for a disease, it is imperative to take the time of day when taking blood samples into account, since this has a significant effect on metabolism," Skene said in a statement. "This is also key for administering medicines and determining when they will be at their most effective.

"Of course, this will have to be considered on a case-by-case basis, since many people such as shift workers will have a different sleep/wake cycle and timings will need to be adapted to their body clocks," she added.

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