Diurnal rhythms in the human urine metabolome during sleep and total sleep deprivation

Abstract

Understanding how metabolite levels change over the 24 hour day is of crucial importance for clinical and epidemiological studies. Additionally, the association between sleep deprivation and metabolic disorders such as diabetes and obesity requires investigation into the links between sleep and metabolism. Here, we characterise time-of-day variation and the effects of sleep deprivation on urinary metabolite profiles. Healthy male participants (n = 15) completed an in-laboratory study comprising one 24 h sleep/wake cycle prior to 24 h of continual wakefulness under highly controlled environmental conditions. Urine samples were collected over set 2–8 h intervals and analysed by 1H NMR spectroscopy. Significant changes were observed with respect to both time of day and sleep deprivation. Of 32 identified metabolites, 7 (22%) exhibited cosine rhythmicity over at least one 24 h period; 5 exhibiting a cosine rhythm on both days. Eight metabolites significantly increased during sleep deprivation compared with sleep (taurine, formate, citrate, 3-indoxyl sulfate, carnitine, 3-hydroxyisobutyrate, TMAO and acetate) and 8 significantly decreased (dimethylamine, 4-DTA, creatinine, ascorbate, 2-hydroxyisobutyrate, allantoin, 4-DEA, 4-hydroxyphenylacetate). These data indicate that sampling time, the presence or absence of sleep and the response to sleep deprivation are highly relevant when identifying biomarkers in urinary metabolic profiling studies.

TrimethylamineN-oxide and prognosis in acute heart failure

“…Sample collections for TMAO analyses were not strictly time-controlled due to emergency admission procedures. Urinary levels are subject to time variation,26 although time variability in blood is currently unknown. Other factors (eg, time since last meal or urination) may alter the relationship of TMAO to renal metabolites and these data would be additive in future experiments.…”

Time is ripe: maturation of metabolomics in chronobiology

“…Figure 2 and Supplemental Table 1 summarize the results from nine key human chronobiology metabolomics studies[12–20] which have identified carnitines, aromatic amino acids, phosphatidylcholines and lysophosphatidylcholines as substantially enriched overlapping metabolite classes that oscillate across circadian time and are perturbed in sleep disruption studies (Figure 2). This evidence would suggest a significant interaction of circadian rhythms and sleep with metabolism through fatty acid metabolism, possibly for both energetic homeostasis via acylcarnitine oxidation and signaling roles that phoshatidylcholines may exert in and across tissues.…”

“…In human biomarker studies, NMR has been used to probe time-of-day variation in saliva metabolic profiles[26] and under different sleep conditions in urine [20]. NMR can be used quantitatively as a rapid and robust primary filter for analyzing circadian oscillations in polar metabolite rich systems.…”

Molecular Mechanisms of Sleep Homeostasis in Flies and Mammals

“…Recent work has identified plasma metabolites altered by either total sleep deprivation or sleep restriction in human subjects (Giskeodegard et al 2015;Weljie et al 2015). Several metabolites were common to the two protocols; both revealed an increase in lipids and in polar metabolites, and indicated a generally oxidized environment.…”