Abstract
Establishing circadian and wake-dependent changes in the human metabolome are critical for understanding and treating human diseases due to circadian misalignment or extended wake. Here, we assessed endogenous circadian rhythms and wake-dependent changes in plasma metabolites in 13 participants (4 females) studied during 40-hours of wakefulness. Four-hourly plasma samples were analyzed by hydrophilic interaction liquid chromatography (HILIC)-LC-MS for 1,740 metabolite signals. Group-averaged (relative to DLMO) and individual participant metabolite profiles were fitted with a combined cosinor and linear regression model. In group-level analyses, 22% of metabolites were rhythmic and 8% were linear, whereas in individual-level analyses, 14% of profiles were rhythmic and 4% were linear. We observed metabolites that were significant at the group-level but not significant in a single individual, and metabolites that were significant in approximately half of individuals but not group-significant. Of the group-rhythmic and group-linear metabolites, only 7% and 12% were also significantly rhythmic or linear, respectively, in ≥50% of participants. Owing to large inter-individual variation in rhythm timing and the magnitude and direction of linear change, acrophase and slope estimates also differed between group- and individual-level analyses. These preliminary findings have important implications for biomarker development and understanding of sleep and circadian regulation of metabolism.
Highlights
Circadian rhythms, endogenously generated cycles of approximately 24 hours, govern many patterns of behavior and physiology including sleep/wake cycles, cognition, feeding patterns, hormone secretion, gene expression and cellular processes
Circadian and wake-dependent modulation of plasma polar metabolites was investigated in 13 healthy adults (4 females) aged 20–32 years (Table 1), who underwent a 40-hour constant routine (CR) protocol (Fig. 1)
Our study presents the first evidence of circadian- and wake-dependent modulation of polar metabolites over the course of 40-hours of extended wakefulness
Summary
Endogenously generated cycles of approximately 24 hours, govern many patterns of behavior and physiology including sleep/wake cycles, cognition, feeding patterns, hormone secretion, gene expression and cellular processes. Analysis of individual metabolomic profiles, has shown substantial inter-individual differences in the timing and abundance of rhythmic lipids and in the magnitude and direction of change in lipids that increase or decrease with time awake[18,19]. Despite this variability, many of the studies published to date have only conducted group-level analyses, which given the underlying inter-individual variation, may not accurately describe circadian and wake-dependent control of metabolite levels. Changes to metabolite levels were subsequently assessed using both group- and individual-level analyses to observe the degree of concordance between these analysis approaches
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