Circadian and wake-dependent changes in human plasma polar metabolites during prolonged wakefulness: A preliminary analysis

• Published in: Scientific reports Vol. 9; no. 1; p. 4428
• Main Authors: Grant, Leilah K., Ftouni, Suzanne, Nijagal, Brunda, De Souza, David P., Tull, Dedreia, McConville, Malcolm J., Rajaratnam, Shantha M. W., Lockley, Steven W., Anderson, Clare
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14-03-2019; Nature Publishing Group
• Subjects: 692/163/2743/2037; 692/308/53/2423; Adult; Circadian rhythm; Circadian Rhythm - physiology; Circadian rhythms; Female; Humanities and Social Sciences; Humans; Lighting; Liquid chromatography; Male; Metabolites; Metabolome; multidisciplinary; Plasma - metabolism; Science; Science (multidisciplinary); Sleep; Sleep - physiology; Sleep and wakefulness; Sleep Disorders, Circadian Rhythm - metabolism; Sleep Disorders, Circadian Rhythm - pathology; Wakefulness - physiology; Young Adult
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-40353-8

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.