Identification of Human Plasma Metabolites Exhibiting Time-of-Day Variation Using an Untargeted Liquid Chromatography–Mass Spectrometry Metabolomic Approach
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Although daily rhythms regulate multiple aspects of human physiology, rhythmic control of the metabolome remains poorly understood. The primary objective of this proof-of-concept study was identification of metabolites in human plasma that exhibit significant 24-h variation. This was assessed via an untargeted metabolomic approach using liquid chromatography-mass spectrometry (LC-MS). Eight lean, healthy, and unmedicated men, mean age 53.6 (SD ± 6.0) yrs, maintained a fixed sleep/wake schedule and dietary regime for 1 wk at home prior to an adaptation night and followed by a 25-h experimental session in the laboratory where the light/dark cycle, sleep/wake, posture, and calorific intake were strictly controlled. Plasma samples from each individual at selected time points were prepared using liquid-phase extraction followed by reverse-phase LC coupled to quadrupole time-of-flight MS analysis in positive ionization mode. Time-of-day variation in the metabolites was screened for using orthogonal partial least square discrimination between selected time points of 10:00 vs. 22:00 h, 16:00 vs. 04:00 h, and 07:00 (d 1) vs. 16:00 h, as well as repeated-measures analysis of variance with time as an independent variable. Subsequently, cosinor analysis was performed on all the sampled time points across the 24-h day to assess for significant daily variation. In this study, analytical variability, assessed using known internal standards, was low with coefficients of variation <10%. A total of 1069 metabolite features were detected and 203 (19%) showed significant time-of-day variation. Of these, 34 metabolites were identified using a combination of accurate mass, tandem MS, and online database searches. These metabolites include corticosteroids, bilirubin, amino acids, acylcarnitines, and phospholipids; of note, the magnitude of the 24-h variation of these identified metabolites was large, with the mean ratio of oscillation range over MESOR (24-h time series mean) of 65% (95% confidence interval [CI]: 49-81%). Importantly, several of these human plasma metabolites, including specific acylcarnitines and phospholipids, were hitherto not known to be 24-h variant. These findings represent an important baseline and will be useful in guiding the design and interpretation of future metabolite-based studies.
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Ang et al. found 25 of 34 lipid species, with lysoPCs 18:2 and 20:3, acylcarnitine 12:0 and 18:0, and phenylalanine overlapping with this study.
“Ang et al. (13) found 25 of 34 to be lipid species, with lysoPCs (18:2, 20:3) acylcarnitine (12:0 and 18:0) and Phe overlapping with our results.”
From Oxalic acid and diacylglycerol 36:3 are cross-species markers of sleep debt (2015) · cites this paper as [13]
Up to 20% of detectable metabolites in human matrices such as plasma and saliva exhibit daily rhythms.
“In addition to these mouse studies, human metabolome analyses also reveal that up to 20% of detectable metabolites in matrices such as plasma and saliva exhibit daily rhythms (44)(45)(46).”
From Circadian rhythms, metabolism, and chrononutrition in rodents and humans (2016) · cites this paper as [45]
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- Authors
- Ang, J. E., Revell, V., Mann, A., Mäntele, S., Otway, D. T., Johnston, J. D., Thumser, A. E., Skene, D. J., & Raynaud, F.
- Affiliations
- Institute of Cancer Research (GB)
- University of Surrey (GB)
- Corresponding author
- Ang, Joo Ern
- Raynaud, Florence
- ORCID
- Venue
- Chronobiology International
- Publisher
- Informa UK Limited
- Published
- 2012-07-23
- Volume
- 29
- Issue
- 7
- Pages
- 868-881
- ISSN
- 0742-0528 (ISSN-L)
- 1525-6073
- PMC
- PMC3433180
- OpenAlex
- W2043615829
- Cited by
- 138
- References
- 35
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 8 · 2023: 14 · 2022: 12 · 2021: 14 · 2020: 14 · 2019: 9 · 2018: 8 · 2017: 10 · 2016: 12 · 2015: 13 · 2014: 9 · 2013: 4
- FWCI
- 3.47
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- cc-by
- Locations
- Chronobiology International (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Surrey Research Insight Open Access (The University of Surrey) (submittedVersion)
- Funders
- Wellcome Trust (090952/Z/09/Z)
- Cancer Research UK (11566, C309/A8274, C309/A2187)
- Biotechnology and Biological Sciences Research Council (BB/I019405/1, BB/D526853/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Sleep and Work-Related Fatigue
- Keywords
- circadian rhythm, diurnal variation, plasma metabolites, acylcarnitines, phospholipids, corticosteroids, bilirubin, amino acids, daily rhythms, cosinor analysis, untargeted metabolomics, sleep timing, metabolite identification
- MeSH terms
- Acetylcarnitine, Blood Chemical Analysis, Chromatography, Liquid, Circadian Rhythm, Humans, Hydrocortisone, Lysophospholipids, Male, Middle Aged, Proline, Mass Spectrometry, Metabolomics, Metabolome
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