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Identification of Human Plasma Metabolites Exhibiting Time-of-Day Variation Using an Untargeted Liquid Chromatography–Mass Spectrometry Metabolomic Approach
Open accessAbstract
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. (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]
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“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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Metadata
- 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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