Separation of circadian- and behavior-driven metabolite rhythms in humans provides a window on peripheral oscillators and metabolism.

🥈 Top 2% JournalJul 12, 2018Proceedings of the National Academy of Sciences of the United States of America

Separating daily body clock and behavior effects on human metabolite rhythms reveals how body organs keep time and manage metabolism

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Abstract

Nearly 95% of metabolites with a 24-h rhythmicity were influenced by external behavioral time cues during a simulated night-shift schedule.

Misaligned sleep/wake and feeding/fasting cycles may disturb peripheral clock functions.
A total of 132 circulating metabolites were analyzed for rhythmicity during a 24-h constant routine.
Approximately half of the metabolites exhibited 24-h rhythmicity under constant routine after both simulated shift schedules.
Traditional circadian markers such as melatonin and cortisol maintained stable phase alignment regardless of shift schedule.
Many metabolites showed altered rhythms, including reversed rhythms or loss of rhythmicity, particularly after the night-shift schedule.

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Misalignment between internal circadian rhythmicity and externally imposed behavioral schedules, such as occurs in shift workers, has been implicated in elevated risk of metabolic disorders. To determine underlying mechanisms, it is essential to assess whether and how peripheral clocks are disturbed during shift work and to what extent this is linked to the central suprachiasmatic nuclei (SCN) pacemaker and/or misaligned behavioral time cues. Investigating rhythms in circulating metabolites as biomarkers of peripheral clock disturbances may offer new insights. We evaluated the impact of misaligned sleep/wake and feeding/fasting cycles on circulating metabolites using a targeted metabolomics approach. Sequential plasma samples obtained during a 24-h constant routine that followed a 3-d simulated night-shift schedule, compared with a simulated day-shift schedule, were analyzed for 132 circulating metabolites. Nearly half of these metabolites showed a 24-h rhythmicity under constant routine following either or both simulated shift schedules. However, while traditional markers of the circadian clock in the SCN-melatonin, cortisol, andexpression-maintained a stable phase alignment after both schedules, only a few metabolites did the same. Many showed reversed rhythms, lost their rhythms, or showed rhythmicity only under constant routine following the night-shift schedule. Here, 95% of the metabolites with a 24-h rhythmicity showed rhythms that were driven by behavioral time cues externally imposed during the preceding simulated shift schedule rather than being driven by the central SCN circadian clock. Characterization of these metabolite rhythms will provide insight into the underlying mechanisms linking shift work and metabolic disorders. PER3

Key numbers

65 of 132

Rhythmicity

Significant 24-h rhythmicity during constant routine under either or both shift conditions.

Stable

that retained stable peak times after both day- and night-shift schedules.

62 of 132

Altered Rhythms

showing changes in timing following simulated night work.

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Abstract

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