Measurement of internal body time by blood metabolomics

Minami, Yoichi; Kasukawa, Takeya; Kakazu, Yuji; Iigo, Masayuki; Sugimoto, Masahiro; Ikeda, Satsuki; Yasui, Akira; Horst, Gijsbertus T. J. van der; Soga, Tomoyoshi; Ueda, Hiroki R.

doi:10.1073/pnas.0900617106

Cited by 247 publications

(192 citation statements)

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“…3A and B-blue shading). Metabolomics indicate that approximately 20% of metabolites fluctuate with a circadian variation [69][70][71]. Blood glucose levels undergo time-of-day variation in humans and rodent models [72].…”

Section: Clocks and Metabolismmentioning

confidence: 99%

Immunometabolism: Is it under the eye of the clock?

Early

Curtis

2016

Seminars in Immunology

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Section: Clocks and Metabolismmentioning

confidence: 99%

Immunometabolism: Is it under the eye of the clock?

Early

Curtis

2016

Seminars in Immunology

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“…20 Furthermore, a recent study using blood metabolome analysis revealed that hundreds of metabolites in mouse plasma show robust circadian oscillation. 21 Third, and more interestingly, recent studies demonstrated that transcriptional coactivators play a critical role in the integration of clock and metabolic functions. PPAR-c coactivator-1a (PGC-1a), an important metabolic coactivator, modulates circadian clocks and energy metabolism simultaneously through coactivating RORs.…”

mentioning

confidence: 99%

SWItch/sucrose nonfermentable (SWI/SNF) complex subunit BAF60a integrates hepatic circadian clock and energy metabolism

et al. 2011

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Many aspects of energy metabolism, including glucose and lipid homeostasis and mitochondrial oxidative metabolism, are under precise control by the mammalian circadian clock. However, the molecular mechanism for coordinate integration of the circadian clock and various metabolic pathways is poorly understood. Here we show that BAF60a, a chromatin-remodeling complex subunit, is rhythmically expressed in the liver of mice. Mice with liver-specific knockdown of BAF60a show abnormalities in the rhythmic expression pattern of clock and metabolic genes and in the circulating metabolite profile. Consistently, knockdown of BAF60a impairs the oscillation of clock genes in serum-shocked HepG 2 cells. At the molecular level, BAF60a activates Bmal1 and G6Pase transcription by way of the coactivation of retinoid-related orphan receptor alpha (RORa). In addition, BAF60a is present near ROR response elements (RORE) on the proximal Bmal1 and G6Pase promoters and turns the chromatin structure into the active state. Conclusion: Our data suggest a critical role for BAF60a in the coordinated regulation of hepatic circadian clock and energy metabolism in mammals. (HEPATOLOGY 2011;54:1410-1420 M any physiological events in mammals, including locomotor activity, sleep, blood pressure, circulating hormones, and energy metabolism show diurnal fluctuation. 1,2 These intrinsic biological rhythms are mainly entrained by light-dark (LD) and feeding cycles. The mammalian master clock resides in the hypothalamic suprachiasmatic nucleus (SCN) and drives slave oscillators distributed in various peripheral tissues through behavioral and neuroendocrine signals. However, Damiola et al. 3 found that peripheral oscillators can be uncoupled and reset from the central pacemaker by restricted feeding. Their findings are supported by the subsequent report showing that restricted feeding entrains the circadian rhythms in peripheral tissues, dominantly in the liver, but leaving SCN rhythms unaffected. 4 Also, both food availability and the temporal pattern of feeding determine the repertoire, phase, and amplitude of the circadian transcriptome in mouse liver. 5 All these studies indicate that nutritional signals play a dominant role in the regulation of peripheral clock function. At the molecular level, Clock and Bmal1 are two basic helix-loop-helix transcription factors that activate the transcription of period (Per) and cryptochrome (Cry) genes. 6 Per and Cry proteins in turn inhibit their own expression by repressing Clock/Bmal1 activity, forming the critical feedback loop within the clock circuitry. In addition, the orphan nuclear receptors of the ROR and Rev-erb families are also implicated in the control of circadian clock function. 7,8 Abbreviations: ChIP, chromatin immunoprecipitation; CO, carbon monoxide; CoIP, coimmunoprecipitation; GFP, green fluorescent protein; GR, glucocorticoid receptor; H3K4me3, trimethylation of lysine 4 of histone 3; H3K9me2, dimethylation of lysine 9 of histone 3; HAT, histone acetyltransferase; HDAC, histone deacetyla...

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“…In mammals, for example, several clock genes regulate circadian gene expression in central and peripheral clock tissues (3)(4)(5)(6)(7)(8)(9), as well as metabolites in the blood (10)(11)(12)(13)(14)(15). Reflecting circadian regulation of such processes, the potency and toxicity of administered drugs depends on an individual's body time (BT) (16)(17)(18)(19)(20)(21)(22).…”

mentioning

confidence: 99%

“…One conventional way to estimate human internal body time is to periodically sample for more than 24 h the level of melatonin or cortisol, which have robust circadian oscillations in the blood (10)(11)(12). Although this strategy directly measures internal body time, it requires labor-intensive constant sampling under controlled environmental conditions to reveal metabolite peaks and rhythms.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Human blood metabolite timetable indicates internal body time

Kasukawa

Sugimoto

Hida

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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A convenient way to estimate internal body time (BT) is essential for chronotherapy and time-restricted feeding, both of which use body-time information to maximize potency and minimize toxicity during drug administration and feeding, respectively. Previously, we proposed a molecular timetable based on circadian-oscillating substances in multiple mouse organs or blood to estimate internal body time from samples taken at only a few time points. Here we applied this molecular-timetable concept to estimate and evaluate internal body time in humans. We constructed a 1.5-d reference timetable of oscillating metabolites in human blood samples with 2-h sampling frequency while simultaneously controlling for the confounding effects of activity level, light, temperature, sleep, and food intake. By using this metabolite timetable as a reference, we accurately determined internal body time within 3 h from just two anti-phase blood samples. Our minimally invasive, moleculartimetable method with human blood enables highly optimized and personalized medicine.metabolomics | circadian rhythm | liquid chromatography mass spectrometry | diagnostic tool M any organisms possess a molecular time-keeping mechanism, a circadian clock, which has endogenous, self-sustained oscillations with a period of about 24 h. Circadian regulation of cell activity occurs in diverse biological processes such as electrical activity, gene/protein expression, and concentration of ions and substances (1, 2). In mammals, for example, several clock genes regulate circadian gene expression in central and peripheral clock tissues (3-9), as well as metabolites in the blood (10-15). Reflecting circadian regulation of such processes, the potency and toxicity of administered drugs depends on an individual's body time (BT) (16)(17)(18)(19)(20)(21)(22). Drug delivery according to body time improves the outcome of pharmacotherapy by maximizing potency and minimizing toxicity (23), and administrating drugs at an inappropriate body time can result in severe side effects (22). For example, rhythm disturbances were induced by administration of IFN-α during the early active phase in mice, although unaffected during the early rest phase (22); and the time of administration of two anticancer drugs, adriamycin (6:00 AM) and cisplatin (6:00 PM), made a lower toxicity effect than its antiphasic administration (24). However, several reports showed that internal body time varies by 5-6 h in healthy humans (25, 26) and as much as 10-12 h in shift workers without forced entrainments (27,28). Therefore, for efficient application of body-time drug delivery or "chronotherapy" (16-20) in a clinical setting, a simple and robust method for estimating an individual's internal body time is needed.Additionally, the timing of food intake may contribute to weight gain (29) and metabolic disease (30) because energy regulation and circadian rhythms are molecularly and physiologically intertwined (31-41). For example, mice fed a high-fat diet during a 12-h light phase gain significantly more ...

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Measurement of internal body time by blood metabolomics

Cited by 247 publications

References 44 publications

Immunometabolism: Is it under the eye of the clock?

Immunometabolism: Is it under the eye of the clock?

SWItch/sucrose nonfermentable (SWI/SNF) complex subunit BAF60a integrates hepatic circadian clock and energy metabolism

Human blood metabolite timetable indicates internal body time

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