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Crosstalk between metabolism and circadian clocks

Nature Reviews Molecular Cell Biology volume 20, pages 227–241 (2019)Cite this article

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Abstract

Humans, like all mammals, partition their daily behaviour into activity (wakefulness) and rest (sleep) phases that differ largely in their metabolic requirements. The circadian clock evolved as an autonomous timekeeping system that aligns behavioural patterns with the solar day and supports the body functions by anticipating and coordinating the required metabolic programmes. The key component of this synchronization is a master clock in the brain, which responds to light–darkness cues from the environment. However, to achieve circadian control of the entire organism, each cell of the body is equipped with its own circadian oscillator that is controlled by the master clock and confers rhythmicity to individual cells and organs through the control of rate-limiting steps of metabolic programmes. Importantly, metabolic regulation is not a mere output function of the circadian system, but nutrient, energy and redox levels signal back to cellular clocks in order to reinforce circadian rhythmicity and to adapt physiology to temporal tissue-specific needs. Thus, multiple systemic and molecular mechanisms exist that connect the circadian clock with metabolism at all levels, from cellular organelles to the whole organism, and deregulation of this circadian–metabolic crosstalk can lead to various pathologies.

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Fig. 1: Transcriptional and metabolic circadian oscillators.
Fig. 2: Entrainment of the clock by light and food.
Fig. 3: Circadian control of mitochondria.
Fig. 4: Cellular circadian metabolism of glucose and feedback of metabolism on the cellular clock.

References

  1. Teleman, A. A. Metabolism meets development at Wiston House. Development 143, 3045–3049 (2016).

    CAS  PubMed  Google Scholar 

  2. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    CAS  PubMed  Google Scholar 

  3. Lopez-Otin, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. DeBerardinis, R. J. & Thompson, C. B. Cellular metabolism and disease: what do metabolic outliers teach us? Cell 148, 1132–1144 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Le Loir, Y., Baron, F. & Gautier, M. Staphylococcus aureus and food poisoning. Genet. Mol. Res. 2, 63–76 (2003).

    PubMed  Google Scholar 

  6. Reinke, H. & Asher, G. Circadian clock control of liver metabolic functions. Gastroenterology 150, 574–580 (2016).

    PubMed  Google Scholar 

  7. Pittendrigh, C. S. & Bruce, V. G. in Rhythmic and Synthetic Processes in Growth (eds Pittendrigh, C. S. et al.) 75–110 (Princeton Univ. Press, 1957).

  8. Neufeld-Cohen, A. et al. Circadian control of oscillations in mitochondrial rate-limiting enzymes and nutrient utilization by PERIOD proteins. Proc. Natl Acad. Sci. USA 113, E1673–E1682 (2016).

    CAS  PubMed  Google Scholar 

  9. Lamia, K. A., Storch, K. F. & Weitz, C. J. Physiological significance of a peripheral tissue circadian clock. Proc. Natl Acad. Sci. USA 105, 15172–15177 (2008).Demonstration of clock-orchestrated interplay of multiple organs in glucose homeostasis.

    CAS  PubMed  Google Scholar 

  10. Borbely, A. A., Daan, S., Wirz-Justice, A. & Deboer, T. The two-process model of sleep regulation: a reappraisal. J. Sleep Res. 25, 131–143 (2016).

    PubMed  Google Scholar 

  11. Greenham, K. & McClung, C. R. Integrating circadian dynamics with physiological processes in plants. Nat. Rev. Genet. 16, 598–610 (2015).

    CAS  PubMed  Google Scholar 

  12. Allada, R. & Chung, B. Y. Circadian organization of behavior and physiology in. Drosophila. Annu. Rev. Physiol. 72, 605–624 (2010).

    CAS  PubMed  Google Scholar 

  13. Shultzaberger, R. K., Boyd, J. S., Diamond, S., Greenspan, R. J. & Golden, S. S. Giving time purpose: the Synechococcus elongatus clock in a broader network context. Annu. Rev. Genet. 49, 485–505 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Takahashi, J. S. Transcriptional architecture of the mammalian circadian clock. Nat. Rev. Genet. 18, 164–179 (2017).

    CAS  PubMed  Google Scholar 

  15. O’Neill, J. S. & Reddy, A. B. Circadian clocks in human red blood cells. Nature 469, 498–503 (2011). Discovery of non-transcriptional circadian rhythms in mammals.

    PubMed  PubMed Central  Google Scholar 

  16. Feeney, K. A. et al. Daily magnesium fluxes regulate cellular timekeeping and energy balance. Nature 532, 375–379 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Henslee, E. A. et al. Rhythmic potassium transport regulates the circadian clock in human red blood cells. Nat. Commun. 8, 1978 (2017).

    PubMed  PubMed Central  Google Scholar 

  18. Zhang, R., Lahens, N. F., Ballance, H. I., Hughes, M. E. & Hogenesch, J. B. A circadian gene expression atlas in mammals: implications for biology and medicine. Proc. Natl Acad. Sci. USA 111, 16219–16224 (2014).

    CAS  PubMed  Google Scholar 

  19. Hatori, M. & Panda, S. The emerging roles of melanopsin in behavioral adaptation to light. Trends Mol. Med. 16, 435–446 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Buijs, F. N. et al. The circadian system: a regulatory feedback network of periphery and brain. Physiology 31, 170–181 (2016).

    PubMed  Google Scholar 

  21. Damiola, F. et al. Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus. Genes Dev. 14, 2950–2961 (2000). Demonstration that daytime feeding in mice uncouples organ clocks from the SCN.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Kalsbeek, A. et al. Mammalian clock output mechanisms. Essays Biochem. 49, 137–151 (2011).

    CAS  PubMed  Google Scholar 

  23. Gerber, A. et al. Blood-borne circadian signal stimulates daily oscillations in actin dynamics and SRF activity. Cell 152, 492–503 (2013).

    CAS  PubMed  Google Scholar 

  24. Balsalobre, A., Damiola, F. & Schibler, U. A serum shock induces circadian gene expression in mammalian tissue culture cells. Cell 93, 929–937 (1998).

    CAS  PubMed  Google Scholar 

  25. Krishnaiah, S. Y. et al. Clock regulation of metabolites reveals coupling between transcription and metabolism. Cell Metab. 25, 961–974 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Loizides-Mangold, U. et al. Lipidomics reveals diurnal lipid oscillations in human skeletal muscle persisting in cellular myotubes cultured in vitro. Proc. Natl Acad. Sci. USA 114, E8565–E8574 (2017).

    CAS  PubMed  Google Scholar 

  27. Kalfalah, F. et al. Crosstalk of clock gene expression and autophagy in aging. Aging 8, 1876–1895 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Nunnari, J. & Suomalainen, A. Mitochondria: in sickness and in health. Cell 148, 1145–1159 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Peek, C. B. et al. Circadian clock NAD+cycle drives mitochondrial oxidative metabolism in mice. Science 342, 1243417 (2013). Demonstration of the circadian rhythmicity of mitochondrial functions.

    PubMed  PubMed Central  Google Scholar 

  30. Jacobi, D. et al. Hepatic Bmal1 regulates rhythmic mitochondrial dynamics and promotes metabolic fitness. Cell Metab. 22, 709–720 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Wai, T. & Langer, T. Mitochondrial dynamics and metabolic regulation. Trends Endocrinol. Metab. 27, 105–117 (2016).

    CAS  PubMed  Google Scholar 

  32. Andrews, J. L. et al. CLOCK and BMAL1 regulate MyoD and are necessary for maintenance of skeletal muscle phenotype and function. Proc. Natl Acad. Sci. USA 107, 19090–19095 (2010).

    CAS  PubMed  Google Scholar 

  33. Kohsaka, A. et al. The circadian clock maintains cardiac function by regulating mitochondrial metabolism in mice. PLOS ONE 9, e112811 (2014).

    PubMed  PubMed Central  Google Scholar 

  34. Schmitt, K. et al. Circadian control of DRP1 activity regulates mitochondrial dynamics and bioenergetics. Cell Metab. 27, 657–666 (2018).

    CAS  PubMed  Google Scholar 

  35. Magnone, M. C. et al. The mammalian circadian clock gene per2 modulates cell death in response to oxidative stress. Front. Neurol. 5, 289 (2014).

    PubMed  Google Scholar 

  36. Osman, C., Voelker, D. R. & Langer, T. Making heads or tails of phospholipids in mitochondria. J. Cell Biol. 192, 7–16 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Aviram, R. et al. Lipidomics analyses reveal temporal and spatial lipid organization and uncover daily oscillations in intracellular organelles. Mol. Cell 62, 636–648 (2016).

    CAS  PubMed  Google Scholar 

  38. Robles, M. S., Cox, J. & Mann, M. In-vivo quantitative proteomics reveals a key contribution of post-transcriptional mechanisms to the circadian regulation of liver metabolism. PLOS Genet. 10, e1004047 (2014).

    PubMed  PubMed Central  Google Scholar 

  39. Mauvoisin, D. et al. Circadian clock-dependent and -independent rhythmic proteomes implement distinct diurnal functions in mouse liver. Proc. Natl Acad. Sci. USA 111, 167–172 (2014).

    CAS  PubMed  Google Scholar 

  40. Gong, C. et al. The daily rhythms of mitochondrial gene expression and oxidative stress regulation are altered by aging in the mouse liver. Chronobiol. Int. 32, 1254–1263 (2015).

    CAS  PubMed  Google Scholar 

  41. Koike, N. et al. Transcriptional architecture and chromatin landscape of the core circadian clock in mammals. Science 338, 349–354 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Masri, S. et al. Circadian acetylome reveals regulation of mitochondrial metabolic pathways. Proc. Natl Acad. Sci. USA 110, 3339–3344 (2013).

    CAS  PubMed  Google Scholar 

  43. Cela, O. et al. Clock genes-dependent acetylation of complex I sets rhythmic activity of mitochondrial OxPhos. Biochim. Biophys. Acta 1863, 596–606 (2016).

    CAS  PubMed  Google Scholar 

  44. Mauvoisin, D. et al. Circadian and feeding rhythms orchestrate the diurnal liver acetylome. Cell Rep. 20, 1729–1743 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Solocinski, K. & Gumz, M. L. The circadian clock in the regulation of renal rhythms. J. Biol. Rhythms 30, 470–486 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Petrenko, V. et al. Pancreatic α- and β-cellular clocks have distinct molecular properties and impact on islet hormone secretion and gene expression. Genes Dev. 31, 383–398 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Mayeuf-Louchart, A., Staels, B. & Duez, H. Skeletal muscle functions around the clock. Diabetes Obes. Metab. 17 (Suppl. 1), 39–46 (2015).

    CAS  PubMed  Google Scholar 

  48. Zwighaft, Z., Reinke, H. & Asher, G. The liver in the eyes of a chronobiologist. J. Biol. Rhythms 31, 115–124 (2016).

    CAS  PubMed  Google Scholar 

  49. Storch, K. F. et al. Extensive and divergent circadian gene expression in liver and heart. Nature 417, 78–83 (2002).

    CAS  PubMed  Google Scholar 

  50. Panda, S. et al. Coordinated transcription of key pathways in the mouse by the circadian clock. Cell 109, 307–320 (2002).

    CAS  PubMed  Google Scholar 

  51. Akhtar, R. A. et al. Circadian cycling of the mouse liver transcriptome, as revealed by cDNA microarray, is driven by the suprachiasmatic nucleus. Curr. Biol. 12, 540–550 (2002).

    CAS  PubMed  Google Scholar 

  52. Rey, G. et al. Genome-wide and phase-specific DNA-binding rhythms of BMAL1 control circadian output functions in mouse liver. PLOS Biol. 9, e1000595 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Dyar, K. A. et al. Atlas of circadian metabolism reveals system-wide coordination and communication between clocks. Cell 174, 1571–1585 (2018).

    CAS  PubMed  Google Scholar 

  54. Eckel-Mahan, K. L. et al. Coordination of the transcriptome and metabolome by the circadian clock. Proc. Natl Acad. Sci. USA 109, 5541–5546 (2012).

    CAS  PubMed  Google Scholar 

  55. Adamovich, Y. et al. Circadian clocks and feeding time regulate the oscillations and levels of hepatic triglycerides. Cell Metab. 19, 319–330 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Atger, F. et al. Circadian and feeding rhythms differentially affect rhythmic mRNA transcription and translation in mouse liver. Proc. Natl Acad. Sci. USA 112, E6579–E6588 (2015).

    CAS  PubMed  Google Scholar 

  57. Doi, R., Oishi, K. & Ishida, N. CLOCK regulates circadian rhythms of hepatic glycogen synthesis through transcriptional activation of Gys2. J. Biol. Chem. 285, 22114–22121 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Lamia, K. A. et al. Cryptochromes mediate rhythmic repression of the glucocorticoid receptor. Nature 480, 552–556 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. So, A. Y., Bernal, T. U., Pillsbury, M. L., Yamamoto, K. R. & Feldman, B. J. Glucocorticoid regulation of the circadian clock modulates glucose homeostasis. Proc. Natl Acad. Sci. USA 106, 17582–17587 (2009).

    CAS  PubMed  Google Scholar 

  60. Vollmers, C. et al. Time of feeding and the intrinsic circadian clock drive rhythms in hepatic gene expression. Proc. Natl Acad. Sci. USA 106, 21453–21458 (2009).

    CAS  PubMed  Google Scholar 

  61. Zhang, E. E. et al. Cryptochrome mediates circadian regulation of cAMP signaling and hepatic gluconeogenesis. Nat. Med. 16, 1152–1156 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Yin, L. et al. Rev-erbα, a heme sensor that coordinates metabolic and circadian pathways. Science 318, 1786–1789 (2007).

    CAS  PubMed  Google Scholar 

  63. Yin, L., Wu, N. & Lazar, M. A. Nuclear receptor Rev-erbα: a heme receptor that coordinates circadian rhythm and metabolism. Nucl. Recept. Signal. 8, e001 (2010).

    PubMed  PubMed Central  Google Scholar 

  64. Preitner, N. et al. Orphan nuclear receptors, molecular clockwork, and the entrainment of peripheral oscillators. Novartis Found. Symp. 253, 89–99; discussion 99–109 (2003).

    CAS  PubMed  Google Scholar 

  65. Zhang, Y. et al. Discrete functions of nuclear receptor Rev-erbα couple metabolism to the clock. Science 348, 1488–1492 (2015).Report of the finding that REV-ERBAα has major metabolic functions outside the core clock mechanism.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Feng, D. et al. A circadian rhythm orchestrated by histone deacetylase 3 controls hepatic lipid metabolism. Science 331, 1315–1319 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Peterson, T. R. et al. mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell 146, 408–420 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Le Martelot, G. et al. REV-ERBα participates in circadian SREBP signaling and bile acid homeostasis. PLOS Biol. 7, e1000181 (2009).

    PubMed  PubMed Central  Google Scholar 

  69. Woldt, E. et al. Rev-erb-α modulates skeletal muscle oxidative capacity by regulating mitochondrial biogenesis and autophagy. Nat. Med. 19, 1039–1046 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Kallen, J. A. et al. X-ray structure of the hRORα LBD at 1.63Å: structural and functional data that cholesterol or a cholesterol derivative is the natural ligand of RORα. Structure 10, 1697–1707 (2002).

    CAS  PubMed  Google Scholar 

  71. Yang, X. et al. Nuclear receptor expression links the circadian clock to metabolism. Cell 126, 801–810 (2006).

    CAS  PubMed  Google Scholar 

  72. Schmutz, I., Ripperger, J. A., Baeriswyl-Aebischer, S. & Albrecht, U. The mammalian clock component PERIOD2 coordinates circadian output by interaction with nuclear receptors. Genes Dev. 24, 345–357 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Kriebs, A. et al. Circadian repressors CRY1 and CRY2 broadly interact with nuclear receptors and modulate transcriptional activity. Proc. Natl Acad. Sci. USA 114, 8776–8781 (2017).

    CAS  PubMed  Google Scholar 

  74. Liu, C., Li, S., Liu, T., Borjigin, J. & Lin, J. D. Transcriptional coactivator PGC-1α integrates the mammalian clock and energy metabolism. Nature 447, 477–481 (2007).

    CAS  PubMed  Google Scholar 

  75. Kohsaka, A. et al. High-fat diet disrupts behavioral and molecular circadian rhythms in mice. Cell Metab. 6, 414–421 (2007).Demonstration of the effect of high-fat diet on circadian clocks.

    CAS  PubMed  Google Scholar 

  76. Gill, S. & Panda, S. A. Smartphone app reveals erratic diurnal eating patterns in humans that can be modulated for health benefits. Cell Metab. 22, 789–798 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Bolli, G. B. et al. Demonstration of a dawn phenomenon in normal human volunteers. Diabetes 33, 1150–1153 (1984).

    CAS  PubMed  Google Scholar 

  78. Feigin, R. D., Klainer, A. S. & Beisel, W. R. Circadian periodicity of blood amino-acids in adult men. Nature 215, 512–514 (1967).

    CAS  PubMed  Google Scholar 

  79. Rivera-Coll, A., Fuentes-Arderiu, X. & Diez-Noguera, A. Circadian rhythmic variations in serum concentrations of clinically important lipids. Clin. Chem. 40, 1549–1553 (1994).

    CAS  PubMed  Google Scholar 

  80. Van Cauter, E., Polonsky, K. S. & Scheen, A. J. Roles of circadian rhythmicity and sleep in human glucose regulation. Endocr. Rev. 18, 716–738 (1997).

    PubMed  Google Scholar 

  81. Dyar, K. A. et al. Muscle insulin sensitivity and glucose metabolism are controlled by the intrinsic muscle clock. Mol. Metab. 3, 29–41 (2014).

    CAS  PubMed  Google Scholar 

  82. Marcheva, B. et al. Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes. Nature 466, 627–631 (2010).The discovery of the role of the pancreatic circadian clock in insulin and glucose homeostasis.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Perelis, M. et al. Pancreatic beta cell enhancers regulate rhythmic transcription of genes controlling insulin secretion. Science 350, aac4250 (2015).

    PubMed  PubMed Central  Google Scholar 

  84. Shi, S. Q., Ansari, T. S., McGuinness, O. P., Wasserman, D. H. & Johnson, C. H. Circadian disruption leads to insulin resistance and obesity. Curr. Biol. 23, 372–381 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Zhou, B. et al. CLOCK/BMAL1 regulates circadian change of mouse hepatic insulin sensitivity by SIRT1. Hepatology 59, 2196–2206 (2014).

    CAS  PubMed  Google Scholar 

  86. Dyar, K. A. et al. Transcriptional programming of lipid and amino acid metabolism by the skeletal muscle circadian clock. PLOS Biol. 16, e2005886 (2018).

    PubMed  PubMed Central  Google Scholar 

  87. Yao, Z., DuBois, D. C., Almon, R. R. & Jusko, W. J. Modeling circadian rhythms of glucocorticoid receptor and glutamine synthetase expression in rat skeletal muscle. Pharm. Res. 23, 670–679 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Benavides, A., Siches, M. & Llobera, M. Circadian rhythms of lipoprotein lipase and hepatic lipase activities in intermediate metabolism of adult rat. Am. J. Physiol. 275, R811–R817 (1998).

    CAS  PubMed  Google Scholar 

  89. Mortola, J. P. Breathing around the clock: an overview of the circadian pattern of respiration. Eur. J. Appl. Physiol. 91, 119–129 (2004).

    PubMed  Google Scholar 

  90. Adamovich, Y., Ladeuix, B., Golik, M., Koeners, M. P. & Asher, G. Rhythmic oxygen levels reset circadian clocks through HIF1α. Cell Metab. 25, 93–101 (2017).

    CAS  PubMed  Google Scholar 

  91. Emans, T. W., Janssen, B. J., Joles, J. A. & Krediet, C. T. P. Circadian rhythm in kidney tissue oxygenation in the rat. Front. Physiol. 8, 205 (2017).

    PubMed  PubMed Central  Google Scholar 

  92. Peek, C. B. et al. Circadian clock interaction with HIF1α mediates oxygenic metabolism and anaerobic glycolysis in skeletal muscle. Cell Metab. 25, 86–92 (2017).

    CAS  PubMed  Google Scholar 

  93. Rodrigo, G. C. & Herbert, K. E. Regulation of vascular function and blood pressure by circadian variation in redox signalling. Free Radic. Biol. Med. 119, 115–120 (2017).

    PubMed  Google Scholar 

  94. Franken, P. A role for clock genes in sleep homeostasis. Curr. Opin. Neurobiol. 23, 864–872 (2013).

    CAS  PubMed  Google Scholar 

  95. Viola, A. U. et al. PER3 polymorphism predicts sleep structure and waking performance. Curr. Biol. 17, 613–618 (2007).

    CAS  PubMed  Google Scholar 

  96. Schmidt, M. H. The energy allocation function of sleep: a unifying theory of sleep, torpor, and continuous wakefulness. Neurosci. Biobehav. Rev. 47, 122–153 (2014).

    PubMed  Google Scholar 

  97. Jung, C. M. et al. Energy expenditure during sleep, sleep deprivation and sleep following sleep deprivation in adult humans. J. Physiol. 589, 235–244 (2011).

    CAS  PubMed  Google Scholar 

  98. Hirota, T. et al. Glucose down-regulates Per1 and Per2 mRNA levels and induces circadian gene expression in cultured Rat-1 fibroblasts. J. Biol. Chem. 277, 44244–44251 (2002).

    CAS  PubMed  Google Scholar 

  99. Oike, H., Nagai, K., Fukushima, T., Ishida, N. & Kobori, M. Feeding cues and injected nutrients induce acute expression of multiple clock genes in the mouse liver. PLOS ONE 6, e23709 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Dang, F. et al. Insulin post-transcriptionally modulates Bmal1 protein to affect the hepatic circadian clock. Nat. Commun. 7, 12696 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Petrenko, V. & Dibner, C. Cell-specific resetting of mouse islet cellular clocks by glucagon, glucagon-like peptide 1 and somatostatin. Acta Physiol 222, e13021 (2017).

    Google Scholar 

  102. Balsalobre, A. et al. Resetting of circadian time in peripheral tissues by glucocorticoid signaling. Science 289, 2344–2347 (2000).

    CAS  PubMed  Google Scholar 

  103. Balsalobre, A., Marcacci, L. & Schibler, U. Multiple signaling pathways elicit circadian gene expression in cultured Rat-1 fibroblasts. Curr. Biol. 10, 1291–1294 (2000).

    CAS  PubMed  Google Scholar 

  104. Hart, G. W., Housley, M. P. & Slawson, C. Cycling of O-linked β-N-acetylglucosamine on nucleocytoplasmic proteins. Nature 446, 1017–1022 (2007).

    CAS  PubMed  Google Scholar 

  105. Ma, Y. et al. O-GlcNAcylation of BMAL1 regulates circadian rhythms in NIH3T3 fibroblasts. Biochem. Biophys. Res. Commun. 431, 382–387 (2013).

    CAS  PubMed  Google Scholar 

  106. Li, M.-D. et al. O-GlcNAc signaling entrains the circadian clock by inhibiting BMAL1/CLOCK ubiquitination. Cell Metab. 17, 303–310 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Kaasik, K. et al. Glucose sensor O-GlcNAcylation coordinates with phosphorylation to regulate circadian clock. Cell Metab. 17, 291–302 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Hui, S. et al. Glucose feeds the TCA cycle via circulating lactate. Nature 551, 115–118 (2017).

    PubMed  PubMed Central  Google Scholar 

  109. Rutter, J., Reick, M., Wu, L. C. & McKnight, S. L. Regulation of clock and NPAS2 DNA binding by the redox state of NAD cofactors. Science 293, 510–514 (2001).

    CAS  PubMed  Google Scholar 

  110. Hogenesch, J. B. et al. Characterization of a subset of the basic-helix-loop-helix-PAS superfamily that interacts with components of the dioxin signaling pathway. J. Biol. Chem. 272, 8581–8593 (1997).

    CAS  PubMed  Google Scholar 

  111. Wu, Y. et al. Reciprocal regulation between the circadian clock and hypoxia signaling at the genome level in mammals. Cell Metab. 25, 73–85 (2017).Refs 90, 92 and 111 are three related publications showing the interplay between oxygen, HIF and circadian clocks.

    CAS  PubMed  Google Scholar 

  112. Klemz, R. et al. Reciprocal regulation of carbon monoxide metabolism and the circadian clock. Nat. Struct. Mol. Biol. 24, 15–22 (2017).

    CAS  PubMed  Google Scholar 

  113. Dioum, E. M. et al. NPAS2: a gas-responsive transcription factor. Science 298, 2385–2387 (2002).

    CAS  PubMed  Google Scholar 

  114. Correa-Costa, M. et al. Carbon monoxide protects the kidney through the central circadian clock and CD39. Proc. Natl Acad. Sci. USA 115, E2302–E2310 (2018).

    CAS  PubMed  Google Scholar 

  115. Zhang, E. E. et al. A genome-wide RNAi screen for modifiers of the circadian clock in human cells. Cell 139, 199–210 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Ramsey, K. M. et al. Circadian clock feedback cycle through NAMPT-mediated NAD+ biosynthesis. Science 324, 651–654 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Nakahata, Y., Sahar, S., Astarita, G., Kaluzova, M. & Sassone-Corsi, P. Circadian control of the NAD+ salvage pathway by CLOCK-SIRT1. Science 324, 654–657 (2009).

    CAS  PubMed  Google Scholar 

  118. Aguilar-Arnal, L., Katada, S., Orozco-Solis, R. & Sassone-Corsi, P. NAD+-SIRT1 control of H3K4 trimethylation through circadian deacetylation of MLL1. Nat. Struct. Mol. Biol. 22, 312–318 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Asher, G. et al. SIRT1 regulates circadian clock gene expression through PER2 deacetylation. Cell 134, 317–328 (2008).

    CAS  PubMed  Google Scholar 

  120. Chang, H. C. & Guarente, L. SIRT1 mediates central circadian control in the SCN by a mechanism that decays with aging. Cell 153, 1448–1460 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Masri, S. et al. Partitioning circadian transcription by SIRT6 leads to segregated control of cellular metabolism. Cell 158, 659–672 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Nakahata, Y. et al. The NAD+-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control. Cell 134, 329–340 (2008).Refs 119 and 122 are two related publications reporting that SIRT1 regulates circadian rhythmicity.

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Musiek, E. S. et al. Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration. J. Clin. Invest. 123, 5389–5400 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Choi, J. Y. et al. Non-thermal plasma-induced apoptosis is modulated by ATR- and PARP1-mediated DNA damage responses and circadian clock. Oncotarget 7, 32980–32989 (2016).

    PubMed  PubMed Central  Google Scholar 

  125. Asher, G. et al. Poly(ADP-ribose) polymerase 1 participates in the phase entrainment of circadian clocks to feeding. Cell 142, 943–953 (2010).

    CAS  PubMed  Google Scholar 

  126. Zhao, H. et al. PARP1- and CTCF-mediated interactions between active and repressed chromatin at the lamina promote oscillating transcription. Mol. Cell 59, 984–997 (2015).

    CAS  PubMed  Google Scholar 

  127. Purushotham, A. et al. Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. Cell Metab. 9, 327–338 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Rodgers, J. T. et al. Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1. Nature 434, 113–118 (2005).

    CAS  PubMed  Google Scholar 

  129. Liu, Y. et al. A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange. Nature 456, 269–273 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Hirano, A., Braas, D., Fu, Y.-H. & Ptacek, L. J. FAD regulates CRYPTOCHROME protein stability and circadian clock in mice. Cell Rep. 19, 255–266 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Rey, G. et al. The pentose phosphate pathway regulates the circadian clock. Cell Metab. 24, 462–473 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Lamia, K. A. et al. AMPK regulates the circadian clock by cryptochrome phosphorylation and degradation. Science 326, 437–440 (2009).Discovery that AMPK regulates circadian rhythmicity.

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Um, J. H. et al. Activation of 5ʹ-AMP-activated kinase with diabetes drug metformin induces casein kinase Iepsilon (CKIepsilon)-dependent degradation of clock protein mPer2. J. Biol. Chem. 282, 20794–20798 (2007).

    CAS  PubMed  Google Scholar 

  134. Canto, C. et al. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 458, 1056–1060 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Zhang, C.-S. et al. Fructose-1,6-bisphosphate and aldolase mediate glucose sensing by AMPK. Nature 548, 112–116 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Yamamoto, H., Nagai, K. & Nakagawa, H. Role of SCN in daily rhythms of plasma glucose, FFA, insulin and glucagon. Chronobiol. Int. 4, 483–491 (1987).

    CAS  PubMed  Google Scholar 

  137. Wellen, K. E. et al. ATP-citrate lyase links cellular metabolism to histone acetylation. Science 324, 1076–1080 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Ariyannur, P. S. et al. Nuclear-cytoplasmic localization of acetyl coenzyme a synthetase-1 in the rat brain. J. Comp. Neurol. 518, 2952–2977 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Zhao, S. et al. Regulation of cellular metabolism by protein lysine acetylation. Science 327, 1000–1004 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Sahar, S. et al. Circadian control of fatty acid elongation by SIRT1 protein-mediated deacetylation of acetyl-coenzyme A synthetase 1. J. Biol. Chem. 289, 6091–6097 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Etchegaray, J. P., Lee, C., Wade, P. A. & Reppert, S. M. Rhythmic histone acetylation underlies transcription in the mammalian circadian clock. Nature 421, 177–182 (2003).

    CAS  PubMed  Google Scholar 

  142. Doi, M., Hirayama, J. & Sassone-Corsi, P. Circadian regulator CLOCK is a histone acetyltransferase. Cell 125, 497–508 (2006).

    CAS  PubMed  Google Scholar 

  143. Zwighaft, Z. et al. Circadian clock control by polyamine levels through a mechanism that declines with age. Cell Metab. 22, 874–885 (2015).

    CAS  PubMed  Google Scholar 

  144. Turek, F. W. et al. Obesity and metabolic syndrome in circadian Clock mutant mice. Science 308, 1043–1045 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Rudic, R. D. et al. BMAL1 and CLOCK, two essential components of the circadian clock, are involved in glucose homeostasis. PLOS Biol. 2, e377 (2004).

    PubMed  PubMed Central  Google Scholar 

  146. Ghiasvand, M. et al. Shift working and risk of lipid disorders: a cross-sectional study. Lipids Health Dis. 5, 9 (2006).

    PubMed  PubMed Central  Google Scholar 

  147. Morgan, L., Hampton, S., Gibbs, M. & Arendt, J. Circadian aspects of postprandial metabolism. Chronobiol. Int. 20, 795–808 (2003).

    CAS  PubMed  Google Scholar 

  148. Pan, A., Schernhammer, E. S., Sun, Q. & Hu, F. B. Rotating night shift work and risk of type 2 diabetes: two prospective cohort studies in women. PLOS Med. 8, e1001141 (2011).

    PubMed  PubMed Central  Google Scholar 

  149. Thosar, S. S., Butler, M. P. & Shea, S. A. Role of the circadian system in cardiovascular disease. J. Clin. Invest. 128, 2157–2167 (2018).

    PubMed  Google Scholar 

  150. Konturek, P. C., Brzozowski, T. & Konturek, S. J. Gut clock: implication of circadian rhythms in the gastrointestinal tract. J. Physiol. Pharmacol. 62, 139–150 (2011).

    CAS  PubMed  Google Scholar 

  151. Schernhammer, E. S. et al. Night-shift work and risk of colorectal cancer in the nurses’ health study. J. Natl Cancer Inst. 95, 825–828 (2003).

    PubMed  Google Scholar 

  152. De Bacquer, D. et al. Rotating shift work and the metabolic syndrome: a prospective study. Int. J. Epidemiol. 38, 848–854 (2009).

    PubMed  Google Scholar 

  153. Zizi, F. et al. Sleep duration and the risk of diabetes mellitus: epidemiologic evidence and pathophysiologic insights. Curr. Diabetes Rep. 10, 43–47 (2010).

    Google Scholar 

  154. Lucassen, E. A., Rother, K. I. & Cizza, G. Interacting epidemics? Sleep curtailment, insulin resistance, and obesity. Ann. NY Acad. Sci. 1264, 110–134 (2012).

    CAS  PubMed  Google Scholar 

  155. Buxton, O. M. et al. Adverse metabolic consequences in humans of prolonged sleep restriction combined with circadian disruption. Sci. Transl Med. 4, 129ra143 (2012).

    Google Scholar 

  156. Mullington, J. M. et al. Sleep loss reduces diurnal rhythm amplitude of leptin in healthy men. J. Neuroendocrinol. 15, 851–854 (2003).

    CAS  PubMed  Google Scholar 

  157. Schmid, S. M., Hallschmid, M., Jauch-Chara, K., Born, J. & Schultes, B. A single night of sleep deprivation increases ghrelin levels and feelings of hunger in normal-weight healthy men. J. Sleep Res. 17, 331–334 (2008).

    PubMed  Google Scholar 

  158. Beccuti, G. & Pannain, S. Sleep and obesity. Curr. Opin. Clin. Nutr. Metab. Care 14, 402–412 (2011).

    PubMed  PubMed Central  Google Scholar 

  159. Cui, H., Lopez, M. & Rahmouni, K. The cellular and molecular bases of leptin and ghrelin resistance in obesity. Nat. Rev. Endocrinol. 13, 338–351 (2017).

    CAS  PubMed  Google Scholar 

  160. Kalsbeek, A. et al. The suprachiasmatic nucleus generates the diurnal changes in plasma leptin levels. Endocrinology 142, 2677–2685 (2001).

    CAS  PubMed  Google Scholar 

  161. Laermans, J., Vancleef, L., Tack, J. & Depoortere, I. Role of the clock gene Bmal1 and the gastric ghrelin-secreting cell in the circadian regulation of the ghrelin-GOAT system. Sci. Rep. 5, 16748 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Kettner, N. M. et al. Circadian dysfunction induces leptin resistance in mice. Cell Metab. 22, 448–459 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Xu, Y. et al. Functional consequences of a CKIδ mutation causing familial advanced sleep phase syndrome. Nature 434, 640–644 (2005).

    CAS  PubMed  Google Scholar 

  164. Hirano, A. et al. A cryptochrome 2 mutation yields advanced sleep phase in humans. eLife 5, e16695 (2016).

    PubMed  PubMed Central  Google Scholar 

  165. Patke, A. et al. Mutation of the human circadian clock gene CRY1 in familial delayed sleep phase disorder. Cell 169, 203–215 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Parsons, M. J. et al. Social jetlag, obesity and metabolic disorder: investigation in a cohort study. Int. J. Obes. 39, 842–848 (2015).

    CAS  Google Scholar 

  167. Roenneberg, T., Allebrandt, K. V., Merrow, M. & Vetter, C. Social jetlag and obesity. Curr. Biol. 22, 939–943 (2012).

    CAS  PubMed  Google Scholar 

  168. Chen, Z., Yoo, S.-H. & Takahashi, J. S. Development and therapeutic potential of small-molecule modulators of circadian systems. Annu. Rev. Pharmacol. Toxicol. 58, 231–252 (2018).

    CAS  PubMed  Google Scholar 

  169. Ouyang, Y., Andersson, C. R., Kondo, T., Golden, S. S. & Johnson, C. H. Resonating circadian clocks enhance fitness in cyanobacteria. Proc. Natl Acad. Sci. USA 95, 8660–8664 (1998).

    CAS  PubMed  Google Scholar 

  170. Woelfle, M. A., Ouyang, Y., Phanvijhitsiri, K. & Johnson, C. H. The adaptive value of circadian clocks: an experimental assessment in cyanobacteria. Curr. Biol. 14, 1481–1486 (2004).

    CAS  PubMed  Google Scholar 

  171. Dodd, A. N. et al. Plant circadian clocks increase photosynthesis, growth, survival, and competitive advantage. Science 309, 630–633 (2005).

    CAS  PubMed  Google Scholar 

  172. Martino, T. A. et al. Circadian rhythm disorganization produces profound cardiovascular and renal disease in hamsters. Am. J. Physiol. Regul. Integr. Comp. Physiol. 294, R1675–R1683 (2008).

    CAS  PubMed  Google Scholar 

  173. Wang, G.-Z. et al. Cycling transcriptional networks optimize energy utilization on a genome scale. Cell Rep. 13, 1868–1880 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Stokkan, K. A., Yamazaki, S., Tei, H., Sakaki, Y. & Menaker, M. Entrainment of the circadian clock in the liver by feeding. Science 291, 490–493 (2001).Demonstration that daytime feeding uncouples organ clocks from the SCN.

    CAS  PubMed  Google Scholar 

  175. Mendoza, J., Graff, C., Dardente, H., Pevet, P. & Challet, E. Feeding cues alter clock gene oscillations and photic responses in the suprachiasmatic nuclei of mice exposed to a light/dark cycle. J. Neurosci. 25, 1514–1522 (2005).

    CAS  PubMed  Google Scholar 

  176. Acosta-Rodriguez, V. A., de Groot, M. H. M., Rijo-Ferreira, F., Green, C. B. & Takahashi, J. S. Mice under caloric restriction self-impose a temporal restriction of food intake as revealed by an automated feeder system. Cell Metab. 26, 267–277 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Potthoff, M. J., Kliewer, S. A. & Mangelsdorf, D. J. Endocrine fibroblast growth factors 15/19 and 21: from feast to famine. Genes Dev. 26, 312–324 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. Bookout, A. L. et al. FGF21 regulates metabolism and circadian behavior by acting on the nervous system. Nat. Med. 19, 1147–1152 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. Hakansson, M. L., Brown, H., Ghilardi, N., Skoda, R. C. & Meister, B. Leptin receptor immunoreactivity in chemically defined target neurons of the hypothalamus. J. Neurosci. 18, 559–572 (1998).

    CAS  PubMed  Google Scholar 

  180. Zigman, J. M., Jones, J. E., Lee, C. E., Saper, C. B. & Elmquist, J. K. Expression of ghrelin receptor mRNA in the rat and the mouse brain. J. Comp. Neurol. 494, 528–548 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Grosbellet, E. et al. Circadian phenotyping of obese and diabetic db/db mice. Biochimie 124, 198–206 (2016).

    CAS  PubMed  Google Scholar 

  182. Mistlberger, R. E. Food-anticipatory circadian rhythms: concepts and methods. Eur. J. Neurosci. 30, 1718–1729 (2009).

    PubMed  Google Scholar 

  183. Orozco-Solis, R. et al. The circadian clock in the ventromedial hypothalamus controls cyclic energy expenditure. Cell Metab. 23, 467–478 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. Eckel-Mahan, K. L. et al. Reprogramming of the circadian clock by nutritional challenge. Cell 155, 1464–1478 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. Abbondante, S., Eckel-Mahan, K. L., Ceglia, N. J., Baldi, P. & Sassone-Corsi, P. Comparative circadian metabolomics reveal differential effects of nutritional challenge in the serum and liver. J. Biol. Chem. 291, 2812–2828 (2016).

    CAS  PubMed  Google Scholar 

  186. Hatori, M. et al. Time-restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high-fat diet. Cell Metab. 15, 848–860 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Sherman, H. et al. Timed high-fat diet resets circadian metabolism and prevents obesity. FASEB J. 26, 3493–3502 (2012).

    CAS  PubMed  Google Scholar 

  188. Salgado-Delgado, R., Angeles-Castellanos, M., Saderi, N., Buijs, R. M. & Escobar, C. Food intake during the normal activity phase prevents obesity and circadian desynchrony in a rat model of night work. Endocrinology 151, 1019–1029 (2010).

    CAS  PubMed  Google Scholar 

  189. Branecky, K. L., Niswender, K. D. & Pendergast, J. S. Disruption of daily rhythms by high-fat diet is reversible. PLOS ONE 10, e0137970 (2015).

    PubMed  PubMed Central  Google Scholar 

  190. Tognini, P. et al. Distinct circadian signatures in liver and gut clocks revealed by ketogenic diet. Cell Metab. 26, 523–538 (2017).

    CAS  PubMed  Google Scholar 

  191. Lynch, S. V. & Pedersen, O. The human intestinal microbiome in health and disease. N. Engl. J. Med. 375, 2369–2379 (2016).

    CAS  PubMed  Google Scholar 

  192. Mukherji, A., Kobiita, A., Ye, T. & Chambon, P. Homeostasis in intestinal epithelium is orchestrated by the circadian clock and microbiota cues transduced by TLRs. Cell 153, 812–827 (2013).

    CAS  PubMed  Google Scholar 

  193. Thaiss, C. A. et al. Transkingdom control of microbiota diurnal oscillations promotes metabolic homeostasis. Cell 159, 514–529 (2014).Refs 186, 187 and 193 report the discovery of the metabolic benefits of time-restricted feeding.

    CAS  PubMed  Google Scholar 

  194. Liang, X., Bushman, F. D. & FitzGerald, G. A. Rhythmicity of the intestinal microbiota is regulated by gender and the host circadian clock. Proc. Natl Acad. Sci. USA 112, 10479–10484 (2015).

    CAS  PubMed  Google Scholar 

  195. Zarrinpar, A., Chaix, A., Yooseph, S. & Panda, S. Diet and feeding pattern affect the diurnal dynamics of the gut microbiome. Cell Metab. 20, 1006–1017 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. Leone, V. et al. Effects of diurnal variation of gut microbes and high-fat feeding on host circadian clock function and metabolism. Cell Host Microbe 17, 681–689 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. Murakami, M. et al. Gut microbiota directs PPARgamma-driven reprogramming of the liver circadian clock by nutritional challenge. EMBO Rep. 17, 1292–1303 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  198. Thaiss, C. A. et al. Microbiota diurnal rhythmicity programs host transcriptome oscillations. Cell 167, 1495–1510 (2016).

    CAS  PubMed  Google Scholar 

  199. Kil, I. S. et al. Circadian oscillation of sulfiredoxin in the mitochondria. Mol. Cell 59, 651–663 (2015).

    CAS  PubMed  Google Scholar 

  200. Edgar, R. S. et al. Peroxiredoxins are conserved markers of circadian rhythms. Nature 485, 459–464 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  201. O’Neill, J. S. et al. Circadian rhythms persist without transcription in a eukaryote. Nature 469, 554–558 (2011).

    PubMed  PubMed Central  Google Scholar 

  202. Grimaldi, B. et al. PER2 controls lipid metabolism by direct regulation of PPARgamma. Cell Metab. 12, 509–520 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  203. Wang, Y. et al. Modulation of retinoic acid receptor-related orphan receptor alpha and gamma activity by 7-oxygenated sterol ligands. J. Biol. Chem. 285, 5013–5025 (2010).

    CAS  PubMed  Google Scholar 

  204. Perrin, L. et al. Human skeletal myotubes display a cell-autonomous circadian clock implicated in basal myokine secretion. Mol. Metab. 4, 834–845 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  205. Philippe, J. & Dibner, C. Thyroid circadian timing: roles in physiology and thyroid malignancies. J. Biol. Rhythms 30, 76–83 (2015).

    CAS  PubMed  Google Scholar 

  206. Mortola, J. F., Laughlin, G. A. & Yen, S. S. A circadian rhythm of serum follicle-stimulating hormone in women. J. Clin. Endocrinol. Metab. 75, 861–864 (1992).

    CAS  PubMed  Google Scholar 

  207. Chung, S., Son, G. H. & Kim, K. Circadian rhythm of adrenal glucocorticoid: its regulation and clinical implications. Biochim. Biophys. Acta 1812, 581–591 (2011).

    CAS  PubMed  Google Scholar 

  208. Waldstreicher, J. et al. Gender differences in the temporal organization of proclactin (PRL) secretion: evidence for a sleep-independent circadian rhythm of circulating PRL levels- a clinical research center study. J. Clin. Endocrinol. Metab. 81, 1483–1487 (1996).

    CAS  PubMed  Google Scholar 

  209. Lynch, H. J., Wurtman, R. J., Moskowitz, M. A., Archer, M. C. & Ho, M. H. Daily rhythm in human urinary melatonin. Science 187, 169–171 (1975).

    CAS  PubMed  Google Scholar 

  210. Eggink, H. M. et al. Complex interaction between circadian rhythm and diet on bile acid homeostasis in male rats. Chronobiol. Int. 34, 1339–1353 (2017).

    CAS  PubMed  Google Scholar 

  211. Ohashi, N., Isobe, S., Ishigaki, S. & Yasuda, H. Circadian rhythm of blood pressure and the renin-angiotensin system in the kidney. Hypertens. Res. 40, 413–422 (2017).

    CAS  PubMed  Google Scholar 

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Acknowledgements

The authors are grateful to R. Aviram and G. Manella for their valuable comments on the manuscript and for their assistance in the figure preparation. G.A. is supported by the European Research Council (ERC-2017 CIRCOMMUNICATION 770869). G.A. is recipient of the European Molecular Biology Organization (EMBO) young investigator award.

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Nature Reviews Molecular Cell Biology thanks A. Weljie, F. Gachon and other anonymous reviewer(s) for their contribution to the peer review of this work.

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Authors and Affiliations

  1. University of Düsseldorf, Medical Faculty, Institute of Clinical Chemistry and Laboratory Diagnostics, Düsseldorf, Germany

    Hans Reinke

  2. IUF Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany

    Hans Reinke

  3. Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel

    Gad Asher

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  1. Hans Reinke
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Glossary

Phase

The relative position of the internal circadian clock time to the external time.

E-box elements

DNA elements (consensus sequence CANNTG) bound by transcription factors, most commonly basic helix–loop–helix domain-containing proteins.

Photic responses

Light-induced molecular changes in cells that contribute to photoentrainment in the suprachiasmatic nucleus.

Arcuate nucleus

A hypothalamic nucleus that contains neuroendocrine and centrally projecting neurons and that has pre-eminent roles in central homeostatic processes, such as energy metabolism.

Ketogenic diet

A high-fat, low-carbohydrate diet that results in elevated levels of ketone bodies in the circulation by promoting the metabolism of lipids over the use of carbohydrates for energy generation.

RORE binding sites

DNA elements (consensus sequence AGGTCA preceded by a 5 bp AT-rich sequence) bound by transcription factors from the RAR-related orphan receptor (ROR) and nuclear receptor subfamily 1 group D (REV-ERBA) nuclear receptor families.

Peroxiredoxins

Ubiquitous, small (20–30 kDa) antioxidant enzymes that catalyse the reduction of hydroperoxides, toxic by-products of aerobic respiration, to alcohols.

Melanopsin

Opsin of intrinsically photoactive retinal ganglion cells involved in non-image-forming visual functions including light-entrainment of the suprachiasmatic nucleus.

Retinal ganglion cells

Neurons in the ganglion cell layer of the retina; their axons form the optic nerve and the retinohypothalamic tract.

Melatonin

A pineal hormone that regulates circadian rhythms and wakefulness; its synthesis is suppressed by light.

Heterotrimeric G proteins

Membrane-associated GTP-binding and/or GDP-binding signalling proteins consisting of three subunits α, β and γ.

RevDR2 elements

DNA elements (direct repeats of two AGGTCA motifs separated by 2 bp) bound by transcription factors from the RAR-related orphan receptor (ROR) and nuclear receptor subfamily 1 group D (REV-ERBA) nuclear receptor families.

Haem

A porphyrin complex with a central iron atom that can bind and transport diatomic gases and can be used as a redox partner in electron transfer reactions.

Oxysterols

Oxidized derivatives of cholesterol with biological activity, for example, as binding partners for nuclear receptors.

Toll-like receptors

Transmembrane receptors with homology to the Drosophila melanogaster Toll protein that recognize microbial pathogen structures.

Operational taxonomic units

Classifiers for clusters of closely related organisms, in particular used for prokaryotes owing to the lack of a traditional system of biological classification.

O-GlcNAcylation

Post-translational modification of proteins, whereby N-acetylglucosamine is covalently attached via an O-glycosidic linkage to serine or threonine residues.

Metabolic flux

Substrate use in a biochemical pathway determined as the turnover rate of a metabolite as opposed to its steady-state levels, which can be constant in different conditions despite widely varying flux rates.

NAD cofactors

NAD molecules that can serve in their reduced form, NADH, as an electron donor and in their oxidized form, NAD+, as an electron acceptor in biochemical reactions.

Prosthetic group

A small molecule that is covalently bound to a protein and is essential for its function. An example of a prosthetic group is haem bound to haemoglobin.

Ischaemia–reperfusion injury

The tissue damage caused by oxidative stress when cells are resupplied with oxygen and nutrients after a period of anoxia, for example, after a stroke.

Poly-ADP-ribosylation

The post-translational modification by transfer of multiple ADP-ribose units to target proteins.

Leptin

An adipocyte-derived hormone that can cross the blood–brain barrier and inhibit hunger by regulating the production of other satiety-controlling hormones in the hypothalamus. The name comes from a Greek word meaning thin.

Ghrelin

(Growth hormone release inducing). A gastrointestinal peptide hormone that stimulates growth hormone secretion from the anterior pituitary and can cross the blood–brain barrier to increase hunger in the hypothalamus antagonistically to leptin.

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Reinke, H., Asher, G. Crosstalk between metabolism and circadian clocks. Nat Rev Mol Cell Biol 20, 227–241 (2019). https://doi.org/10.1038/s41580-018-0096-9

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