Review Article | Published:

Circadian blueprint of metabolic pathways in the brain

Nature Reviews Neurosciencevolume 20pages7182 (2019) | Download Citation



The circadian clock is an endogenous, time-tracking system that directs multiple metabolic and physiological functions required for homeostasis. The master or central clock located within the suprachiasmatic nucleus in the hypothalamus governs peripheral clocks present in all systemic tissues, contributing to their alignment and ultimately to temporal coordination of physiology. Accumulating evidence reveals the presence of additional clocks in the brain and suggests the possibility that circadian circuits may feed back to these from the periphery. Here, we highlight recent advances in the communications between clocks and discuss how they relate to circadian physiology and metabolism.

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  1. 1.

    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).

  2. 2.

    Mure, L. S. et al. Diurnal transcriptome atlas of a primate across major neural and peripheral tissues. Science 359, eaao0318 (2018).

  3. 3.

    Masri, S. & Sassone-Corsi, P. Plasticity and specificity of the circadian epigenome. Nat. Neurosci. 13, 1324–1329 (2010).

  4. 4.

    Mehra, A., Baker, C. L., Loros, J. J. & Dunlap, J. C. Post-translational modifications in circadian rhythms. Trends Biochem. Sci. 34, 483–490 (2009).

  5. 5.

    Crosio, C., Cermakian, N., Allis, C. D. & Sassone-Corsi, P. Light induces chromatin modification in cells of the mammalian circadian clock. Nat. Neurosci. 3, 1241–1247 (2000).

  6. 6.

    Aguilar-Arnal, L. & Sassone-Corsi, P. Chromatin landscape and circadian dynamics: spatial and temporal organization of clock transcription. Proc. Natl Acad. Sci. USA 112, 6863–6870 (2015).

  7. 7.

    Masri, S. & Sassone-Corsi, P. Sirtuins and the circadian clock: bridging chromatin and metabolism. Sci. Signal 7, re6 (2014).

  8. 8.

    Mai, J. K., Kedziora, O., Teckhaus, L. & Sofroniew, M. V. Evidence for subdivisions in the human suprachiasmatic nucleus. J. Comp. Neurol. 305, 508–525 (1991).

  9. 9.

    Abrahamson, E. E. & Moore, R. Y. Suprachiasmatic nucleus in the mouse: retinal innervation, intrinsic organization and efferent projections. Brain Res. 916, 172–191 (2001).

  10. 10.

    Harmar, A. J. et al. The VPAC(2) receptor is essential for circadian function in the mouse suprachiasmatic nuclei. Cell 109, 497–508 (2002).

  11. 11.

    Aton, S. J., Colwell, C. S., Harmar, A. J., Waschek, J. & Herzog, E. D. Vasoactive intestinal polypeptide mediates circadian rhythmicity and synchrony in mammalian clock neurons. Nat. Neurosci. 8, 476–483 (2005).

  12. 12.

    Mieda, M. et al. Cellular clocks in AVP neurons of the SCN are critical for interneuronal coupling regulating circadian behavior rhythm. Neuron 85, 1103–1116 (2015).

  13. 13.

    Mieda, M., Okamoto, H. & Sakurai, T. Manipulating the cellular circadian period of arginine vasopressin neurons alters the behavioral circadian period. Curr. Biol. 26, 2535–2542 (2016).

  14. 14.

    Park, J. et al. Single-cell transcriptional analysis reveals novel neuronal phenotypes and interaction networks involved in the central circadian clock. Front. Neurosci. 10, 481 (2016).

  15. 15.

    Petit, J. M. & Magistretti, P. J. Regulation of neuron-astrocyte metabolic coupling across the sleep-wake cycle. Neuroscience 323, 135–156 (2016).

  16. 16.

    Iadecola, C. & Nedergaard, M. Glial regulation of the cerebral microvasculature. Nat. Neurosci. 10, 1369–1376 (2007).

  17. 17.

    Perea, G., Navarrete, M. & Araque, A. Tripartite synapses: astrocytes process and control synaptic information. Trends Neurosci. 32, 421–431 (2009).

  18. 18.

    Prolo, L. M., Takahashi, J. S. & Herzog, E. D. Circadian rhythm generation and entrainment in astrocytes. J. Neurosci. 25, 404–408 (2005).

  19. 19.

    Yagita, K., Yamanaka, I., Emoto, N., Kawakami, K. & Shimada, S. Real-time monitoring of circadian clock oscillations in primary cultures of mammalian cells using Tol2 transposon-mediated gene transfer strategy. BMC Biotechnol. 10, 3 (2010).

  20. 20.

    Womac, A. D., Burkeen, J. F., Neuendorff, N., Earnest, D. J. & Zoran, M. J. Circadian rhythms of extracellular ATP accumulation in suprachiasmatic nucleus cells and cultured astrocytes. Eur. J. Neurosci. 30, 869–876 (2009).

  21. 21.

    Prosser, R. A., Edgar, D. M., Heller, H. C. & Miller, J. D. A possible glial role in the mammalian circadian clock. Brain Res. 643, 296–301 (1994).

  22. 22.

    Barca-Mayo, O. et al. Astrocyte deletion of Bmal1 alters daily locomotor activity and cognitive functions via GABA signalling. Nat. Commun. 8, 14336 (2017). This article is one of three studies demonstrating the central role of astrocyte signalling for circadian pacemaking in the SCN.

  23. 23.

    Brancaccio, M., Patton, A. P., Chesham, J. E., Maywood, E. S. & Hastings, M. H. Astrocytes control circadian timekeeping in the suprachiasmatic nucleus via glutamatergic signaling. Neuron 93, 1420–1435 (2017). This article is one of three studies demonstrating the central role of astrocyte signalling for circadian pacemaking in the SCN.

  24. 24.

    Tso, C. F. et al. Astrocytes regulate daily rhythms in the suprachiasmatic nucleus and behavior. Curr. Biol. 27, 1055–1061 (2017). This article is one of three studies demonstrating the central role of astrocyte signalling for circadian pacemaking in the SCN.

  25. 25.

    Liu, C. & Reppert, S. M. GABA synchronizes clock cells within the suprachiasmatic circadian clock. Neuron 25, 123–128 (2000).

  26. 26.

    Albus, H., Vansteensel, M. J., Michel, S., Block, G. D. & Meijer, J. H. A. GABAergic mechanism is necessary for coupling dissociable ventral and dorsal regional oscillators within the circadian clock. Curr. Biol. 15, 886–893 (2005).

  27. 27.

    Yoon, B. E., Woo, J. & Lee, C. J. Astrocytes as GABA-ergic and GABA-ceptive cells. Neurochem. Res. 37, 2474–2479 (2012).

  28. 28.

    Doengi, M. et al. GABA uptake-dependent Ca2+ signaling in developing olfactory bulb astrocytes. Proc. Natl Acad. Sci. USA 106, 17570–17575 (2009).

  29. 29.

    Araque, A. et al. Gliotransmitters travel in time and space. Neuron 81, 728–739 (2014).

  30. 30.

    Pellerin, L. & Magistretti, P. J. Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. Proc. Natl Acad. Sci. USA 91, 10625–10629 (1994).

  31. 31.

    Schwartz, W. J. & Gainer, H. Suprachiasmatic nucleus: use of 14C-labeled deoxyglucose uptake as a functional marker. Science 197, 1089–1091 (1977).

  32. 32.

    Dash, M. B., Bellesi, M., Tononi, G. & Cirelli, C. Sleep/wake dependent changes in cortical glucose concentrations. J. Neurochem. 124, 79–89 (2013).

  33. 33.

    Spanagel, R. et al. The clock gene Per2 influences the glutamatergic system and modulates alcohol consumption. Nat. Med. 11, 35–42 (2005).

  34. 34.

    Clasadonte, J., Scemes, E., Wang, Z., Boison, D. & Haydon, P. G. Connexin 43-mediated astroglial metabolic networks contribute to the regulation of the sleep-wake cycle. Neuron 95, 1365–1380 (2017).

  35. 35.

    Myers, M. G. Jr & Olson, D. P. Central nervous system control of metabolism. Nature 491, 357–363 (2012).

  36. 36.

    Abe, M. et al. Circadian rhythms in isolated brain regions. J. Neurosci. 22, 350–356 (2002). This study was one of the first to show that extra-SCN brain regions harbour an autonomous circadian oscillator.

  37. 37.

    Williams, K. W. & Elmquist, J. K. From neuroanatomy to behavior: central integration of peripheral signals regulating feeding behavior. Nat. Neurosci. 15, 1350–1355 (2012).

  38. 38.

    Guzman-Ruiz, M. et al. The suprachiasmatic nucleus changes the daily activity of the arcuate nucleus α-MSH neurons in male rats. Endocrinology 155, 525–535 (2014).

  39. 39.

    Yi, C. X. et al. Ventromedial arcuate nucleus communicates peripheral metabolic information to the suprachiasmatic nucleus. Endocrinology 147, 283–294 (2006).

  40. 40.

    Akabayashi, A., Levin, N., Paez, X., Alexander, J. T. & Leibowitz, S. F. Hypothalamic neuropeptide Y and its gene expression: relation to light/dark cycle and circulating corticosterone. Mol. Cell Neurosci. 5, 210–218 (1994).

  41. 41.

    Xu, B., Kalra, P. S., Farmerie, W. G. & Kalra, S. P. Daily changes in hypothalamic gene expression of neuropeptide Y, galanin, proopiomelanocortin, and adipocyte leptin gene expression and secretion: effects of food restriction. Endocrinology 140, 2868–2875 (1999).

  42. 42.

    Li, A. J. et al. Leptin-sensitive neurons in the arcuate nuclei contribute to endogenous feeding rhythms. Am. J. Physiol. Regul. Integr. Comp. Physiol. 302, R1313–R1326 (2012).

  43. 43.

    Wiater, M. F. et al. Circadian integration of sleep-wake and feeding requires NPY receptor-expressing neurons in the mediobasal hypothalamus. Am. J. Physiol. Regul. Integr. Comp. Physiol. 301, R1569–R1583 (2011).

  44. 44.

    Chao, P. T., Yang, L., Aja, S., Moran, T. H. & Bi, S. Knockdown of NPY expression in the dorsomedial hypothalamus promotes development of brown adipocytes and prevents diet-induced obesity. Cell Metab. 13, 573–583 (2011).

  45. 45.

    Erion, R., King, A. N., Wu, G., Hogenesch, J. B. & Sehgal, A. Neural clocks and Neuropeptide F/Y regulate circadian gene expression in a peripheral metabolic tissue. eLife 5, e13552 (2016).

  46. 46.

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

  47. 47.

    Storch, K. F. & Weitz, C. J. Daily rhythms of food-anticipatory behavioral activity do not require the known circadian clock. Proc. Natl Acad. Sci. USA 106, 6808–6813 (2009).

  48. 48.

    Yang, S. et al. The role of mPer2 clock gene in glucocorticoid and feeding rhythms. Endocrinology 150, 2153–2160 (2009).

  49. 49.

    Feillet, C. A. et al. Lack of food anticipation in Per2 mutant mice. Curr. Biol. 16, 2016–2022 (2006).

  50. 50.

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

  51. 51.

    Iijima, M. et al. Altered food-anticipatory activity rhythm in cryptochrome-deficient mice. Neurosci. Res. 52, 166–173 (2005).

  52. 52.

    Liu, Z. et al. PER1 phosphorylation specifies feeding rhythm in mice. Cell Rep. 7, 1509–1520 (2014).

  53. 53.

    Chappuis, S. et al. Role of the circadian clock gene Per2 in adaptation to cold temperature. Mol. Metab. 2, 184–193 (2013).

  54. 54.

    Gerhart-Hines, Z. et al. The nuclear receptor Rev-erbα controls circadian thermogenic plasticity. Nature 503, 410–413 (2013).

  55. 55.

    Delezie, J. et al. Rev-erbα in the brain is essential for circadian food entrainment. Sci. Rep. 6, 29386 (2016).

  56. 56.

    Orozco-Solis, R. et al. The circadian clock in the ventromedial hypothalamus controls cyclic energy expenditure. Cell Metab. 23, 467–478 (2016). This study identified a novel function of the VMH clock for circadian energy expenditure control.

  57. 57.

    Refinetti, R. & Menaker, M. The circadian rhythm of body temperature. Physiol. Behav. 51, 613–637 (1992).

  58. 58.

    Morrison, S. F., Madden, C. J. & Tupone, D. Central neural regulation of brown adipose tissue thermogenesis and energy expenditure. Cell Metab. 19, 741–756 (2014).

  59. 59.

    Bartness, T. J., Song, C. K. & Demas, G. E. SCN efferents to peripheral tissues: implications for biological rhythms. J. Biol. Rhythms 16, 196–204 (2001).

  60. 60.

    Guzman-Ruiz, M. A. et al. Role of the suprachiasmatic and arcuate nuclei in diurnal temperature regulation in the rat. J. Neurosci. 35, 15419–15429 (2015).

  61. 61.

    Grayson, B. E., Seeley, R. J. & Sandoval, D. A. Wired on sugar: the role of the CNS in the regulation of glucose homeostasis. Nat. Rev. Neurosci. 14, 24–37 (2013).

  62. 62.

    Lagerlof, O. et al. The nutrient sensor OGT in PVN neurons regulates feeding. Science 351, 1293–1296 (2016).

  63. 63.

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

  64. 64.

    Asher, G. & Sassone-Corsi, P. Time for food: the intimate interplay between nutrition, metabolism, and the circadian clock. Cell 161, 84–92 (2015).

  65. 65.

    Panda, S. Circadian physiology of metabolism. Science 354, 1008–1015 (2016).

  66. 66.

    Masri, S. & Sassone-Corsi, P. The circadian clock: a framework linking metabolism, epigenetics and neuronal function. Nat. Rev. Neurosci. 14, 69–75 (2013).

  67. 67.

    LeSauter, J., Romero, P., Cascio, M. & Silver, R. Attachment site of grafted SCN influences precision of restored circadian rhythm. J. Biol. Rhythms 12, 327–338 (1997).

  68. 68.

    Silver, R., LeSauter, J., Tresco, P. A. & Lehman, M. N. A diffusible coupling signal from the transplanted suprachiasmatic nucleus controlling circadian locomotor rhythms. Nature 382, 810–813 (1996).

  69. 69.

    Lehman, M. N. et al. Circadian rhythmicity restored by neural transplant. Immunocytochemical characterization of the graft and its integration with the host brain. J. Neurosci. 7, 1626–1638 (1987).

  70. 70.

    Guo, H., Brewer, J. M., Champhekar, A., Harris, R. B. & Bittman, E. L. Differential control of peripheral circadian rhythms by suprachiasmatic-dependent neural signals. Proc. Natl Acad. Sci. USA 102, 3111–3116 (2005).

  71. 71.

    Gamble, K. L., Berry, R., Frank, S. J. & Young, M. E. Circadian clock control of endocrine factors. Nat. Rev. Endocrinol. 10, 466–475 (2014).

  72. 72.

    Spiga, F., Walker, J. J., Terry, J. R. & Lightman, S. L. HPA axis-rhythms. Compr. Physiol. 4, 1273–1298 (2014).

  73. 73.

    Simpson, E. R. & Waterman, M. R. Regulation of the synthesis of steroidogenic enzymes in adrenal cortical cells by ACTH. Annu. Rev. Physiol. 50, 427–440 (1988).

  74. 74.

    Buijs, R. M. et al. Anatomical and functional demonstration of a multisynaptic suprachiasmatic nucleus adrenal (cortex) pathway. Eur. J. Neurosci. 11, 1535–1544 (1999).

  75. 75.

    Ishida, A. et al. Light activates the adrenal gland: timing of gene expression and glucocorticoid release. Cell Metab. 2, 297–307 (2005).

  76. 76.

    Oster, H. et al. The circadian rhythm of glucocorticoids is regulated by a gating mechanism residing in the adrenal cortical clock. Cell Metab. 4, 163–173 (2006).

  77. 77.

    Son, G. H. et al. Adrenal peripheral clock controls the autonomous circadian rhythm of glucocorticoid by causing rhythmic steroid production. Proc. Natl Acad. Sci. USA 105, 20970–20975 (2008).

  78. 78.

    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).

  79. 79.

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

  80. 80.

    Reddy, A. B. et al. Glucocorticoid signaling synchronizes the liver circadian transcriptome. Hepatology 45, 1478–1488 (2007).

  81. 81.

    Yamamoto, T. et al. Acute physical stress elevates mouse period1 mRNA expression in mouse peripheral tissues via a glucocorticoid-responsive element. J. Biol. Chem. 280, 42036–42043 (2005).

  82. 82.

    Stimson, R. H. et al. Acute physiological effects of glucocorticoids on fuel metabolism in humans are permissive but not direct. Diabetes Obes. Metab. 19, 883–891 (2017).

  83. 83.

    Lee, P. et al. Brown adipose tissue exhibits a glucose-responsive thermogenic biorhythm in humans. Cell Metab. 23, 602–609 (2016).

  84. 84.

    Brown, S. A., Zumbrunn, G., Fleury-Olela, F., Preitner, N. & Schibler, U. Rhythms of mammalian body temperature can sustain peripheral circadian clocks. Curr. Biol. 12, 1574–1583 (2002).

  85. 85.

    Buhr, E. D., Yoo, S. H. & Takahashi, J. S. Temperature as a universal resetting cue for mammalian circadian oscillators. Science 330, 379–385 (2010).

  86. 86.

    Saini, C., Morf, J., Stratmann, M., Gos, P. & Schibler, U. Simulated body temperature rhythms reveal the phase-shifting behavior and plasticity of mammalian circadian oscillators. Genes Dev. 26, 567–580 (2012).

  87. 87.

    Tamaru, T. et al. Synchronization of circadian Per2 rhythms and HSF1-BMAL1:CLOCK interaction in mouse fibroblasts after short-term heat shock pulse. PLOS ONE 6, e24521 (2011).

  88. 88.

    Morf, J. et al. Cold-inducible RNA-binding protein modulates circadian gene expression posttranscriptionally. Science 338, 379–383 (2012).

  89. 89.

    Borjigin, J., Zhang, L. S. & Calinescu, A. A. Circadian regulation of pineal gland rhythmicity. Mol. Cell Endocrinol. 349, 13–19 (2012).

  90. 90.

    Slominski, R. M., Reiter, R. J., Schlabritz-Loutsevitch, N., Ostrom, R. S. & Slominski, A. T. Melatonin membrane receptors in peripheral tissues: distribution and functions. Mol. Cell Endocrinol. 351, 152–166 (2012).

  91. 91.

    Alonso-Vale, M. I. et al. Melatonin and the circadian entrainment of metabolic and hormonal activities in primary isolated adipocytes. J. Pineal Res. 45, 422–429 (2008).

  92. 92.

    Peschke, E., Bach, A. G. & Muhlbauer, E. Parallel signaling pathways of melatonin in the pancreatic β-cell. J. Pineal Res. 40, 184–191 (2006).

  93. 93.

    Peschke, E. et al. Receptor (MT1) mediated influence of melatonin on cAMP concentration and insulin secretion of rat insulinoma cells INS-1. J. Pineal Res. 33, 63–71 (2002).

  94. 94.

    Muhlbauer, E., Albrecht, E., Hofmann, K., Bazwinsky-Wutschke, I. & Peschke, E. Melatonin inhibits insulin secretion in rat insulinoma β-cells (INS-1) heterologously expressing the human melatonin receptor isoform MT2. J. Pineal Res. 51, 361–372 (2011).

  95. 95.

    Lima, F. B. et al. Pinealectomy causes glucose intolerance and decreases adipose cell responsiveness to insulin in rats. Am. J. Physiol. 275, E934–E941 (1998).

  96. 96.

    Picinato, M. C., Haber, E. P., Carpinelli, A. R. & Cipolla-Neto, J. Daily rhythm of glucose-induced insulin secretion by isolated islets from intact and pinealectomized rat. J. Pineal Res. 33, 172–177 (2002).

  97. 97.

    Tuomi, T. et al. Increased melatonin signaling is a risk factor for type 2 diabetes. Cell Metab. 23, 1067–1077 (2016).

  98. 98.

    La Fleur, S. E. Daily rhythms in glucose metabolism: suprachiasmatic nucleus output to peripheral tissue. J. Neuroendocrinol. 15, 315–322 (2003).

  99. 99.

    la Fleur, S. E., Kalsbeek, A., Wortel, J., Fekkes, M. L. & Buijs, R. M. A daily rhythm in glucose tolerance: a role for the suprachiasmatic nucleus. Diabetes 50, 1237–1243 (2001).

  100. 100.

    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).

  101. 101.

    Ruiter, M. et al. The daily rhythm in plasma glucagon concentrations in the rat is modulated by the biological clock and by feeding behavior. Diabetes 52, 1709–1715 (2003).

  102. 102.

    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).

  103. 103.

    Nonogaki, K. New insights into sympathetic regulation of glucose and fat metabolism. Diabetologia 43, 533–549 (2000).

  104. 104.

    Kalsbeek, A., La Fleur, S., Van Heijningen, C. & Buijs, R. M. Suprachiasmatic GABAergic inputs to the paraventricular nucleus control plasma glucose concentrations in the rat via sympathetic innervation of the liver. J. Neurosci. 24, 7604–7613 (2004).

  105. 105.

    Yi, C. X. et al. A major role for perifornical orexin neurons in the control of glucose metabolism in rats. Diabetes 58, 1998–2005 (2009).

  106. 106.

    Tsuneki, H., Wada, T. & Sasaoka, T. Role of orexin in the regulation of glucose homeostasis. Acta Physiol. (Oxf.) 198, 335–348 (2010).

  107. 107.

    Yoshida, K., McCormack, S., Espana, R. A., Crocker, A. & Scammell, T. E. Afferents to the orexin neurons of the rat brain. J. Comp. Neurol. 494, 845–861 (2006).

  108. 108.

    Zhang, S. et al. Lesions of the suprachiasmatic nucleus eliminate the daily rhythm of hypocretin-1 release. Sleep 27, 619–627 (2004).

  109. 109.

    Gotter, A. L. et al. The duration of sleep promoting efficacy by dual orexin receptor antagonists is dependent upon receptor occupancy threshold. BMC Neurosci. 14, 90 (2013).

  110. 110.

    Tsuneki, H. et al. Hypothalamic orexin prevents hepatic insulin resistance via daily bidirectional regulation of autonomic nervous system in mice. Diabetes 64, 459–470 (2015).

  111. 111.

    Nishino, S., Ripley, B., Overeem, S., Lammers, G. J. & Mignot, E. Hypocretin (orexin) deficiency in human narcolepsy. Lancet 355, 39–40 (2000).

  112. 112.

    Schuld, A., Hebebrand, J., Geller, F. & Pollmacher, T. Increased body-mass index in patients with narcolepsy. Lancet 355, 1274–1275 (2000).

  113. 113.

    Honda, Y., Doi, Y., Ninomiya, R. & Ninomiya, C. Increased frequency of non-insulin-dependent diabetes mellitus among narcoleptic patients. Sleep 9, 254–259 (1986).

  114. 114.

    Lopez, M., Nogueiras, R., Tena-Sempere, M. & Dieguez, C. Hypothalamic AMPK: a canonical regulator of whole-body energy balance. Nat. Rev. Endocrinol. 12, 421–432 (2016).

  115. 115.

    Minokoshi, Y. et al. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428, 569–574 (2004).

  116. 116.

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

  117. 117.

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

  118. 118.

    Barnea, M., Chapnik, N., Genzer, Y. & Froy, O. The circadian clock machinery controls adiponectin expression. Mol. Cell Endocrinol. 399, 284–287 (2015).

  119. 119.

    Gavrila, A. et al. Diurnal and ultradian dynamics of serum adiponectin in healthy men: comparison with leptin, circulating soluble leptin receptor, and cortisol patterns. J. Clin. Endocrinol. Metab. 88, 2838–2843 (2003).

  120. 120.

    Kubota, N. et al. Adiponectin stimulates AMP-activated protein kinase in the hypothalamus and increases food intake. Cell Metab. 6, 55–68 (2007).

  121. 121.

    Um, J. H. et al. AMPK regulates circadian rhythms in a tissue- and isoform-specific manner. PLOS ONE 6, e18450 (2011).

  122. 122.

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

  123. 123.

    Cao, R. et al. Translational control of entrainment and synchrony of the suprachiasmatic circadian clock by mTOR/4E-BP1 signaling. Neuron 79, 712–724 (2013).

  124. 124.

    Zheng, X. & Sehgal, A. AKT and TOR signaling set the pace of the circadian pacemaker. Curr. Biol. 20, 1203–1208 (2010).

  125. 125.

    Ramanathan, C. et al. mTOR signaling regulates central and peripheral circadian clock function. PLOS Genet. 14, e1007369 (2018).

  126. 126.

    Brooks, C. L. & Gu, W. How does SIRT1 affect metabolism, senescence and cancer? Nat. Rev. Cancer 9, 123–128 (2009).

  127. 127.

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

  128. 128.

    Nakahata, Y. et al. The NAD+-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control. Cell 134, 329–340 (2008).

  129. 129.

    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).

  130. 130.

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

  131. 131.

    Ramadori, G. et al. SIRT1 deacetylase in POMC neurons is required for homeostatic defenses against diet-induced obesity. Cell Metab. 12, 78–87 (2010).

  132. 132.

    Cakir, I. et al. Hypothalamic Sirt1 regulates food intake in a rodent model system. PLOS ONE 4, e8322 (2009).

  133. 133.

    Orozco-Solis, R., Ramadori, G., Coppari, R. & Sassone-Corsi, P. SIRT1 relays nutritional inputs to the circadian clock through the Sf1 neurons of the ventromedial hypothalamus. Endocrinology 156, 2174–2184 (2015).

  134. 134.

    Ramadori, G. et al. Brain SIRT1: anatomical distribution and regulation by energy availability. J. Neurosci. 28, 9989–9996 (2008).

  135. 135.

    Yoon, M. J. et al. SIRT1-mediated eNAMPT secretion from adipose tissue regulates hypothalamic NAD+ and function in mice. Cell Metab. 21, 706–717 (2015).

  136. 136.

    Badman, M. K. et al. Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab. 5, 426–437 (2007).

  137. 137.

    Galman, C. et al. The circulating metabolic regulator FGF21 is induced by prolonged fasting and PPARalpha activation in man. Cell Metab. 8, 169–174 (2008).

  138. 138.

    Tong, X. et al. Transcriptional repressor E4-binding protein 4 (E4BP4) regulates metabolic hormone fibroblast growth factor 21 (FGF21) during circadian cycles and feeding. J. Biol. Chem. 285, 36401–36409 (2010).

  139. 139.

    Chavan, R. et al. REV-ERBalpha regulates Fgf21 expression in the liver via hepatic nuclear factor 6. Biol. Open 6, 1–7 (2017).

  140. 140.

    Oishi, K., Uchida, D. & Ishida, N. Circadian expression of FGF21 is induced by PPARalpha activation in the mouse liver. FEBS Lett. 582, 3639–3642 (2008).

  141. 141.

    Andersen, B., Beck-Nielsen, H. & Hojlund, K. Plasma FGF21 displays a circadian rhythm during a 72-h fast in healthy female volunteers. Clin. Endocrinol. (Oxf.) 75, 514–519 (2011).

  142. 142.

    Bookout, A. L. et al. FGF21 regulates metabolism and circadian behavior by acting on the nervous system. Nat. Med. 19, 1147–1152 (2013). This is a nice example of how a peripheral metabolic regulator can modulate the central clock in the SCN.

  143. 143.

    Bass, J. & Lazar, M. A. Circadian time signatures of fitness and disease. Science 354, 994–999 (2016).

  144. 144.

    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).

  145. 145.

    Mukherji, A. et al. Shifting eating to the circadian rest phase misaligns the peripheral clocks with the master SCN clock and leads to a metabolic syndrome. Proc. Natl Acad. Sci. USA 112, E6691–E6698 (2015).

  146. 146.

    Kohsaka, A. et al. High-fat diet disrupts behavioral and molecular circadian rhythms in mice. Cell Metab. 6, 414–421 (2007).

  147. 147.

    Meyer-Kovac, J. et al. Hepatic gene therapy rescues high-fat diet responses in circadian Clock mutant mice. Mol. Metab. 6, 512–523 (2017).

  148. 148.

    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).

  149. 149.

    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). This study is a nice demonstration of how feeding time can impact peripheral circadian rhythms and metabolic fitness.

  150. 150.

    Chaix, A., Zarrinpar, A., Miu, P. & Panda, S. Time-restricted feeding is a preventative and therapeutic intervention against diverse nutritional challenges. Cell Metab. 20, 991–1005 (2014).

  151. 151.

    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).

  152. 152.

    Wehrens, S. M. T. et al. Meal timing regulates the human circadian system. Curr. Biol. 27, 1768–1775 (2017). This study demonstrates that meal timing affects daily rhythms also in humans.

  153. 153.

    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).

  154. 154.

    Mendoza, J., Pevet, P. & Challet, E. High-fat feeding alters the clock synchronization to light. J. Physiol. 586, 5901–5910 (2008).

  155. 155.

    Dyar, K. A. et al. Atlas of circadian metabolism reveals system-wide coordination and communication between clocks. Cell 174, 1571–1585 (2018). This study provides a comprehensive analysis of circadian metabolic profiles across multiple tissues.

  156. 156.

    Eckel-Mahan, K. L. et al. Reprogramming of the circadian clock by nutritional challenge. Cell 155, 1464–1478 (2013). This study provides the first comprehensive evidence that nutritional challenges can rewire peripheral clocks.

  157. 157.

    Ryan, K. K. et al. A role for central nervous system PPAR-gamma in the regulation of energy balance. Nat. Med. 17, 623–626 (2011).

  158. 158.

    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).

  159. 159.

    Sato, S. et al. Circadian reprogramming in the liver identifies metabolic pathways of aging. Cell 170, 664–677 (2017).

  160. 160.

    Solanas, G. et al. Aged stem cells reprogram their daily rhythmic functions to adapt to stress. Cell 170, 678–692 (2017).

  161. 161.

    Verdin, E. NAD+ in aging, metabolism, and neurodegeneration. Science 350, 1208–1213 (2015).

  162. 162.

    Zhu, X. H., Lu, M., Lee, B. Y., Ugurbil, K. & Chen, W. In vivo NAD assay reveals the intracellular NAD contents and redox state in healthy human brain and their age dependences. Proc. Natl Acad. Sci. USA 112, 2876–2881 (2015).

  163. 163.

    Yoshino, J., Baur, J. A. & Imai, S. I. NAD+intermediates: the biology and therapeutic potential of NMN and NR. Cell Metab. 27, 513–528 (2017).

  164. 164.

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

  165. 165.

    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).

  166. 166.

    Mendoza, J., Drevet, K., Pevet, P. & Challet, E. Daily meal timing is not necessary for resetting the main circadian clock by calorie restriction. J. Neuroendocrinol. 20, 251–260 (2008).

  167. 167.

    Carneiro, L. et al. Evidence for hypothalamic ketone body sensing: impact on food intake and peripheral metabolic responses in mice. Am. J. Physiol. Endocrinol. Metab. 310, E103–E115 (2016).

  168. 168.

    Chavan, R. et al. Liver-derived ketone bodies are necessary for food anticipation. Nat. Commun. 7, 10580 (2016).

  169. 169.

    Genzer, Y., Dadon, M., Burg, C., Chapnik, N. & Froy, O. Ketogenic diet delays the phase of circadian rhythms and does not affect AMP-activated protein kinase (AMPK) in mouse liver. Mol. Cell Endocrinol. 417, 124–130 (2015).

  170. 170.

    Shimazu, T. et al. Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science 339, 211–214 (2013).

  171. 171.

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

  172. 172.

    Xie, Z. et al. Metabolic regulation of gene expression by histone lysine β-hydroxybutyrylation. Mol. Cell 62, 194–206 (2016).

  173. 173.

    Paoli, A., Rubini, A., Volek, J. S. & Grimaldi, K. A. Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets. Eur. J. Clin. Nutr. 67, 789–796 (2013).

  174. 174.

    Newman, J. C. et al. Ketogenic diet reduces midlife mortality and improves memory in aging mice. Cell Metab. 26, 547–557 (2017).

  175. 175.

    Valnegri, P. et al. A circadian clock in hippocampus is regulated by interaction between oligophrenin-1 and Rev-erbα. Nat. Neurosci. 14, 1293–1301 (2011).

  176. 176.

    Fernandez, F. et al. Circadian rhythm. Dysrhythmia in the suprachiasmatic nucleus inhibits memory processing. Science 346, 854–857 (2014).

  177. 177.

    Gill, S., Le, H. D., Melkani, G. C. & Panda, S. Time-restricted feeding attenuates age-related cardiac decline in Drosophila. Science 347, 1265–1269 (2015).

  178. 178.

    Katewa, S. D. et al. Peripheral circadian clocks mediate dietary restriction-dependent changes in lifespan and fat metabolism in Drosophila. Cell Metab. 23, 143–154 (2016).

  179. 179.

    Eckel-Mahan, K. & Sassone-Corsi, P. Metabolism and the circadian clock converge. Physiol. Rev. 93, 107–135 (2013).

  180. 180.

    Gallego, M. & Virshup, D. M. Post-translational modifications regulate the ticking of the circadian clock. Nat. Rev. Mol. Cell Biol. 8, 139–148 (2007).

  181. 181.

    Ceglia, N. et al. CircadiOmics: circadian omic web portal. Nucleic Acids Res. 46, W157–W162 (2018).

  182. 182.

    Guan, D. et al. Diet-induced circadian enhancer remodeling synchronizes opposing hepatic lipid metabolic processes. Cell 174, 831–842 (2018).

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The authors thank all members of the Sassone–Corsi laboratory for helpful discussions. Funding for C.M.G. was provided by the National Cancer Institute of the US National Institutes of Health (NIH T32 2T32CA009054-36A1) and by the European Research Council (ERC MSCA-IF-2016 MetEpiClock 749869). Financial support for P.S.-C. was provided by the National Institute of Health, INSERM, a KAUST–UCI partnership and a Novo Nordisk Challenge Grant.

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Nature Reviews Neuroscience thanks the anonymous reviewers for their contribution to the peer review of this work.

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  1. Department of Biological Chemistry, Center for Epigenetics and Metabolism, School of Medicine, University of California, Irvine, CA, USA

    • Carolina Magdalen Greco
    •  & Paolo Sassone–Corsi


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P.S.-C. and C.M.G. researched data for article, made substantial contributions to discussion of content and wrote, reviewed and edited the manuscript before submission.

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The authors declare no competing interests.

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Correspondence to Paolo Sassone–Corsi.


Promoter element

The proximal DNA regulatory element immediately upstream of the transcription start site (TSS).

Chromatin transitions

Promoter elements governed by specific epigenetic modifications that can shift from an ‘active’ accessible state to a ‘repressed’ state and vice versa.


Timing systems composed of transcriptional and translational feedback loops with an endogenous periodicity of approximately 24 hours.


Characterized by an abnormal increase of food consumption.

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