Journal of Molecular Medicine

, Volume 97, Issue 6, pp 741–759 | Cite as

Circadian rhythms: a possible new player in non-alcoholic fatty liver disease pathophysiology

  • Davide Gnocchi
  • Carlo Custodero
  • Carlo Sabbà
  • Antonio MazzoccaEmail author


Over the last decades, a better knowledge of the molecular machinery supervising the regulation of circadian clocks has been achieved, and numerous findings have helped in unravelling the outstanding significance of the molecular clock for the proper regulation of our physiologic and metabolic homeostasis. Non-alcoholic fatty liver disease (NAFLD) is currently considered as one of the emerging liver pathologies in the Western countries due to the modification of eating habits and lifestyle. Although NAFLD is considered a pretty benign condition, it can progress towards non-alcoholic steatohepatitis (NASH) and eventually hepatocellular carcinoma (HCC). The pathogenic mechanisms involved in NAFLD development are complex, since this disease is a multifactorial condition. Major metabolic deregulations along with a genetic background are believed to take part in this process. In this light, the aim of this review is to give a comprehensive description of how our circadian machinery is regulated and to describe to what extent our internal clock is involved in the regulation of hormonal and metabolic homeostasis, and by extension in the development and progression of NAFLD/NASH and eventually in the onset of HCC.


Non-alcoholic fatty liver disease (NAFLD) Non-alcoholic steatohepatitis (NASH) Hepatocellular carcinoma (HCC) Circadian rhythms Metabolism Metabolic syndrome Insulin resistance 



Non-alcoholic fatty liver disease


Non-alcoholic steatohepatitis


Alcoholic fatty liver disease


Hepatocellular carcinoma


Metabolic syndrome


Body mass index


Polyunsaturated fatty acids


Patatin-like phospholipase domain-coding protein


Insulin resistance


Free fatty acid


Single nucleotide polymorphisms


Genome-wide association studies


Author contributions

Conceptualisation and writing—original draft preparation, D.G.; conceptualisation and writing—review and editing, A.M.; writing—review and editing, C.C., C.S.

Funding information

The work was supported by the AIRC (Italian Association for Cancer Research) Investigator Grant (IG) 2015 Id.17758 (to A. Mazzocca).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.


  1. 1.
    Ratziu V, Bellentani S, Cortez-Pinto H, Day C, Marchesini G (2010) A position statement on NAFLD/NASH based on the EASL 2009 special conference. J Hepatol 53:372–384Google Scholar
  2. 2.
    Vajro P, Lenta S, Socha P, Dhawan A, McKiernan P, Baumann U, Durmaz O, Lacaille F, McLin V, Nobili V (2012) Diagnosis of nonalcoholic fatty liver disease in children and adolescents: position paper of the ESPGHAN Hepatology Committee. J Pediatr Gastroenterol Nutr 54:700–713Google Scholar
  3. 3.
    Brunt EM (2012) Nonalcoholic fatty liver disease: what the pathologist can tell the clinician. Dig Dis 30(Suppl 1):61–68Google Scholar
  4. 4.
    White DL, Kanwal F, El-Serag HB (2012) Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin Gastroenterol Hepatol 10:1342–1359.e42Google Scholar
  5. 5.
    Dowla S, Aslibekyan S, Goss A, Fontaine K, Ashraf AP (2018) Dyslipidemia is associated with pediatric nonalcoholic fatty liver disease. J Clin Lipidol 12:981–987Google Scholar
  6. 6.
    Liu K, McCaughan GW (2018) Epidemiology and etiologic associations of non-alcoholic fatty liver disease and associated HCC. Adv Exp Med Biol 1061:3–18Google Scholar
  7. 7.
    Mahady SE, Adams LA (2018) Burden of non-alcoholic fatty liver disease in Australia. J Gastroenterol Hepatol 33(Suppl 1):1–11Google Scholar
  8. 8.
    Pimpin L, Cortez-Pinto H, Negro F, Corbould E, Lazarus JV, Webber L, Sheron N, Committee EHS (2018) Burden of liver disease in Europe: epidemiology and analysis of risk factors to identify prevention policies. J Hepatol 69:718–735Google Scholar
  9. 9.
    Younossi ZM, Blissett D, Blissett R, Henry L, Stepanova M, Younossi Y, Racila A, Hunt S, Beckerman R (2016) The economic and clinical burden of nonalcoholic fatty liver disease in the United States and Europe. Hepatology 64:1577–1586Google Scholar
  10. 10.
    Newton JL, Jones DE, Henderson E, Kane L, Wilton K, Burt AD, Day CP (2008) Fatigue in non-alcoholic fatty liver disease (NAFLD) is significant and associates with inactivity and excessive daytime sleepiness but not with liver disease severity or insulin resistance. Gut 57:807–813Google Scholar
  11. 11.
    Mittal S, Sada YH, El-Serag HB, Kanwal F, Duan Z, Temple S, May SB, Kramer JR, Richardson PA, Davila JA (2015) Temporal trends of nonalcoholic fatty liver disease-related hepatocellular carcinoma in the veteran affairs population. Clin Gastroenterol Hepatol 13:594–601.e1Google Scholar
  12. 12.
    Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M (2016) Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 64:73–84Google Scholar
  13. 13.
    Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, Charlton M, Sanyal AJ (2012) The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 55:2005–2023Google Scholar
  14. 14.
    Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, Ferrell LD, Liu YC, Torbenson MS, Unalp-Arida A et al (2005) Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 41:1313–1321Google Scholar
  15. 15.
    Castera L, Vilgrain V, Angulo P (2013) Noninvasive evaluation of NAFLD. Nat Rev Gastroenterol Hepatol 10:666–675Google Scholar
  16. 16.
    Kaneda H, Hashimoto E, Yatsuji S, Tokushige K, Shiratori K (2006) Hyaluronic acid levels can predict severe fibrosis and platelet counts can predict cirrhosis in patients with nonalcoholic fatty liver disease. J Gastroenterol Hepatol 21:1459–1465Google Scholar
  17. 17.
    Guha IN, Parkes J, Roderick P, Chattopadhyay D, Cross R, Harris S, Kaye P, Burt AD, Ryder SD, Aithal GP et al (2008) Noninvasive markers of fibrosis in nonalcoholic fatty liver disease: validating the European Liver Fibrosis Panel and exploring simple markers. Hepatology 47:455–460Google Scholar
  18. 18.
    Feldstein AE, Wieckowska A, Lopez AR, Liu YC, Zein NN, McCullough AJ (2009) Cytokeratin-18 fragment levels as noninvasive biomarkers for nonalcoholic steatohepatitis: a multicenter validation study. Hepatology 50:1072–1078Google Scholar
  19. 19.
    Harrison SA, Oliver D, Arnold HL, Gogia S, Neuschwander-Tetri BA (2008) Development and validation of a simple NAFLD clinical scoring system for identifying patients without advanced disease. Gut 57:1441–1447Google Scholar
  20. 20.
    Pang Q, Zhang JY, Song SD, Qu K, Xu XS, Liu SS, Liu C (2015) Central obesity and nonalcoholic fatty liver disease risk after adjusting for body mass index. World J Gastroenterol 21:1650–1662Google Scholar
  21. 21.
    Ueno T, Sugawara H, Sujaku K, Hashimoto O, Tsuji R, Tamaki S, Torimura T, Inuzuka S, Sata M, Tanikawa K (1997) Therapeutic effects of restricted diet and exercise in obese patients with fatty liver. J Hepatol 27:103–107Google Scholar
  22. 22.
    Palmer M, Schaffner F (1990) Effect of weight reduction on hepatic abnormalities in overweight patients. Gastroenterology 99:1408–1413Google Scholar
  23. 23.
    Wong VW, Wong GL, Choi PC, Chan AW, Li MK, Chan HY, Chim AM, Yu J, Sung JJ, Chan HL (2010) Disease progression of non-alcoholic fatty liver disease: a prospective study with paired liver biopsies at 3 years. Gut 59:969–974Google Scholar
  24. 24.
    Berlanga A, Guiu-Jurado E, Porras JA, Auguet T (2014) Molecular pathways in non-alcoholic fatty liver disease. Clin Exp Gastroenterol 7:221–239Google Scholar
  25. 25.
    Malaguarnera M, Di Rosa M, Nicoletti F, Malaguarnera L (2009) Molecular mechanisms involved in NAFLD progression. J Mol Med (Berl) 87:679–695Google Scholar
  26. 26.
    Savage DB, Semple RK (2010) Recent insights into fatty liver, metabolic dyslipidaemia and their links to insulin resistance. Curr Opin Lipidol 21:329–336Google Scholar
  27. 27.
    Kawano Y, Cohen DE (2013) Mechanisms of hepatic triglyceride accumulation in non-alcoholic fatty liver disease. J Gastroenterol 48:434–441Google Scholar
  28. 28.
    Tilg H, Moschen AR (2010) Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 52:1836–1846Google Scholar
  29. 29.
    Zhang XQ, Xu CF, Yu CH, Chen WX, Li YM (2014) Role of endoplasmic reticulum stress in the pathogenesis of nonalcoholic fatty liver disease. World J Gastroenterol 20:1768–1776Google Scholar
  30. 30.
    Sumida Y, Niki E, Naito Y, Yoshikawa T (2013) Involvement of free radicals and oxidative stress in NAFLD/NASH. Free Radic Res 47:869–880Google Scholar
  31. 31.
    Neuschwander-Tetri BA (2010) Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites. Hepatology 52:774–788Google Scholar
  32. 32.
    Frasinariu OE, Ceccarelli S, Alisi A, Moraru E, Nobili V (2013) Gut-liver axis and fibrosis in nonalcoholic fatty liver disease: an input for novel therapies. Dig Liver Dis 45:543–551Google Scholar
  33. 33.
    De Minicis S, Svegliati-Baroni G (2011) Fibrogenesis in nonalcoholic steatohepatitis. Expert Rev Gastroenterol Hepatol 5:179–187Google Scholar
  34. 34.
    Bunning E, Moser I (1973) Light-induced phase shifts of circadian leaf movements of phaseolus: comparison with the effects of potassium and of ethyl alcohol. Proc Natl Acad Sci U S A 70:3387–3389Google Scholar
  35. 35.
    Pittendrigh CS (1967) Circadian systems. I. The driving oscillation and its assay in Drosophila pseudoobscura. Proc Natl Acad Sci U S A 58:1762–1767Google Scholar
  36. 36.
    Pittendrigh CS, Skopik SD (1970) Circadian systems. V. The driving oscillation and the temporal sequence of development. Proc Natl Acad Sci U S A 65:500–507Google Scholar
  37. 37.
    Skopik SD, Pittendrigh CS (1967) Circadian systems, II. The oscillation in the individual Drosophila pupa; its independence of developmental stage. Proc Natl Acad Sci U S A 58:1862–1869Google Scholar
  38. 38.
    Richter CP (1967) Sleep and activity: their relation to the 24-hour clock. Res Publ Assoc Res Nerv Ment Dis 45:8–29Google Scholar
  39. 39.
    Richter CP (1971) Inborn nature of the rat’s 24-hour clock. J Comp Physiol Psychol 75:1–4Google Scholar
  40. 40.
    Stephan FK, Zucker I (1972) Circadian rhythms in drinking behavior and locomotor activity of rats are eliminated by hypothalamic lesions. Proc Natl Acad Sci U S A 69:1583–1586Google Scholar
  41. 41.
    Moore RY, Eichler VB (1972) Loss of a circadian adrenal corticosterone rhythm following suprachiasmatic lesions in the rat. Brain Res 42:201–206Google Scholar
  42. 42.
    Inouye ST, Kawamura H (1979) Persistence of circadian rhythmicity in a mammalian hypothalamic “island” containing the suprachiasmatic nucleus. Proc Natl Acad Sci U S A 76:5962–5966Google Scholar
  43. 43.
    Ralph MR, Foster RG, Davis FC, Menaker M (1990) Transplanted suprachiasmatic nucleus determines circadian period. Science 247:975–978Google Scholar
  44. 44.
    Ralph MR, Menaker M (1988) A mutation of the circadian system in golden hamsters. Science 241:1225–1227Google Scholar
  45. 45.
    Berson DM, Dunn FA, Takao M (2002) Phototransduction by retinal ganglion cells that set the circadian clock. Science 295:1070–1073Google Scholar
  46. 46.
    Damiola F, Le Minh N, Preitner N, Kornmann B, Fleury-Olela F, Schibler U (2000) Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus. Genes Dev 14:2950–2961Google Scholar
  47. 47.
    Stokkan KA, Yamazaki S, Tei H, Sakaki Y, Menaker M (2001) Entrainment of the circadian clock in the liver by feeding. Science 291:490–493Google Scholar
  48. 48.
    Leak RK, Card JP, Moore RY (1999) Suprachiasmatic pacemaker organization analyzed by viral transynaptic transport. Brain Res 819:23–32Google Scholar
  49. 49.
    Schwartz MD, Urbanski HF, Nunez AA, Smale L (2011) Projections of the suprachiasmatic nucleus and ventral subparaventricular zone in the Nile grass rat (Arvicanthis niloticus). Brain Res 1367:146–161Google Scholar
  50. 50.
    Hermes ML, Coderre EM, Buijs RM, Renaud LP (1996) GABA and glutamate mediate rapid neurotransmission from suprachiasmatic nucleus to hypothalamic paraventricular nucleus in rat. J Physiol 496(Pt 3):749–757Google Scholar
  51. 51.
    Kalsbeek A, Buijs RM (1992) Peptidergic transmitters of the suprachiasmatic nuclei and the control of circadian rhythmicity. Prog Brain Res 92:321–333Google Scholar
  52. 52.
    Kalsbeek A, Buijs RM, Engelmann M, Wotjak CT, Landgraf R (1995) In vivo measurement of a diurnal variation in vasopressin release in the rat suprachiasmatic nucleus. Brain Res 682:75–82Google Scholar
  53. 53.
    Kalsbeek A, Buijs RM, van Heerikhuize JJ, Arts M, van der Woude TP (1992) Vasopressin-containing neurons of the suprachiasmatic nuclei inhibit corticosterone release. Brain Res 580:62–67Google Scholar
  54. 54.
    Kraves S, Weitz CJ (2006) A role for cardiotrophin-like cytokine in the circadian control of mammalian locomotor activity. Nat Neurosci 9:212–219Google Scholar
  55. 55.
    Cheng MY, Bullock CM, Li C, Lee AG, Bermak JC, Belluzzi J, Weaver DR, Leslie FM, Zhou QY (2002) Prokineticin 2 transmits the behavioural circadian rhythm of the suprachiasmatic nucleus. Nature 417:405–410Google Scholar
  56. 56.
    Kramer A, Yang FC, Snodgrass P, Li X, Scammell TE, Davis FC, Weitz CJ (2001) Regulation of daily locomotor activity and sleep by hypothalamic EGF receptor signaling. Science 294:2511–2515Google Scholar
  57. 57.
    Li X, Sankrithi N, Davis FC (2002) Transforming growth factor-alpha is expressed in astrocytes of the suprachiasmatic nucleus in hamster: role of glial cells in circadian clocks. Neuroreport 13:2143–2147Google Scholar
  58. 58.
    Konopka RJ, Benzer S (1971) Clock mutants of Drosophila melanogaster. Proc Natl Acad Sci U S A 68:2112–2116Google Scholar
  59. 59.
    Siwicki KK, Eastman C, Petersen G, Rosbash M, Hall JC (1988) Antibodies to the period gene product of Drosophila reveal diverse tissue distribution and rhythmic changes in the visual system. Neuron 1:141–150Google Scholar
  60. 60.
    Hardin PE, Hall JC, Rosbash M (1990) Feedback of the Drosophila period gene product on circadian cycling of its messenger RNA levels. Nature 343:536–540Google Scholar
  61. 61.
    Sehgal A, Rothenfluh-Hilfiker A, Hunter-Ensor M, Chen Y, Myers MP, Young MW (1995) Rhythmic expression of timeless: a basis for promoting circadian cycles in period gene autoregulation. Science 270:808–810Google Scholar
  62. 62.
    Vitaterna MH, King DP, Chang AM, Kornhauser JM, Lowrey PL, McDonald JD, Dove WF, Pinto LH, Turek FW, Takahashi JS (1994) Mutagenesis and mapping of a mouse gene, clock, essential for circadian behavior. Science 264:719–725Google Scholar
  63. 63.
    Rutila JE, Suri V, Le M, So WV, Rosbash M, Hall JC (1998) CYCLE is a second bHLH-PAS clock protein essential for circadian rhythmicity and transcription of Drosophila period and timeless. Cell 93:805–814Google Scholar
  64. 64.
    Veleri S, Brandes C, Helfrich-Forster C, Hall JC, Stanewsky R (2003) A self-sustaining, light-entrainable circadian oscillator in the Drosophila brain. Curr Biol 13:1758–1767Google Scholar
  65. 65.
    Shigeyoshi Y, Taguchi K, Yamamoto S, Takekida S, Yan L, Tei H, Moriya T, Shibata S, Loros JJ, Dunlap JC et al (1997) Light-induced resetting of a mammalian circadian clock is associated with rapid induction of the mPer1 transcript. Cell 91:1043–1053Google Scholar
  66. 66.
    Tei H, Okamura H, Shigeyoshi Y, Fukuhara C, Ozawa R, Hirose M, Sakaki Y (1997) Circadian oscillation of a mammalian homologue of the Drosophila period gene. Nature 389:512–516Google Scholar
  67. 67.
    Zylka MJ, Shearman LP, Weaver DR, Reppert SM (1998) Three period homologs in mammals: differential light responses in the suprachiasmatic circadian clock and oscillating transcripts outside of brain. Neuron 20:1103–1110Google Scholar
  68. 68.
    Gekakis N, Staknis D, Nguyen HB, Davis FC, Wilsbacher LD, King DP, Takahashi JS, Weitz CJ (1998) Role of the CLOCK protein in the mammalian circadian mechanism. Science 280:1564–1569Google Scholar
  69. 69.
    Thresher RJ, Vitaterna MH, Miyamoto Y, Kazantsev A, Hsu DS, Petit C, Selby CP, Dawut L, Smithies O, Takahashi JS et al (1998) Role of mouse cryptochrome blue-light photoreceptor in circadian photoresponses. Science 282:1490–1494Google Scholar
  70. 70.
    van der Horst GT, Muijtjens M, Kobayashi K, Takano R, Kanno S, Takao M, de Wit J, Verkerk A, Eker AP, van Leenen D et al (1999) Mammalian Cry1 and Cry2 are essential for maintenance of circadian rhythms. Nature 398:627–630Google Scholar
  71. 71.
    Vitaterna MH, Selby CP, Todo T, Niwa H, Thompson C, Fruechte EM, Hitomi K, Thresher RJ, Ishikawa T, Miyazaki J et al (1999) Differential regulation of mammalian period genes and circadian rhythmicity by cryptochromes 1 and 2. Proc Natl Acad Sci U S A 96:12114–12119Google Scholar
  72. 72.
    Guillaumond F, Dardente H, Giguere V, Cermakian N (2005) Differential control of Bmal1 circadian transcription by REV-ERB and ROR nuclear receptors. J Biol Rhythm 20:391–403Google Scholar
  73. 73.
    Liu AC, Tran HG, Zhang EE, Priest AA, Welsh DK, Kay SA (2008) Redundant function of REV-ERBalpha and beta and non-essential role for Bmal1 cycling in transcriptional regulation of intracellular circadian rhythms. PLoS Genet 4:e1000023. Google Scholar
  74. 74.
    Preitner N, Damiola F, Lopez-Molina L, Zakany J, Duboule D, Albrecht U, Schibler U (2002) The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell 110:251–260Google Scholar
  75. 75.
    Sato TK, Panda S, Miraglia LJ, Reyes TM, Rudic RD, McNamara P, Naik KA, FitzGerald GA, Kay SA, Hogenesch JB (2004) A functional genomics strategy reveals Rora as a component of the mammalian circadian clock. Neuron 43:527–537Google Scholar
  76. 76.
    Cho H, Zhao X, Hatori M, Yu RT, Barish GD, Lam MT, Chong LW, DiTacchio L, Atkins AR, Glass CK et al (2012) Regulation of circadian behaviour and metabolism by REV-ERB-alpha and REV-ERB-beta. Nature 485:123–127Google Scholar
  77. 77.
    Camacho F, Cilio M, Guo Y, Virshup DM, Patel K, Khorkova O, Styren S, Morse B, Yao Z, Keesler GA (2001) Human casein kinase Idelta phosphorylation of human circadian clock proteins period 1 and 2. FEBS Lett 489:159–165Google Scholar
  78. 78.
    Eide EJ, Woolf MF, Kang H, Woolf P, Hurst W, Camacho F, Vielhaber EL, Giovanni A, Virshup DM (2005) Control of mammalian circadian rhythm by CKIepsilon-regulated proteasome-mediated PER2 degradation. Mol Cell Biol 25:2795–2807Google Scholar
  79. 79.
    Hattar S, Liao HW, Takao M, Berson DM, Yau KW (2002) Melanopsin-containing retinal ganglion cells: architecture, projections, and intrinsic photosensitivity. Science 295:1065–1070Google Scholar
  80. 80.
    Hattar S, Lucas RJ, Mrosovsky N, Thompson S, Douglas RH, Hankins MW, Lem J, Biel M, Hofmann F, Foster RG et al (2003) Melanopsin and rod-cone photoreceptive systems account for all major accessory visual functions in mice. Nature 424:76–81Google Scholar
  81. 81.
    Albrecht U, Zheng B, Larkin D, Sun ZS, Lee CC (2001) MPer1 and mper2 are essential for normal resetting of the circadian clock. J Biol Rhythm 16:100–104Google Scholar
  82. 82.
    Bae K, Jin X, Maywood ES, Hastings MH, Reppert SM, Weaver DR (2001) Differential functions of mPer1, mPer2, and mPer3 in the SCN circadian clock. Neuron 30:525–536Google Scholar
  83. 83.
    Zheng B, Albrecht U, Kaasik K, Sage M, Lu W, Vaishnav S, Li Q, Sun ZS, Eichele G, Bradley A et al (2001) Nonredundant roles of the mPer1 and mPer2 genes in the mammalian circadian clock. Cell 105:683–694Google Scholar
  84. 84.
    Doi M, Hirayama J, Sassone-Corsi P (2006) Circadian regulator CLOCK is a histone acetyltransferase. Cell 125:497–508Google Scholar
  85. 85.
    Hirayama J, Sahar S, Grimaldi B, Tamaru T, Takamatsu K, Nakahata Y, Sassone-Corsi P (2007) CLOCK-mediated acetylation of BMAL1 controls circadian function. Nature 450:1086–1090Google Scholar
  86. 86.
    Yoo SH, Yamazaki S, Lowrey PL, Shimomura K, Ko CH, Buhr ED, Siepka SM, Hong HK, Oh WJ, Yoo OJ et al (2004) PERIOD2::LUCIFERASE real-time reporting of circadian dynamics reveals persistent circadian oscillations in mouse peripheral tissues. Proc Natl Acad Sci U S A 101:5339–5346Google Scholar
  87. 87.
    Balsalobre A, Damiola F, Schibler U (1998) A serum shock induces circadian gene expression in mammalian tissue culture cells. Cell 93:929–937Google Scholar
  88. 88.
    Brown SA, Fleury-Olela F, Nagoshi E, Hauser C, Juge C, Meier CA, Chicheportiche R, Dayer JM, Albrecht U, Schibler U (2005) The period length of fibroblast circadian gene expression varies widely among human individuals. PLoS Biol 3:e338. Google Scholar
  89. 89.
    Nagoshi E, Brown SA, Dibner C, Kornmann B, Schibler U (2005) Circadian gene expression in cultured cells. Methods Enzymol 393:543–557Google Scholar
  90. 90.
    Nagoshi E, Saini C, Bauer C, Laroche T, Naef F, Schibler U (2004) Circadian gene expression in individual fibroblasts: cell-autonomous and self-sustained oscillators pass time to daughter cells. Cell 119:693–705Google Scholar
  91. 91.
    Yagita K, Tamanini F, van Der Horst GT, Okamura H (2001) Molecular mechanisms of the biological clock in cultured fibroblasts. Science 292:278–281Google Scholar
  92. 92.
    Granados-Fuentes D, Saxena MT, Prolo LM, Aton SJ, Herzog ED (2004) Olfactory bulb neurons express functional, entrainable circadian rhythms. Eur J Neurosci 19:898–906Google Scholar
  93. 93.
    Granados-Fuentes D, Prolo LM, Abraham U, Herzog ED (2004) The suprachiasmatic nucleus entrains, but does not sustain, circadian rhythmicity in the olfactory bulb. J Neurosci 24:615–619Google Scholar
  94. 94.
    Granados-Fuentes D, Tseng A, Herzog ED (2006) A circadian clock in the olfactory bulb controls olfactory responsivity. J Neurosci 26:12219–12225Google Scholar
  95. 95.
    Yan J, Wang H, Liu Y, Shao C (2008) Analysis of gene regulatory networks in the mammalian circadian rhythm. PLoS Comput Biol 4:e1000193. Google Scholar
  96. 96.
    Akhtar RA, Reddy AB, Maywood ES, Clayton JD, King VM, Smith AG, Gant TW, Hastings MH, Kyriacou CP (2002) Circadian cycling of the mouse liver transcriptome, as revealed by cDNA microarray, is driven by the suprachiasmatic nucleus. Curr Biol 12:540–550Google Scholar
  97. 97.
    Cailotto C, Lei J, van der Vliet J, van Heijningen C, van Eden CG, Kalsbeek A, Pevet P, Buijs RM (2009) Effects of nocturnal light on (clock) gene expression in peripheral organs: a role for the autonomic innervation of the liver. PLoS One 4:e5650. Google Scholar
  98. 98.
    Ishida A, Mutoh T, Ueyama T, Bando H, Masubuchi S, Nakahara D, Tsujimoto G, Okamura H (2005) Light activates the adrenal gland: timing of gene expression and glucocorticoid release. Cell Metab 2:297–307Google Scholar
  99. 99.
    Kalsbeek A, Foppen E, Schalij I, Van Heijningen C, van der Vliet J, Fliers E, Buijs RM (2008) Circadian control of the daily plasma glucose rhythm: an interplay of GABA and glutamate. PLoS One 3:e3194. Google Scholar
  100. 100.
    Kornmann B, Schaad O, Bujard H, Takahashi JS, Schibler U (2007) System-driven and oscillator-dependent circadian transcription in mice with a conditionally active liver clock. PLoS Biol 5:e34. Google Scholar
  101. 101.
    Vollmers C, Gill S, DiTacchio L, Pulivarthy SR, Le HD, Panda S (2009) Time of feeding and the intrinsic circadian clock drive rhythms in hepatic gene expression. Proc Natl Acad Sci U S A 106:21453–21458Google Scholar
  102. 102.
    Strader AD, Woods SC (2005) Gastrointestinal hormones and food intake. Gastroenterology 128:175–191Google Scholar
  103. 103.
    Buhr ED, Yoo SH, Takahashi JS (2010) Temperature as a universal resetting cue for mammalian circadian oscillators. Science 330:379–385Google Scholar
  104. 104.
    Saini C, Morf J, Stratmann M, Gos P, Schibler U (2012) Simulated body temperature rhythms reveal the phase-shifting behavior and plasticity of mammalian circadian oscillators. Genes Dev 26:567–580Google Scholar
  105. 105.
    Eckel-Mahan KL, Patel VR, Mohney RP, Vignola KS, Baldi P, Sassone-Corsi P (2012) Coordination of the transcriptome and metabolome by the circadian clock. Proc Natl Acad Sci U S A 109:5541–5546Google Scholar
  106. 106.
    Kasukawa T, Sugimoto M, Hida A, Minami Y, Mori M, Honma S, Honma K, Mishima K, Soga T, Ueda HR (2012) Human blood metabolite timetable indicates internal body time. Proc Natl Acad Sci U S A 109:15036–15041Google Scholar
  107. 107.
    Minami Y, Kasukawa T, Kakazu Y, Iigo M, Sugimoto M, Ikeda S, Yasui A, van der Horst GT, Soga T, Ueda HR (2009) Measurement of internal body time by blood metabolomics. Proc Natl Acad Sci U S A 106:9890–9895Google Scholar
  108. 108.
    Chalkiadaki A, Guarente L (2012) Sirtuins mediate mammalian metabolic responses to nutrient availability. Nat Rev Endocrinol 8:287–296Google Scholar
  109. 109.
    Belden WJ, Dunlap JC (2008) SIRT1 is a circadian deacetylase for core clock components. Cell 134:212–214Google Scholar
  110. 110.
    Nakahata Y, Kaluzova M, Grimaldi B, Sahar S, Hirayama J, Chen D, Guarente LP, Sassone-Corsi P (2008) The NAD+-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control. Cell 134:329–340Google Scholar
  111. 111.
    Nakahata Y, Sahar S, Astarita G, Kaluzova M, Sassone-Corsi P (2009) Circadian control of the NAD+ salvage pathway by CLOCK-SIRT1. Science 324:654–657Google Scholar
  112. 112.
    Asher G, Gatfield D, Stratmann M, Reinke H, Dibner C, Kreppel F, Mostoslavsky R, Alt FW, Schibler U (2008) SIRT1 regulates circadian clock gene expression through PER2 deacetylation. Cell 134:317–328Google Scholar
  113. 113.
    Chang HC, Guarente L (2013) SIRT1 mediates central circadian control in the SCN by a mechanism that decays with aging. Cell 153:1448–1460Google Scholar
  114. 114.
    Lamia KA, Sachdeva UM, DiTacchio L, Williams EC, Alvarez JG, Egan DF, Vasquez DS, Juguilon H, Panda S, Shaw RJ et al (2009) AMPK regulates the circadian clock by cryptochrome phosphorylation and degradation. Science 326:437–440Google Scholar
  115. 115.
    Rudic RD, McNamara P, Curtis AM, Boston RC, Panda S, Hogenesch JB, Fitzgerald GA (2004) BMAL1 and CLOCK, two essential components of the circadian clock, are involved in glucose homeostasis. PLoS Biol 2:e377. Google Scholar
  116. 116.
    Zhang EE, Liu Y, Dentin R, Pongsawakul PY, Liu AC, Hirota T, Nusinow DA, Sun X, Landais S, Kodama Y et al (2010) Cryptochrome mediates circadian regulation of cAMP signaling and hepatic gluconeogenesis. Nat Med 16:1152–1156Google Scholar
  117. 117.
    Yin L, Wu N, Curtin JC, Qatanani M, Szwergold NR, Reid RA, Waitt GM, Parks DJ, Pearce KH, Wisely GB et al (2007) Rev-erbalpha, a heme sensor that coordinates metabolic and circadian pathways. Science 318:1786–1789Google Scholar
  118. 118.
    Solt LA, Wang Y, Banerjee S, Hughes T, Kojetin DJ, Lundasen T, Shin Y, Liu J, Cameron MD, Noel R et al (2012) Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists. Nature 485:62–68Google Scholar
  119. 119.
    LeSauter J, Hoque N, Weintraub M, Pfaff DW, Silver R (2009) Stomach ghrelin-secreting cells as food-entrainable circadian clocks. Proc Natl Acad Sci U S A 106:13582–13587Google Scholar
  120. 120.
    Hirota T, Lewis WG, Liu AC, Lee JW, Schultz PG, Kay SA (2008) A chemical biology approach reveals period shortening of the mammalian circadian clock by specific inhibition of GSK-3beta. Proc Natl Acad Sci U S A 105:20746–20751Google Scholar
  121. 121.
    Lamia KA, Storch KF, Weitz CJ (2008) Physiological significance of a peripheral tissue circadian clock. Proc Natl Acad Sci U S A 105:15172–15177Google Scholar
  122. 122.
    Balsalobre A, Brown SA, Marcacci L, Tronche F, Kellendonk C, Reichardt HM, Schutz G, Schibler U (2000) Resetting of circadian time in peripheral tissues by glucocorticoid signaling. Science 289:2344–2347Google Scholar
  123. 123.
    Englund A, Kovanen L, Saarikoski ST, Haukka J, Reunanen A, Aromaa A, Lonnqvist J, Partonen T (2009) NPAS2 and PER2 are linked to risk factors of the metabolic syndrome. J Circadian Rhythms 7:5Google Scholar
  124. 124.
    Le Martelot G, Claudel T, Gatfield D, Schaad O, Kornmann B, Lo Sasso G, Moschetta A, Schibler U (2009) REV-ERBalpha participates in circadian SREBP signaling and bile acid homeostasis. PLoS Biol 7:e1000181Google Scholar
  125. 125.
    Lee SM, Zhang Y, Tsuchiya H, Smalling R, Jetten AM, Wang L (2015) Small heterodimer partner/neuronal PAS domain protein 2 axis regulates the oscillation of liver lipid metabolism. Hepatology 61:497–505Google Scholar
  126. 126.
    Green CB, Douris N, Kojima S, Strayer CA, Fogerty J, Lourim D, Keller SR, Besharse JC (2007) Loss of nocturnin, a circadian deadenylase, confers resistance to hepatic steatosis and diet-induced obesity. Proc Natl Acad Sci U S A 104:9888–9893Google Scholar
  127. 127.
    Garbarino-Pico E, Niu S, Rollag MD, Strayer CA, Besharse JC, Green CB (2007) Immediate early response of the circadian polyA ribonuclease nocturnin to two extracellular stimuli. RNA 13:745–755Google Scholar
  128. 128.
    Douris N, Kojima S, Pan X, Lerch-Gaggl AF, Duong SQ, Hussain MM, Green CB (2011) Nocturnin regulates circadian trafficking of dietary lipid in intestinal enterocytes. Curr Biol 21:1347–1355Google Scholar
  129. 129.
    Marcheva B, Ramsey KM, Buhr ED, Kobayashi Y, Su H, Ko CH, Ivanova G, Omura C, Mo S, Vitaterna MH et al (2010) Disruption of the CLOCK components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes. Nature 466:627–631Google Scholar
  130. 130.
    Sadacca LA, Lamia KA, deLemos AS, Blum B, Weitz CJ (2011) An intrinsic circadian clock of the pancreas is required for normal insulin release and glucose homeostasis in mice. Diabetologia 54:120–124Google Scholar
  131. 131.
    Sookoian S, Castano G, Gemma C, Gianotti TF, Pirola CJ (2007) Common genetic variations in CLOCK transcription factor are associated with nonalcoholic fatty liver disease. World J Gastroenterol 13:4242–4248Google Scholar
  132. 132.
    Chalasani N, Guo X, Loomba R, Goodarzi MO, Haritunians T, Kwon S, Cui J, Taylor KD, Wilson L, Cummings OW et al (2010) Genome-wide association study identifies variants associated with histologic features of nonalcoholic fatty liver disease. Gastroenterology 139:1567–1576, e1561-1566Google Scholar
  133. 133.
    Speliotes EK, Yerges-Armstrong LM, Wu J, Hernaez R, Kim LJ, Palmer CD, Gudnason V, Eiriksdottir G, Garcia ME, Launer LJ et al (2011) Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet 7:e1001324Google Scholar
  134. 134.
    Chambers JC, Zhang W, Sehmi J, Li X, Wass MN, Van der Harst P, Holm H, Sanna S, Kavousi M, Baumeister SE et al (2011) Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma. Nat Genet 43:1131–1138Google Scholar
  135. 135.
    Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, Boerwinkle E, Cohen JC, Hobbs HH (2008) Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 40:1461–1465Google Scholar
  136. 136.
    Anstee QM, Day CP (2013) The genetics of NAFLD. Nat Rev Gastroenterol Hepatol 10:645–655Google Scholar
  137. 137.
    Dickmeis T (2009) Glucocorticoids and the circadian clock. J Endocrinol 200:3–22Google Scholar
  138. 138.
    Kalsbeek A, van Heerikhuize JJ, Wortel J, Buijs RM (1996) A diurnal rhythm of stimulatory input to the hypothalamo-pituitary-adrenal system as revealed by timed intrahypothalamic administration of the vasopressin V1 antagonist. J Neurosci 16:5555–5565Google Scholar
  139. 139.
    Dijk DJ, Duffy JF, Silva EJ, Shanahan TL, Boivin DB, Czeisler CA (2012) Amplitude reduction and phase shifts of melatonin, cortisol and other circadian rhythms after a gradual advance of sleep and light exposure in humans. PLoS One 7:e30037Google Scholar
  140. 140.
    Doane LD, Kremen WS, Eaves LJ, Eisen SA, Hauger R, Hellhammer D, Levine S, Lupien S, Lyons MJ, Mendoza S et al (2010) Associations between jet lag and cortisol diurnal rhythms after domestic travel. Health Psychol 29:117–123Google Scholar
  141. 141.
    Carroll TB, Findling JW (2010) The diagnosis of Cushing’s syndrome. Rev Endocr Metab Disord 11:147–153Google Scholar
  142. 142.
    Antoni MH, Lutgendorf SK, Cole SW, Dhabhar FS, Sephton SE, McDonald PG, Stefanek M, Sood AK (2006) The influence of bio-behavioural factors on tumour biology: pathways and mechanisms. Nat Rev Cancer 6:240–248Google Scholar
  143. 143.
    Thaker PH, Han LY, Kamat AA, Arevalo JM, Takahashi R, Lu C, Jennings NB, Armaiz-Pena G, Bankson JA, Ravoori M et al (2006) Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat Med 12:939–944Google Scholar
  144. 144.
    Gomez-Abellan P, Diez-Noguera A, Madrid JA, Lujan JA, Ordovas JM, Garaulet M (2012) Glucocorticoids affect 24 h clock genes expression in human adipose tissue explant cultures. PLoS One 7:e50435. Google Scholar
  145. 145.
    Pezuk P, Mohawk JA, Wang LA, Menaker M (2012) Glucocorticoids as entraining signals for peripheral circadian oscillators. Endocrinology 153:4775–4783Google Scholar
  146. 146.
    Kiessling S, Eichele G, Oster H (2010) Adrenal glucocorticoids have a key role in circadian resynchronization in a mouse model of jet lag. J Clin Invest 120:2600–2609Google Scholar
  147. 147.
    Targher G, Bertolini L, Rodella S, Zoppini G, Zenari L, Falezza G (2006) Associations between liver histology and cortisol secretion in subjects with nonalcoholic fatty liver disease. Clin Endocrinol 64:337–341Google Scholar
  148. 148.
    Hubel JM, Schmidt SA, Mason RA, Haenle MM, Oeztuerk S, Koenig W, Boehm BO, Kratzer W, Graeter T, Flechtner-Mors M et al (2015) Influence of plasma cortisol and other laboratory parameters on nonalcoholic fatty liver disease. Horm Metab Res 47:479–484Google Scholar
  149. 149.
    Barclay JL, Shostak A, Leliavski A, Tsang AH, Johren O, Muller-Fielitz H, Landgraf D, Naujokat N, van der Horst GT, Oster H (2013) High-fat diet-induced hyperinsulinemia and tissue-specific insulin resistance in cry-deficient mice. Am J Physiol Endocrinol Metab 304:E1053–E1063Google Scholar
  150. 150.
    Zhao Y, Zhang Y, Zhou M, Wang S, Hua Z, Zhang J (2012) Loss of mPer2 increases plasma insulin levels by enhanced glucose-stimulated insulin secretion and impaired insulin clearance in mice. FEBS Lett 586:1306–1311Google Scholar
  151. 151.
    Esquirol Y, Bongard V, Ferrieres J, Verdier H, Perret B (2012) Shiftwork and higher pancreatic secretion: early detection of an intermediate state of insulin resistance? Chronobiol Int 29:1258–1266Google Scholar
  152. 152.
    Tucker P, Marquie JC, Folkard S, Ansiau D, Esquirol Y (2012) Shiftwork and metabolic dysfunction. Chronobiol Int 29:549–555Google Scholar
  153. 153.
    Tahara Y, Otsuka M, Fuse Y, Hirao A, Shibata S (2011) Refeeding after fasting elicits insulin-dependent regulation of Per2 and Rev-erbalpha with shifts in the liver clock. J Biol Rhythm 26:230–240Google Scholar
  154. 154.
    Yamajuku D, Inagaki T, Haruma T, Okubo S, Kataoka Y, Kobayashi S, Ikegami K, Laurent T, Kojima T, Noutomi K et al (2012) Real-time monitoring in three-dimensional hepatocytes reveals that insulin acts as a synchronizer for liver clock. Sci Rep 2:439Google Scholar
  155. 155.
    Hirota T, Okano T, Kokame K, Shirotani-Ikejima H, Miyata T, Fukada Y (2002) Glucose down-regulates Per1 and Per2 mRNA levels and induces circadian gene expression in cultured Rat-1 fibroblasts. J Biol Chem 277:44244–44251Google Scholar
  156. 156.
    Abizaid A, Liu ZW, Andrews ZB, Shanabrough M, Borok E, Elsworth JD, Roth RH, Sleeman MW, Picciotto MR, Tschop MH et al (2006) Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite. J Clin Invest 116:3229–3239Google Scholar
  157. 157.
    Date Y, Shimbara T, Koda S, Toshinai K, Ida T, Murakami N, Miyazato M, Kokame K, Ishizuka Y, Ishida Y et al (2006) Peripheral ghrelin transmits orexigenic signals through the noradrenergic pathway from the hindbrain to the hypothalamus. Cell Metab 4:323–331Google Scholar
  158. 158.
    Toshinai K, Yamaguchi H, Sun Y, Smith RG, Yamanaka A, Sakurai T, Date Y, Mondal MS, Shimbara T, Kawagoe T et al (2006) Des-acyl ghrelin induces food intake by a mechanism independent of the growth hormone secretagogue receptor. Endocrinology 147:2306–2314Google Scholar
  159. 159.
    Schiavo-Cardozo D, Lima MM, Pareja JC, Geloneze B (2013) Appetite-regulating hormones from the upper gut: disrupted control of xenin and ghrelin in night workers. Clin Endocrinol 79:807–811Google Scholar
  160. 160.
    Yannielli PC, Molyneux PC, Harrington ME, Golombek DA (2007) Ghrelin effects on the circadian system of mice. J Neurosci 27:2890–2895Google Scholar
  161. 161.
    Gavrila A, Peng CK, Chan JL, Mietus JE, Goldberger AL, Mantzoros CS (2003) Diurnal and ultradian dynamics of serum adiponectin in healthy men: comparison with leptin, circulating soluble leptin receptor, and cortisol patterns. J Clin Endocrinol Metab 88:2838–2843Google Scholar
  162. 162.
    Scheer FA, Chan JL, Fargnoli J, Chamberland J, Arampatzi K, Shea SA, Blackburn GL, Mantzoros CS (2010) Day/night variations of high-molecular-weight adiponectin and lipocalin-2 in healthy men studied under fed and fasted conditions. Diabetologia 53:2401–2405Google Scholar
  163. 163.
    Harwood HJ Jr (2012) The adipocyte as an endocrine organ in the regulation of metabolic homeostasis. Neuropharmacology 63:57–75Google Scholar
  164. 164.
    Hu E, Liang P, Spiegelman BM (1996) AdipoQ is a novel adipose-specific gene dysregulated in obesity. J Biol Chem 271:10697–10703Google Scholar
  165. 165.
    Yang WS, Lee WJ, Funahashi T, Tanaka S, Matsuzawa Y, Chao CL, Chen CL, Tai TY, Chuang LM (2001) Weight reduction increases plasma levels of an adipose-derived anti-inflammatory protein, adiponectin. J Clin Endocrinol Metab 86:3815–3819Google Scholar
  166. 166.
    Barnea M, Shamay A, Stark AH, Madar Z (2006) A high-fat diet has a tissue-specific effect on adiponectin and related enzyme expression. Obesity (Silver Spring) 14:2145–2153Google Scholar
  167. 167.
    Bullen JW Jr, Bluher S, Kelesidis T, Mantzoros CS (2007) Regulation of adiponectin and its receptors in response to development of diet-induced obesity in mice. Am J Physiol Endocrinol Metab 292:E1079–E1086Google Scholar
  168. 168.
    Hashinaga T, Wada N, Otabe S, Yuan X, Kurita Y, Kakino S, Tanaka K, Sato T, Kojima M, Ohki T et al (2013) Modulation by adiponectin of circadian clock rhythmicity in model mice for metabolic syndrome. Endocr J 60:483–492Google Scholar
  169. 169.
    Gautron L, Elmquist JK (2011) Sixteen years and counting: an update on leptin in energy balance. J Clin Invest 121:2087–2093Google Scholar
  170. 170.
    Mendoza J, Lopez-Lopez C, Revel FG, Jeanneau K, Delerue F, Prinssen E, Challet E, Moreau JL, Grundschober C (2011) Dimorphic effects of leptin on the circadian and hypocretinergic systems of mice. J Neuroendocrinol 23:28–38Google Scholar
  171. 171.
    Prosser RA, Bergeron HE (2003) Leptin phase-advances the rat suprachiasmatic circadian clock in vitro. Neurosci Lett 336:139–142Google Scholar
  172. 172.
    Kaczmarek JL, Thompson SV, Holscher HD (2017) Complex interactions of circadian rhythms, eating behaviors, and the gastrointestinal microbiota and their potential impact on health. Nutr Rev 75:673–682Google Scholar
  173. 173.
    Zhao L, Zhang F, Ding X, Wu G, Lam YY, Wang X, Fu H, Xue X, Lu C, Ma J et al (2018) Gut bacteria selectively promoted by dietary fibers alleviate type 2 diabetes. Science 359:1151–1156Google Scholar
  174. 174.
    Wu G, Tang W, He Y, Hu J, Gong S, He Z, Wei G, Lv L, Jiang Y, Zhou H et al (2018) Light exposure influences the diurnal oscillation of gut microbiota in mice. Biochem Biophys Res Commun 501:16–23Google Scholar
  175. 175.
    Wu T, Yang L, Jiang J, Ni Y, Zhu J, Zheng X, Wang Q, Lu X, Fu Z (2018) Chronic glucocorticoid treatment induced circadian clock disorder leads to lipid metabolism and gut microbiota alterations in rats. Life Sci 192:173–182Google Scholar
  176. 176.
    Benedict C, Vogel H, Jonas W, Woting A, Blaut M, Schurmann A, Cedernaes J (2016) Gut microbiota and glucometabolic alterations in response to recurrent partial sleep deprivation in normal-weight young individuals. Mol Metab 5:1175–1186Google Scholar
  177. 177.
    Murakami M, Tognini P, Liu Y, Eckel-Mahan KL, Baldi P, Sassone-Corsi P (2016) Gut microbiota directs PPARgamma-driven reprogramming of the liver circadian clock by nutritional challenge. EMBO Rep 17:1292–1303Google Scholar
  178. 178.
    Wang Y, Kuang Z, Yu X, Ruhn KA, Kubo M, Hooper LV (2017) The intestinal microbiota regulates body composition through NFIL3 and the circadian clock. Science 357:912–916Google Scholar
  179. 179.
    Paulose JK, Wright JM, Patel AG, Cassone VM (2016) Human gut Bacteria are sensitive to melatonin and express endogenous circadian rhythmicity. PLoS One 11:e0146643. Google Scholar
  180. 180.
    Cambras T, Weller JR, Angles-Pujoras M, Lee ML, Christopher A, Diez-Noguera A, Krueger JM, de la Iglesia HO (2007) Circadian desynchronization of core body temperature and sleep stages in the rat. Proc Natl Acad Sci U S A 104:7634–7639Google Scholar
  181. 181.
    Castanon-Cervantes O, Wu M, Ehlen JC, Paul K, Gamble KL, Johnson RL, Besing RC, Menaker M, Gewirtz AT, Davidson AJ (2010) Dysregulation of inflammatory responses by chronic circadian disruption. J Immunol 185:5796–5805Google Scholar
  182. 182.
    Filipski E, Subramanian P, Carriere J, Guettier C, Barbason H, Levi F (2009) Circadian disruption accelerates liver carcinogenesis in mice. Mutat Res 680:95–105Google Scholar
  183. 183.
    Tsai LL, Tsai YC, Hwang K, Huang YW, Tzeng JE (2005) Repeated light-dark shifts speed up body weight gain in male F344 rats. Am J Physiol Endocrinol Metab 289:E212–E217Google Scholar
  184. 184.
    Bellastella A, Pisano G, Iorio S, Pasquali D, Orio F, Venditto T, Sinisi AA (1998) Endocrine secretions under abnormal light-dark cycles and in the blind. Horm Res 49:153–157Google Scholar
  185. 185.
    de la Iglesia HO, Cambras T, Schwartz WJ, Diez-Noguera A (2004) Forced desynchronization of dual circadian oscillators within the rat suprachiasmatic nucleus. Curr Biol 14:796–800Google Scholar
  186. 186.
    Scheer FA, Hilton MF, Mantzoros CS, Shea SA (2009) Adverse metabolic and cardiovascular consequences of circadian misalignment. Proc Natl Acad Sci U S A 106:4453–4458Google Scholar
  187. 187.
    Leproult R, Holmback U, Van Cauter E (2014) Circadian misalignment augments markers of insulin resistance and inflammation, independently of sleep loss. Diabetes 63:1860–1869Google Scholar
  188. 188.
    Shetty A, Hsu JW, Manka PP, Syn WK (2018) Role of the circadian clock in the metabolic syndrome and nonalcoholic fatty liver disease. Dig Dis Sci 63:3187–3206Google Scholar
  189. 189.
    Imaizumi H, Takahashi A, Tanji N, Abe K, Sato Y, Anzai Y, Watanabe H, Ohira H (2015) The association between sleep duration and non-alcoholic fatty liver disease among Japanese men and women. Obes Facts 8:234–242Google Scholar
  190. 190.
    Trovato FM, Martines GF, Brischetto D, Trovato G, Catalano D (2016) Neglected features of lifestyle: their relevance in non-alcoholic fatty liver disease. World J Hepatol 8:1459–1465Google Scholar
  191. 191.
    Trovato FM, Martines GF, Brischetto D, Catalano D, Musumeci G, Trovato GM (2016) Fatty liver disease and lifestyle in youngsters: diet, food intake frequency, exercise, sleep shortage and fashion. Liver Int 36:427–433Google Scholar
  192. 192.
    Bernsmeier C, Weisskopf DM, Pflueger MO, Mosimann J, Campana B, Terracciano L, Beglinger C, Heim MH, Cajochen C (2015) Sleep disruption and daytime sleepiness correlating with disease severity and insulin resistance in non-alcoholic fatty liver disease: a comparison with healthy controls. PLoS One 10:e0143293. Google Scholar
  193. 193.
    Katsagoni CN, Papatheodoridis GV, Papageorgiou MV, Ioannidou P, Deutsch M, Alexopoulou A, Papadopoulos N, Fragopoulou E, Kontogianni MD (2017) A “healthy diet-optimal sleep” lifestyle pattern is inversely associated with liver stiffness and insulin resistance in patients with nonalcoholic fatty liver disease. Appl Physiol Nutr Metab 42:250–256Google Scholar
  194. 194.
    Katsagoni CN, Georgoulis M, Papatheodoridis GV, Fragopoulou E, Ioannidou P, Papageorgiou M, Alexopoulou A, Papadopoulos N, Deutsch M, Kontogianni MD (2017) Associations between lifestyle characteristics and the presence of nonalcoholic fatty liver disease: a case-control study. Metab Syndr Relat Disord 15:72–79Google Scholar
  195. 195.
    Qu H, Wang H, Deng M, Wei H, Deng H (2014) Associations between longer habitual day napping and non-alcoholic fatty liver disease in an elderly Chinese population. PLoS One 9:e105583. Google Scholar
  196. 196.
    Mindikoglu AL, Opekun AR, Gagan SK, Devaraj S (2017) Impact of time-restricted feeding and dawn-to-sunset fasting on circadian rhythm, obesity, metabolic syndrome, and nonalcoholic fatty liver disease. Gastroenterol Res Pract 2017:3932491Google Scholar
  197. 197.
    Mukherji A, Kobiita A, Damara M, Misra N, Meziane H, Champy MF, Chambon P (2015) 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 U S A 112:E6691–E6698Google Scholar
  198. 198.
    Soeda J, Cordero P, Li J, Mouralidarane A, Asilmaz E, Ray S, Nguyen V, Carter R, Novelli M, Vinciguerra M et al (2017) Hepatic rhythmicity of endoplasmic reticulum stress is disrupted in perinatal and adult mice models of high-fat diet-induced obesity. Int J Food Sci Nutr 68:455–466Google Scholar
  199. 199.
    Fleet T, Stashi E, Zhu B, Rajapakshe K, Marcelo KL, Kettner NM, Gorman BK, Coarfa C, Fu L, O’Malley BW et al (2016) Genetic and environmental models of circadian disruption link SRC-2 function to hepatic pathology. J Biol Rhythm 31:443–460Google Scholar
  200. 200.
    Kettner NM, Voicu H, Finegold MJ, Coarfa C, Sreekumar A, Putluri N, Katchy CA, Lee C, Moore DD, Fu L (2016) Circadian homeostasis of liver metabolism suppresses Hepatocarcinogenesis. Cancer Cell 30:909–924Google Scholar
  201. 201.
    Montagnese S, De Pitta C, De Rui M, Corrias M, Turco M, Merkel C, Amodio P, Costa R, Skene DJ, Gatta A (2014) Sleep-wake abnormalities in patients with cirrhosis. Hepatology 59:705–712Google Scholar
  202. 202.
    De Cruz S, Espiritu JR, Zeidler M, Wang TS (2012) Sleep disorders in chronic liver disease. Semin Respir Crit Care Med 33:26–35Google Scholar
  203. 203.
    Chen P, Kakan X, Zhang J (2010) Altered circadian rhythm of the clock genes in fibrotic livers induced by carbon tetrachloride. FEBS Lett 584:1597–1601Google Scholar
  204. 204.
    Chen P, Han Z, Yang P, Zhu L, Hua Z, Zhang J (2010) Loss of clock gene mPer2 promotes liver fibrosis induced by carbon tetrachloride. Hepatol Res 40:1117–1127Google Scholar
  205. 205.
    Li T, Eheim AL, Klein S, Uschner FE, Smith AC, Brandon-Warner E, Ghosh S, Bonkovsky HL, Trebicka J, Schrum LW (2014) Novel role of nuclear receptor Rev-erbalpha in hepatic stellate cell activation: potential therapeutic target for liver injury. Hepatology 59:2383–2396Google Scholar
  206. 206.
    Ma KY, Zhang ZS, Zhao SX, Chang Q, Wong YM, Yeung SY, Huang Y, Chen ZY (2009) Red yeast rice increases excretion of bile acids in hamsters. Biomed Environ Sci 22:269–277Google Scholar
  207. 207.
    Chen P, Kakan X, Wang S, Dong W, Jia A, Cai C, Zhang J (2013) Deletion of clock gene Per2 exacerbates cholestatic liver injury and fibrosis in mice. Exp Toxicol Pathol 65:427–432Google Scholar
  208. 208.
    Han Y, Onori P, Meng F, DeMorrow S, Venter J, Francis H, Franchitto A, Ray D, Kennedy L, Greene J et al (2014) Prolonged exposure of cholestatic rats to complete dark inhibits biliary hyperplasia and liver fibrosis. Am J Physiol Gastrointest Liver Physiol 307:G894–G904Google Scholar
  209. 209.
    Feillet C, van der Horst GT, Levi F, Rand DA, Delaunay F (2015) Coupling between the circadian clock and cell cycle oscillators: implication for healthy cells and malignant growth. Front Neurol 6:96Google Scholar
  210. 210.
    Kelleher FC, Rao A, Maguire A (2014) Circadian molecular clocks and cancer. Cancer Lett 342:9–18Google Scholar
  211. 211.
    Fu L, Pelicano H, Liu J, Huang P, Lee C (2002) The circadian gene Period2 plays an important role in tumor suppression and DNA damage response in vivo. Cell 111:41–50Google Scholar
  212. 212.
    Lee S, Donehower LA, Herron AJ, Moore DD, Fu L (2010) Disrupting circadian homeostasis of sympathetic signaling promotes tumor development in mice. PLoS One 5:e10995Google Scholar
  213. 213.
    Lin YM, Chang JH, Yeh KT, Yang MY, Liu TC, Lin SF, Su WW, Chang JG (2008) Disturbance of circadian gene expression in hepatocellular carcinoma. Mol Carcinog 47:925–933Google Scholar
  214. 214.
    Huisman SA, Oklejewicz M, Ahmadi AR, Tamanini F, Ijzermans JN, van der Horst GT, de Bruin RW (2015) Colorectal liver metastases with a disrupted circadian rhythm phase shift the peripheral clock in liver and kidney. Int J Cancer 136:1024–1032Google Scholar
  215. 215.
    Davidson AJ, Straume M, Block GD, Menaker M (2006) Daily timed meals dissociate circadian rhythms in hepatoma and healthy host liver. Int J Cancer 118:1623–1627Google Scholar
  216. 216.
    Zhao B, Lu J, Yin J, Liu H, Guo X, Yang Y, Ge N, Zhu Y, Zhang H, Xing J (2012) A functional polymorphism in PER3 gene is associated with prognosis in hepatocellular carcinoma. Liver Int 32:1451–1459Google Scholar
  217. 217.
    Hirota T, Lee JW, St John PC, Sawa M, Iwaisako K, Noguchi T, Pongsawakul PY, Sonntag T, Welsh DK, Brenner DA et al (2012) Identification of small molecule activators of cryptochrome. Science 337:1094–1097Google Scholar
  218. 218.
    Hirota T, Lee JW, Lewis WG, Zhang EE, Breton G, Liu X, Garcia M, Peters EC, Etchegaray JP, Traver D et al (2010) High-throughput chemical screen identifies a novel potent modulator of cellular circadian rhythms and reveals CKIalpha as a clock regulatory kinase. PLoS Biol 8:e1000559Google Scholar
  219. 219.
    Geerdink M, Walbeek TJ, Beersma DG, Hommes V, Gordijn MC (2016) Short blue light pulses (30 min) in the morning support a sleep-advancing protocol in a home setting. J Biol Rhythm 31:483–497Google Scholar
  220. 220.
    Najjar RP, Zeitzer JM (2016) Temporal integration of light flashes by the human circadian system. J Clin Invest 126:938–947Google Scholar
  221. 221.
    Ferrell JM, Chiang JY (2015) Circadian rhythms in liver metabolism and disease. Acta Pharm Sin B 5:113–122Google Scholar
  222. 222.
    Hermida RC, Ayala DE, Fernandez JR, Portaluppi F, Fabbian F, Smolensky MH (2011) Circadian rhythms in blood pressure regulation and optimization of hypertension treatment with ACE inhibitor and ARB medications. Am J Hypertens 24:383–391Google Scholar
  223. 223.
    Hermida RC, Ayala DE, Smolensky MH, Fernandez JR, Mojon A, Portaluppi F (2016) Chronotherapy with conventional blood pressure medications improves management of hypertension and reduces cardiovascular and stroke risks. Hypertens Res 39:277–292Google Scholar
  224. 224.
    Portaluppi F, Smolensky MH (2010) Perspectives on the chronotherapy of hypertension based on the results of the MAPEC study. Chronobiol Int 27:1652–1667Google Scholar
  225. 225.
    Smolensky MH, Hermida RC, Ayala DE, Tiseo R, Portaluppi F (2010) Administration-time-dependent effects of blood pressure-lowering medications: basis for the chronotherapy of hypertension. Blood Press Monit 15:173–180Google Scholar
  226. 226.
    Stranges PM, Drew AM, Rafferty P, Shuster JE, Brooks AD (2015) Treatment of hypertension with chronotherapy: is it time of drug administration? Ann Pharmacother 49:323–334Google Scholar
  227. 227.
    Buttgereit F, Doering G, Schaeffler A, Witte S, Sierakowski S, Gromnica-Ihle E, Jeka S, Krueger K, Szechinski J, Alten R (2008) Efficacy of modified-release versus standard prednisone to reduce duration of morning stiffness of the joints in rheumatoid arthritis (CAPRA-1): a double-blind, randomised controlled trial. Lancet 371:205–214Google Scholar
  228. 228.
    Haspel JA, Chettimada S, Shaik RS, Chu JH, Raby BA, Cernadas M, Carey V, Process V, Hunninghake GM, Ifedigbo E et al (2014) Circadian rhythm reprogramming during lung inflammation. Nat Commun 5:4753Google Scholar
  229. 229.
    Narasimamurthy R, Hatori M, Nayak SK, Liu F, Panda S, Verma IM (2012) Circadian clock protein cryptochrome regulates the expression of proinflammatory cytokines. Proc Natl Acad Sci U S A 109:12662–12667Google Scholar
  230. 230.
    Bunney BG, Li JZ, Walsh DM, Stein R, Vawter MP, Cartagena P, Barchas JD, Schatzberg AF, Myers RM, Watson SJ et al (2015) Circadian dysregulation of clock genes: clues to rapid treatments in major depressive disorder. Mol Psychiatry 20:48–55Google Scholar
  231. 231.
    Levi F (2001) Circadian chronotherapy for human cancers. Lancet Oncol 2:307–315Google Scholar
  232. 232.
    Ortiz-Tudela E, Mteyrek A, Ballesta A, Innominato PF, Levi F (2013) Cancer chronotherapeutics: experimental, theoretical, and clinical aspects. Handb Exp Pharmacol 261–288.
  233. 233.
    Hara R, Wan K, Wakamatsu H, Aida R, Moriya T, Akiyama M, Shibata S (2001) Restricted feeding entrains liver clock without participation of the suprachiasmatic nucleus. Genes Cells 6:269–278Google Scholar
  234. 234.
    Sato M, Murakami M, Node K, Matsumura R, Akashi M (2014) The role of the endocrine system in feeding-induced tissue-specific circadian entrainment. Cell Rep 8:393–401Google Scholar
  235. 235.
    Landgraf D, Tsang AH, Leliavski A, Koch CE, Barclay JL, Drucker DJ, Oster H (2015) Oxyntomodulin regulates resetting of the liver circadian clock by food. Elife 4:e06253. Google Scholar
  236. 236.
    Furutani A, Ikeda Y, Itokawa M, Nagahama H, Ohtsu T, Furutani N, Kamagata M, Yang ZH, Hirasawa A, Tahara Y et al (2015) Fish oil accelerates diet-induced entrainment of the mouse peripheral clock via GPR120. PLoS One 10:e0132472Google Scholar
  237. 237.
    Hirao A, Tahara Y, Kimura I, Shibata S (2009) A balanced diet is necessary for proper entrainment signals of the mouse liver clock. PLoS One 4:e6909Google Scholar
  238. 238.
    Itokawa M, Hirao A, Nagahama H, Otsuka M, Ohtsu T, Furutani N, Hirao K, Hatta T, Shibata S (2013) Time-restricted feeding of rapidly digested starches causes stronger entrainment of the liver clock in PER2::LUCIFERASE knock-in mice. Nutr Res 33:109–119Google Scholar
  239. 239.
    Hirao A, Nagahama H, Tsuboi T, Hirao M, Tahara Y, Shibata S (2010) Combination of starvation interval and food volume determines the phase of liver circadian rhythm in Per2::Luc knock-in mice under two meals per day feeding. Am J Physiol Gastrointest Liver Physiol 299:G1045–G1053Google Scholar
  240. 240.
    Kuroda H, Tahara Y, Saito K, Ohnishi N, Kubo Y, Seo Y, Otsuka M, Fuse Y, Ohura Y, Hirao A et al (2012) Meal frequency patterns determine the phase of mouse peripheral circadian clocks. Sci Rep 2:711Google Scholar
  241. 241.
    Barclay JL, Husse J, Bode B, Naujokat N, Meyer-Kovac J, Schmid SM, Lehnert H, Oster H (2012) Circadian desynchrony promotes metabolic disruption in a mouse model of shiftwork. PLoS One 7:e37150Google Scholar
  242. 242.
    Chaix A, Zarrinpar A, Miu P, Panda S (2014) Time-restricted feeding is a preventative and therapeutic intervention against diverse nutritional challenges. Cell Metab 20:991–1005Google Scholar
  243. 243.
    Hatori M, Vollmers C, Zarrinpar A, DiTacchio L, Bushong EA, Gill S, Leblanc M, Chaix A, Joens M, Fitzpatrick JA et al (2012) Time-restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high-fat diet. Cell Metab 15:848–860Google Scholar
  244. 244.
    Gilbert MR, Douris N, Tongjai S, Green CB (2011) Nocturnin expression is induced by fasting in the white adipose tissue of restricted fed mice. PLoS One 6:e17051Google Scholar
  245. 245.
    Narishige S, Kuwahara M, Shinozaki A, Okada S, Ikeda Y, Kamagata M, Tahara Y, Shibata S (2014) Effects of caffeine on circadian phase, amplitude and period evaluated in cells in vitro and peripheral organs in vivo in PER2::LUCIFERASE mice. Br J Pharmacol 171:5858–5869Google Scholar
  246. 246.
    Oike H, Kobori M, Suzuki T, Ishida N (2011) Caffeine lengthens circadian rhythms in mice. Biochem Biophys Res Commun 410:654–658Google Scholar
  247. 247.
    Burke TM, Markwald RR, McHill AW, Chinoy ED, Snider JA, Bessman SC, Jung CM, O’Neill JS, Wright KP Jr (2015) Effects of caffeine on the human circadian clock in vivo and in vitro. Sci Transl Med 7:305ra146Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Davide Gnocchi
    • 1
  • Carlo Custodero
    • 1
  • Carlo Sabbà
    • 1
  • Antonio Mazzocca
    • 1
    Email author
  1. 1.Interdisciplinary Department of MedicineUniversity of Bari School of MedicineBariItaly

Personalised recommendations