The biological clock controls at the molecular level several aspects of mammalian physiology, by regulating daily oscillations of crucial biological processes such as nutrient metabolism in the liver. Disruption of the circadian clock circuitry has recently been identified as an independent risk factor for cancer and classified as a potential group 2A carcinogen to humans. Hepatocellular carcinoma (HCC) is the prevailing histological type of primary liver cancer, one of the most important causes of cancer-related death worldwide. HCC onset and progression is related to B and C viral hepatitis, alcoholic and especially non-alcoholic fatty liver disease (NAFLD)-related milieu of fibrosis, cirrhosis, and chronic inflammation. In this review, we recapitulate the state-of-the-art knowledge on the interplay between the biological clock and the oncogenic pathways and mechanisms involved in hepatocarcinogenesis. Finally, we propose how a deeper understanding of circadian clock circuitry-cancer pathways' crosstalk is promising for developing new strategies for HCC prevention and management.

Bioinformatics Unit Fondazione IRCCS Casa Sollievo della Sofferenza 71013 San Giovanni Rotondo Italy

Department of Medical Sciences and Chronobiology Laboratory Fondazione IRCCS Casa Sollievo della Sofferenza 71013 San Giovanni Rotondo Italy

Fondazione Policlinico Universitario A Gemelli IRCCS Catholic University of the Sacred Heart 00168 Rome Italy

International Clinical Research Center St Anne's University Hospital 65691 Brno Czech Republic

Zobrazit více v PubMed

Bray F., Ferlay J., Soerjomataram I., Siegel R.L., Torre L.A., Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018;68:394–424. doi: 10.3322/caac.21492. PubMed DOI

Akinyemiju T., Abera S., Ahmed M., Alam N., Alemayohu M.A., Allen C., Al-Raddadi R., Alvis-Guzman N., Amoako Y., Artaman A., et al. The Burden of Primary Liver Cancer and Underlying Etiologies from 1990 to 2015 at the Global, Regional, and National Level: Results from the Global Burden of Disease Study 2015. JAMA Oncol. 2017;3:1683–1691. PubMed PMC

Anstee Q.M., Reeves H.L., Kotsiliti E., Govaere O., Heikenwalder M. From NASH to HCC: Current concepts and future challenges. Nat. Rev. Gastroenterol. Hepatol. 2019;16:411–428. doi: 10.1038/s41575-019-0145-7. PubMed DOI

Bruix J., Gores G.J., Mazzaferro V. Hepatocellular carcinoma: Clinical frontiers and perspectives. Gut. 2014;63:844–855. doi: 10.1136/gutjnl-2013-306627. PubMed DOI PMC

Albrecht U. Timing to perfection: The biology of central and peripheral circadian clocks. Neuron. 2012;74:246–260. doi: 10.1016/j.neuron.2012.04.006. PubMed DOI

Lowrey P.L., Takahashi J.S. Genetics of circadian rhythms in Mammalian model organisms. Adv. Genet. 2011;74:175–230. PubMed PMC

Anderson G., Beischlag T.V., Vinciguerra M., Mazzoccoli G. The circadian clock circuitry and the AHR signaling pathway in physiology and pathology. Biochem. Pharmacol. 2013;85:1405–1416. doi: 10.1016/j.bcp.2013.02.022. PubMed DOI

Takahashi J.S. Transcriptional architecture of the mammalian circadian clock. Nat. Rev. Genet. 2017;18:164–179. doi: 10.1038/nrg.2016.150. PubMed DOI PMC

Mazzoccoli G., Laukkanen M.O., Vinciguerra M., Colangelo T., Colantuoni V. A Timeless Link between Circadian Patterns and Disease. Trends Mol. Med. 2016;22:68–81. doi: 10.1016/j.molmed.2015.11.007. PubMed DOI

Ripperger J.A., Albrecht U. REV-ERB-erating nuclear receptor functions in circadian metabolism and physiology. Cell Res. 2012;22:1319–1321. doi: 10.1038/cr.2012.81. PubMed DOI PMC

Partch C.L., Green C.B., Takahashi J.S. Molecular architecture of the mammalian circadian clock. Trends Cell Biol. 2014;24:90–99. doi: 10.1016/j.tcb.2013.07.002. PubMed DOI PMC

Mohawk J.A., Green C.B., Takahashi J.S. Central and peripheral circadian clocks in mammals. Annu. Rev. Neurosci. 2012;35:445–462. doi: 10.1146/annurev-neuro-060909-153128. PubMed DOI PMC

Koike N., Yoo S.H., Huang H.C., Kumar V., Lee C., Kim T.K., Takahashi J.S. Transcriptional architecture and chromatin landscape of the core circadian clock in mammals. Science. 2012;338:349–354. doi: 10.1126/science.1226339. PubMed DOI PMC

Sahar S., Zocchi L., Kinoshita C., Borrelli E., Sassone-Corsi P. Regulation of BMAL1 protein stability and circadian function by GSK3beta-mediated phosphorylation. PLoS ONE. 2010;5:e8561. doi: 10.1371/journal.pone.0008561. PubMed DOI PMC

Cardone L., Hirayama J., Giordano F., Tamaru T., Palvimo J.J., Sassone-Corsi P. Circadian clock control by SUMOylation of BMAL1. Science. 2005;309:1390–1394. doi: 10.1126/science.1110689. PubMed DOI

Lee J., Lee Y., Lee M.J., Park E., Kang S.H., Chung C.H., Lee K.H., Kim K. Dual modification of BMAL1 by SUMO2/3 and ubiquitin promotes circadian activation of the CLOCK/BMAL1 complex. Mol. Cell. Biol. 2008;28:6056–6065. doi: 10.1128/MCB.00583-08. PubMed DOI PMC

Nakahata Y., Kaluzova M., Grimaldi B., Sahar S., Hirayama J., Chen D., Guarente L.P., Sassone-Corsi P. The NAD+-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control. Cell. 2008;134:329–340. doi: 10.1016/j.cell.2008.07.002. PubMed DOI PMC

Nakahata Y., Sahar S., Astarita G., Kaluzova M., Sassone-Corsi P. Circadian control of the NAD+ salvage pathway by CLOCK-SIRT1. Science. 2009;324:654–657. doi: 10.1126/science.1170803. PubMed DOI PMC

Asher G., Gatfield D., Stratmann M., Reinke H., Dibner C., Kreppel F., Mostoslavsky R., Alt F.W., Schibler U. SIRT1 regulates circadian clock gene expression through PER2 deacetylation. Cell. 2008;134:317–328. doi: 10.1016/j.cell.2008.06.050. PubMed DOI

Ramsey K.M., Yoshino J., Brace C.S., Abrassart D., Kobayashi Y., Marcheva B., Hong H.K., Chong J.L., Buhr E.D., Lee C., et al. Circadian clock feedback cycle through NAMPT-mediated NAD+ biosynthesis. Science. 2009;324:651–654. doi: 10.1126/science.1171641. PubMed DOI PMC

Bozek K., Relogio A., Kielbasa S.M., Heine M., Dame C., Kramer A., Herzel H. Regulation of clock-controlled genes in mammals. PLoS ONE. 2009;4:e4882. doi: 10.1371/journal.pone.0004882. PubMed DOI PMC

Hughes M.E., DiTacchio L., Hayes K.R., Vollmers C., Pulivarthy S., Baggs J.E., Panda S., Hogenesch J.B. Harmonics of circadian gene transcription in mammals. PLoS Genet. 2009;5:e1000442. doi: 10.1371/journal.pgen.1000442. PubMed DOI PMC

Matsuo T., Yamaguchi S., Mitsui S., Emi A., Shimoda F., Okamura H. Control mechanism of the circadian clock for timing of cell division in vivo. Science. 2003;302:255–259. doi: 10.1126/science.1086271. PubMed DOI

Hunt T., Sassone-Corsi P. Riding tandem: Circadian clocks and the cell cycle. Cell. 2007;129:461–464. doi: 10.1016/j.cell.2007.04.015. PubMed DOI

Filipski E., King V.M., Li X., Granda T.G., Mormont M.C., Liu X., Claustrat B., Hastings M.H., Levi F. Host circadian clock as a control point in tumor progression. J. Natl. Cancer Inst. 2002;94:690–697. doi: 10.1093/jnci/94.9.690. PubMed DOI

Santoni-Rugiu E., Jensen M.R., Thorgeirsson S.S. Disruption of the pRb/E2F pathway and inhibition of apoptosis are major oncogenic events in liver constitutively expressing c-myc and transforming growth factor alpha. Cancer Res. 1998;58:123–134. PubMed

Pascale R.M., Simile M.M., De Miglio M.R., Muroni M.R., Calvisi D.F., Asara G., Casabona D., Frau M., Seddaiu M.A., Feo F. Cell cycle deregulation in liver lesions of rats with and without genetic predisposition to hepatocarcinogenesis. Hepatology. 2002;35:1341–1350. doi: 10.1053/jhep.2002.33682. PubMed DOI

Greenbaum L.E. Cell cycle regulation and hepatocarcinogenesis. Cancer Biol. Ther. 2004;3:1200–1207. doi: 10.4161/cbt.3.12.1392. PubMed DOI

Filipski E., Subramanian P., Carriere J., Guettier C., Barbason H., Levi F. Circadian disruption accelerates liver carcinogenesis in mice. Mutat. Res. 2009;680:95–105. doi: 10.1016/j.mrgentox.2009.10.002. PubMed DOI

Fleet T., Stashi E., Zhu B., Rajapakshe K., Marcelo K.L., Kettner N.M., Gorman B.K., Coarfa C., Fu L., O'Malley B.W., et al. Genetic and Environmental Models of Circadian Disruption Link SRC-2 Function to Hepatic Pathology. J. Biol. Rhythm. 2016;31:443–460. doi: 10.1177/0748730416657921. PubMed DOI PMC

Kettner N.M., Voicu H., Finegold M.J., Coarfa C., Sreekumar A., Putluri N., Katchy C.A., Lee C., Moore D.D., Fu L. Circadian Homeostasis of Liver Metabolism Suppresses Hepatocarcinogenesis. Cancer Cell. 2016;30:909–924. doi: 10.1016/j.ccell.2016.10.007. PubMed DOI PMC

Lin Y.M., Chang J.H., Yeh K.T., Yang M.Y., Liu T.C., Lin S.F., Su W.W., Chang J.G. Disturbance of circadian gene expression in hepatocellular carcinoma. Mol. Carcinog. 2008;47:925–933. doi: 10.1002/mc.20446. PubMed DOI

Yang S.L., Yu C., Jiang J.X., Liu L.P., Fang X., Wu C. Hepatitis B virus X protein disrupts the balance of the expression of circadian rhythm genes in hepatocellular carcinoma. Oncol. Lett. 2014;8:2715–2720. doi: 10.3892/ol.2014.2570. PubMed DOI PMC

Yu C., Yang S.L., Fang X., Jiang J.X., Sun C.Y., Huang T. Hypoxia disrupts the expression levels of circadian rhythm genes in hepatocellular carcinoma. Mol. Med. Rep. 2015;11:4002–4008. doi: 10.3892/mmr.2015.3199. PubMed DOI

Mazzoccoli G., Miele L., Oben J., Grieco A., Vinciguerra M. Biology, Epidemiology, Clinical Aspects of Hepatocellular Carcinoma and the Role of Sorafenib. Curr. Drug Targ. 2016;17:783–799. doi: 10.2174/1389450117666151209120831. PubMed DOI

Mazzoccoli G., De Cosmo S., Mazza T. The Biological Clock: A Pivotal Hub in Non-alcoholic Fatty Liver Disease Pathogenesis. Front. Physiol. 2018;9:193. doi: 10.3389/fphys.2018.00193. PubMed DOI PMC

Nusse R., Clevers H. Wnt/beta-Catenin Signaling, Disease, and Emerging Therapeutic Modalities. Cell. 2017;169:985–999. doi: 10.1016/j.cell.2017.05.016. PubMed DOI

Rey G., Cesbron F., Rougemont J., Reinke H., Brunner M., Naef F. Genome-wide and phase-specific DNA-binding rhythms of BMAL1 control circadian output functions in mouse liver. PLoS Biol. 2011;9:e1000595. doi: 10.1371/journal.pbio.1000595. PubMed DOI PMC

Guo B., Chatterjee S., Li L., Kim J.M., Lee J., Yechoor V.K., Minze L.J., Hsueh W., Ma K. The clock gene, brain and muscle Arnt-like 1, regulates adipogenesis via Wnt signaling pathway. FASEB J. 2012;26:3453–3463. doi: 10.1096/fj.12-205781. PubMed DOI PMC

Boucsein A., Benzler J., Hempp C., Stohr S., Helfer G., Tups A. Photoperiodic and Diurnal Regulation of WNT Signaling in the Arcuate Nucleus of the Female Djungarian Hamster, Phodopus sungorus. Endocrinology. 2016;157:799–809. doi: 10.1210/en.2015-1708. PubMed DOI

Matsu-Ura T., Moore S.R., Hong C.I. WNT Takes Two to Tango: Molecular Links between the Circadian Clock and the Cell Cycle in Adult Stem Cells. J. Biol. Rhythm. 2018;33:5–14. doi: 10.1177/0748730417745913. PubMed DOI PMC

Sotak M., Sumova A., Pacha J. Cross-talk between the circadian clock and the cell cycle in cancer. Ann. Med. 2014;46:221–232. doi: 10.3109/07853890.2014.892296. PubMed DOI

Janich P., Pascual G., Merlos-Suarez A., Batlle E., Ripperger J., Albrecht U., Cheng H.Y., Obrietan K., Di Croce L., Benitah S.A. The circadian molecular clock creates epidermal stem cell heterogeneity. Nature. 2011;480:209–214. doi: 10.1038/nature10649. PubMed DOI

Jia Y., Wang Y., Xie J. The Hedgehog pathway: Role in cell differentiation, polarity and proliferation. Arch. Toxicol. 2015;89:179–191. doi: 10.1007/s00204-014-1433-1. PubMed DOI PMC

Sicklick J.K., Li Y.X., Jayaraman A., Kannangai R., Qi Y., Vivekanandan P., Ludlow J.W., Owzar K., Chen W., Torbenson M.S., et al. Dysregulation of the Hedgehog pathway in human hepatocarcinogenesis. Carcinogenesis. 2006;27:748–757. doi: 10.1093/carcin/bgi292. PubMed DOI

Marbach-Breitruck E., Matz-Soja M., Abraham U., Schmidt-Heck W., Sales S., Rennert C., Kern M., Aleithe S., Spormann L., Thiel C., et al. Tick-tock hedgehog-mutual crosstalk with liver circadian clock promotes liver steatosis. J. Hepatol. 2019;70:1192–1202. doi: 10.1016/j.jhep.2019.01.022. PubMed DOI

Mazzoccoli G., Keshavarzian A., Vinciguerra M. Hedgehog signaling keeps liver clock in check. J. Hepatol. 2019;70:1054–1056. doi: 10.1016/j.jhep.2019.02.009. PubMed DOI

Morrison D.K. MAP kinase pathways. Cold Spring Harb. Perspect. Biol. 2012;4:a011254. doi: 10.1101/cshperspect.a011254. PubMed DOI PMC

De Paula R.M., Lamb T.M., Bennett L., Bell-Pedersen D. A connection between MAPK pathways and circadian clocks. Cell Cycle. 2008;7:2630–2634. doi: 10.4161/cc.7.17.6516. PubMed DOI PMC

Goldsmith C.S., Bell-Pedersen D. Diverse roles for MAPK signaling in circadian clocks. Adv. Genet. 2013;84:1–39. PubMed PMC

Bennett L.D., Beremand P., Thomas T.L., Bell-Pedersen D. Circadian activation of the mitogen-activated protein kinase MAK-1 facilitates rhythms in clock-controlled genes in Neurospora crassa. Eukaryot. Cell. 2013;12:59–69. doi: 10.1128/EC.00207-12. PubMed DOI PMC

Caster S.Z., Castillo K., Sachs M.S., Bell-Pedersen D. Circadian clock regulation of mRNA translation through eukaryotic elongation factor eEF-2. Proc. Natl. Acad. Sci. USA. 2016;113:9605–9610. doi: 10.1073/pnas.1525268113. PubMed DOI PMC

Weichhart T. Mammalian target of rapamycin: A signaling kinase for every aspect of cellular life. Method. Mol. Biol. 2012;821:1–14. PubMed

Cao R. mTOR Signaling, Translational Control, and the Circadian Clock. Front. Genet. 2018;9:367. doi: 10.3389/fgene.2018.00367. PubMed DOI PMC

Wu R., Dang F., Li P., Wang P., Xu Q., Liu Z., Li Y., Wu Y., Chen Y., Liu Y. The Circadian Protein Period2 Suppresses mTORC1 Activity via Recruiting Tsc1 to mTORC1 Complex. Cell Metab. 2019;29:653–667. doi: 10.1016/j.cmet.2018.11.006. PubMed DOI

Giallongo S., Lo Re O., Vinciguerra M. Macro Histone Variants: Emerging Rheostats of Gastrointestinal Cancers. Cancers. 2019;11:676. doi: 10.3390/cancers11050676. PubMed DOI PMC

Zhao F. Dysregulated Epigenetic Modifications in the Pathogenesis of NAFLD-HCC. Adv. Exp. Med. Biol. 2018;1061:79–93. PubMed

Berdasco M., Esteller M. Clinical epigenetics: Seizing opportunities for translation. Nat. Rev. Genet. 2019;20:109–127. doi: 10.1038/s41576-018-0074-2. PubMed DOI

Emmett M.J., Lazar M.A. Integrative regulation of physiology by histone deacetylase 3. Nat. Rev. Mol. Cell Biol. 2019;20:102–115. doi: 10.1038/s41580-018-0076-0. PubMed DOI PMC

Fekry B., Ribas-Latre A., Baumgartner C., Deans J.R., Kwok C., Patel P., Fu L., Berdeaux R., Sun K., Kolonin M.G., et al. Incompatibility of the circadian protein BMAL1 and HNF4alpha in hepatocellular carcinoma. Nat. Commun. 2018;9:4349. doi: 10.1038/s41467-018-06648-6. PubMed DOI PMC

Buschbeck M., Hake S.B. Variants of core histones and their roles in cell fate decisions, development and cancer. Nat. Rev. Mol. Cell Biol. 2017;18:299–314. doi: 10.1038/nrm.2016.166. PubMed DOI

Lo Re O., Vinciguerra M. Histone MacroH2A1: A Chromatin Point of Intersection between Fasting, Senescence and Cellular Regeneration. Genes. 2017;8:367. doi: 10.3390/genes8120367. PubMed DOI PMC

Borghesan M., Fusilli C., Rappa F., Panebianco C., Rizzo G., Oben J.A., Mazzoccoli G., Faulkes C., Pata I., Agodi A., et al. DNA Hypomethylation and Histone Variant macroH2A1 Synergistically Attenuate Chemotherapy-Induced Senescence to Promote Hepatocellular Carcinoma Progression. Cancer Res. 2016;76:594–606. doi: 10.1158/0008-5472.CAN-15-1336. PubMed DOI PMC

Sceusi E.L., Loose D.S., Wray C.J. Clinical implications of DNA methylation in hepatocellular carcinoma. HPB. 2011;13:369–376. doi: 10.1111/j.1477-2574.2011.00303.x. PubMed DOI PMC

Jueliger S., Lyons J., Cannito S., Pata I., Pata P., Shkolnaya M., Lo Re O., Peyrou M., Villarroya F., Pazienza V., et al. Efficacy and epigenetic interactions of novel DNA hypomethylating agent guadecitabine (SGI-110) in preclinical models of hepatocellular carcinoma. Epigenetics. 2016;11:709–720. doi: 10.1080/15592294.2016.1214781. PubMed DOI PMC

Kapoor A., Goldberg M.S., Cumberland L.K., Ratnakumar K., Segura M.F., Emanuel P.O., Menendez S., Vardabasso C., Leroy G., Vidal C.I., et al. The histone variant macroH2A suppresses melanoma progression through regulation of CDK8. Nature. 2010;468:1105–1109. doi: 10.1038/nature09590. PubMed DOI PMC

Creppe C., Janich P., Cantarino N., Noguera M., Valero V., Musulen E., Douet J., Posavec M., Martin-Caballero J., Sumoy L., et al. MacroH2A1 regulates the balance between self-renewal and differentiation commitment in embryonic and adult stem cells. Mol. Cell. Biol. 2012;32:1442–1452. doi: 10.1128/MCB.06323-11. PubMed DOI PMC

Lo Re O., Fusilli C., Rappa F., Van Haele M., Douet J., Pindjakova J., Rocha S.W., Pata I., Valcikova B., Uldrijan S., et al. Induction of cancer cell stemness by depletion of macrohistone H2A1 in hepatocellular carcinoma. Hepatology. 2018;67:636–650. doi: 10.1002/hep.29519. PubMed DOI

Lo Re O., Douet J., Buschbeck M., Fusilli C., Pazienza V., Panebianco C., Castracani C.C., Mazza T., Li Volti G., Vinciguerra M. Histone variant macroH2A1 rewires carbohydrate and lipid metabolism of hepatocellular carcinoma cells towards cancer stem cells. Epigenetics. 2018;13:829–845. doi: 10.1080/15592294.2018.1514239. PubMed DOI PMC

Rey G., Valekunja U.K., Feeney K.A., Wulund L., Milev N.B., Stangherlin A., Ansel-Bollepalli L., Velagapudi V., O'Neill J.S., Reddy A.B. The Pentose Phosphate Pathway Regulates the Circadian Clock. Cell Metab. 2016;24:462–473. doi: 10.1016/j.cmet.2016.07.024. PubMed DOI PMC

Le Martelot G., Claudel T., Gatfield D., Schaad O., Kornmann B., Lo Sasso G., Moschetta A., Schibler U. REV-ERBalpha participates in circadian SREBP signaling and bile acid homeostasis. PLoS Biol. 2009;7:e1000181. PubMed PMC

Zheng Z., Kim H., Qiu Y., Chen X., Mendez R., Dandekar A., Zhang X., Zhang C., Liu A.C., Yin L., et al. CREBH Couples Circadian Clock With Hepatic Lipid Metabolism. Diabetes. 2016;65:3369–3383. doi: 10.2337/db16-0298. PubMed DOI PMC

Borghesan M., Mazzoccoli G., Sheedfar F., Oben J., Pazienza V., Vinciguerra M. Histone variants and lipid metabolism. Biochem. Soc. Trans. 2014;42:1409–1413. doi: 10.1042/BST20140119. PubMed DOI

Sheedfar F., Vermeer M., Pazienza V., Villarroya J., Rappa F., Cappello F., Mazzoccoli G., Villarroya F., van der Molen H., Hofker M.H., et al. Genetic ablation of macrohistone H2A1 leads to increased leanness, glucose tolerance and energy expenditure in mice fed a high-fat diet. Int. J. Obes. 2015;39:331–338. doi: 10.1038/ijo.2014.91. PubMed DOI

Pazienza V., Borghesan M., Mazza T., Sheedfar F., Panebianco C., Williams R., Mazzoccoli G., Andriulli A., Nakanishi T., Vinciguerra M. SIRT1-metabolite binding histone macroH2A1.1 protects hepatocytes against lipid accumulation. Aging. 2014;6:35–47. doi: 10.18632/aging.100632. PubMed DOI PMC

Liu X., Dang Y., Matsu-Ura T., He Y., He Q., Hong C.I., Liu Y. DNA Replication Is Required for Circadian Clock Function by Regulating Rhythmic Nucleosome Composition. Mol. Cell. 2017;67:203–213. doi: 10.1016/j.molcel.2017.05.029. PubMed DOI PMC

Sato H., Wu B., Delahaye F., Singer R.H., Greally J.M. Retargeting of macroH2A following mitosis to cytogenetic-scale heterochromatic domains. J. Cell Biol. 2019;218:1810–1823. doi: 10.1083/jcb.201811109. PubMed DOI PMC

Barzily-Rokni M., Friedman N., Ron-Bigger S., Isaac S., Michlin D., Eden A. Synergism between DNA methylation and macroH2A1 occupancy in epigenetic silencing of the tumor suppressor gene p16(CDKN2A) Nucleic Acid. Res. 2011;39:1326–1335. doi: 10.1093/nar/gkq994. PubMed DOI PMC

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. 2017;26:267–277 e2. doi: 10.1016/j.cmet.2017.06.007. PubMed DOI PMC

Chaix A., Zarrinpar A., Miu P., Panda S. Time-restricted feeding is a preventative and therapeutic intervention against diverse nutritional challenges. Cell Metab. 2014;20:991–1005. doi: 10.1016/j.cmet.2014.11.001. PubMed DOI PMC

Longo V.D., Panda S. Fasting, Circadian Rhythms, and Time-Restricted Feeding in Healthy Lifespan. Cell Metab. 2016;23:1048–1059. doi: 10.1016/j.cmet.2016.06.001. PubMed DOI PMC

Asher G., Sassone-Corsi P. Time for food: The intimate interplay between nutrition, metabolism, and the circadian clock. Cell. 2015;161:84–92. doi: 10.1016/j.cell.2015.03.015. PubMed DOI

Sherman H., Genzer Y., Cohen R., Chapnik N., Madar Z., Froy O. Timed high-fat diet resets circadian metabolism and prevents obesity. FASEB J. 2012;26:3493–3502. doi: 10.1096/fj.12-208868. PubMed DOI

Jakubowicz D., Barnea M., Wainstein J., Froy O. High caloric intake at breakfast vs. dinner differentially influences weight loss of overweight and obese women. Obesity. 2013;21:2504–2512. doi: 10.1002/oby.20460. PubMed DOI

Jakubowicz D., Wainstein J., Ahren B., Bar-Dayan Y., Landau Z., Rabinovitz H.R., Froy O. High-energy breakfast with low-energy dinner decreases overall daily hyperglycaemia in type 2 diabetic patients: A randomised clinical trial. Diabetologia. 2015;58:912–919. doi: 10.1007/s00125-015-3524-9. PubMed DOI

Garaulet M., Gomez-Abellan P., Alburquerque-Bejar J.J., Lee Y.C., Ordovas J.M., Scheer F.A. Timing of food intake predicts weight loss effectiveness. Int. J. Obes. 2013;37:604–611. doi: 10.1038/ijo.2012.229. PubMed DOI PMC

Morris C.J., Garcia J.I., Myers S., Yang J.N., Trienekens N., Scheer F.A. The Human Circadian System Has a Dominating Role in Causing the Morning/Evening Difference in Diet-Induced Thermogenesis. Obesity. 2015;23:2053–2058. doi: 10.1002/oby.21189. PubMed DOI PMC

Johnston J.D., Ordovas J.M., Scheer F.A., Turek F.W. Circadian Rhythms, Metabolism, and Chrononutrition in Rodents and Humans. Adv. Nutr. 2016;7:399–406. doi: 10.3945/an.115.010777. PubMed DOI PMC

Circulating histone signature of human lean metabolic-associated fatty liver disease (MAFLD)