Home LiteratureArticle Details
PMID: 22841001 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review

Clocks, metabolism, and the epigenome.

Molecular cell ·Vol. 47 ·No. 2 ·2012-07-27 ·Pages 158-67

Feng D, Lazar MA

Abstract

Many behaviors and physiological activities in living organisms display circadian rhythms, allowing the organisms to anticipate and prepare for the diurnal changes in the living environment. In this way, metabolic processes are aligned with the periodic environmental changes and behavioral cycles, such as the sleep/wake and fasting/feeding cycles. Disturbances of this alignment significantly increase the risk of metabolic diseases. Meanwhile, the circadian clock receives signals from the environment and feedback from metabolic pathways, and adjusts its activity and function. Growing evidence connects the circadian clock with epigenomic regulators. Here we review the recent advances in understanding the crosstalk between the circadian clock and energy metabolism through epigenomic programming and transcriptional regulation.

MeSH Terms
Animals Cell Nucleus/metabolism Circadian Rhythm Cytoplasm/metabolism Epigenomics Gene Expression Regulation Glucose/metabolism Heme/chemistry Histones/metabolism Homeostasis Humans Lipids/chemistry Liver/metabolism Models, Biological Risk Transcription, Genetic
Chemicals
Histones Lipids Heme Glucose
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Feng Dan
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Lazar Mitchell A
References (103)
103 references, click to expand
  1. Integration of microRNA miR-122 in hepatic circadian gene expression.
    Genes Dev. 2009 Jun 1;23(11):1313-26 PMID: 19487572
  2. Regulation of circadian behaviour and metabolism by REV-ERB-α and REV-ERB-β.
    Nature. 2012 Mar 29;485(7396):123-7 PMID: 22460952
  3. Genome-wide and phase-specific DNA-binding rhythms of BMAL1 control circadian output functions in mouse liver.
    PLoS Biol. 2011 Feb;9(2):e1000595 PMID: 21364973
  4. The orphan nuclear receptor Rev-erbalpha recruits the N-CoR/histone deacetylase 3 corepressor to regulate the circadian Bmal1 gene.
    Mol Endocrinol. 2005 Jun;19(6):1452-9 PMID: 15761026
  5. Circadian rhythms, sleep, and metabolism.
    J Clin Invest. 2011 Jun;121(6):2133-41 PMID: 21633182
  6. Peripheral CLOCK regulates target-tissue glucocorticoid receptor transcriptional activity in a circadian fashion in man.
    PLoS One. 2011;6(9):e25612 PMID: 21980503
  7. Structure of Rev-erbalpha bound to N-CoR reveals a unique mechanism of nuclear receptor-co-repressor interaction.
    Nat Struct Mol Biol. 2010 Jul;17(7):808-14 PMID: 20581824
  8. PERIOD1-associated proteins modulate the negative limb of the mammalian circadian oscillator.
    Science. 2005 Apr 29;308(5722):693-6 PMID: 15860628
  9. A molecular mechanism for circadian clock negative feedback.
    Science. 2011 Jun 17;332(6036):1436-9 PMID: 21680841
  10. Rhythmic CLOCK-BMAL1 binding to multiple E-box motifs drives circadian Dbp transcription and chromatin transitions.
    Nat Genet. 2006 Mar;38(3):369-74 PMID: 16474407
  11. A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange.
    Nature. 2008 Nov 13;456(7219):269-73 PMID: 18849969
  12. PER2 controls lipid metabolism by direct regulation of PPARγ.
    Cell Metab. 2010 Nov 3;12(5):509-20 PMID: 21035761
  13. SIRT1 regulates circadian clock gene expression through PER2 deacetylation.
    Cell. 2008 Jul 25;134(2):317-28 PMID: 18662546
  14. Insights from genomic profiling of transcription factors.
    Nat Rev Genet. 2009 Sep;10(9):605-16 PMID: 19668247
  15. Circadian integration of metabolism and energetics.
    Science. 2010 Dec 3;330(6009):1349-54 PMID: 21127246
  16. The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator.
    Cell. 2002 Jul 26;110(2):251-60 PMID: 12150932
  17. The NAD+-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control.
    Cell. 2008 Jul 25;134(2):329-40 PMID: 18662547
  18. Circadian orchestration of the hepatic proteome.
    Curr Biol. 2006 Jun 6;16(11):1107-15 PMID: 16753565
  19. Calorie restriction: is AMPK a key sensor and effector?
    Physiology (Bethesda). 2011 Aug;26(4):214-24 PMID: 21841070
  20. Circadian dysregulation disrupts bile acid homeostasis.
    PLoS One. 2009 Aug 31;4(8):e6843 PMID: 19718444
  21. Regulation of clock and NPAS2 DNA binding by the redox state of NAD cofactors.
    Science. 2001 Jul 20;293(5529):510-4 PMID: 11441146
  22. System-driven and oscillator-dependent circadian transcription in mice with a conditionally active liver clock.
    PLoS Biol. 2007 Feb;5(2):e34 PMID: 17298173
  23. Regulation of bile acid synthesis by the nuclear receptor Rev-erbalpha.
    Gastroenterology. 2008 Aug;135(2):689-98 PMID: 18565334
  24. Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists.
    Nature. 2012 Mar 29;485(7396):62-8 PMID: 22460951
  25. Shift work and chronic disease: the epidemiological evidence.
    Occup Med (Lond). 2011 Mar;61(2):78-89 PMID: 21355031
  26. The clock gene Per2 links the circadian system to the estrogen receptor.
    Oncogene. 2007 Dec 13;26(57):7916-20 PMID: 17599055
  27. Glucocorticoid signaling synchronizes the liver circadian transcriptome.
    Hepatology. 2007 Jun;45(6):1478-88 PMID: 17538967
  28. AMPK regulates circadian rhythms in a tissue- and isoform-specific manner.
    PLoS One. 2011 Mar 31;6(3):e18450 PMID: 21483791
  29. Circadian clocks in human red blood cells.
    Nature. 2011 Jan 27;469(7331):498-503 PMID: 21270888
  30. Reciprocal regulation of brain and muscle Arnt-like protein 1 and peroxisome proliferator-activated receptor alpha defines a novel positive feedback loop in the rodent liver circadian clock.
    Mol Endocrinol. 2006 Aug;20(8):1715-27 PMID: 16556735
  31. Time of feeding and the intrinsic circadian clock drive rhythms in hepatic gene expression.
    Proc Natl Acad Sci U S A. 2009 Dec 15;106(50):21453-8 PMID: 19940241
  32. Negative feedback maintenance of heme homeostasis by its receptor, Rev-erbalpha.
    Genes Dev. 2009 Sep 15;23(18):2201-9 PMID: 19710360
  33. SWItch/sucrose nonfermentable (SWI/SNF) complex subunit BAF60a integrates hepatic circadian clock and energy metabolism.
    Hepatology. 2011 Oct;54(4):1410-20 PMID: 21725993
  34. REV-ERBalpha participates in circadian SREBP signaling and bile acid homeostasis.
    PLoS Biol. 2009 Sep;7(9):e1000181 PMID: 19721697
  35. Rev-erbalpha, a heme sensor that coordinates metabolic and circadian pathways.
    Science. 2007 Dec 14;318(5857):1786-9 PMID: 18006707
  36. Relationship between AMPK and the transcriptional balance of clock-related genes in skeletal muscle.
    Am J Physiol Endocrinol Metab. 2008 Nov;295(5):E1032-7 PMID: 18728219
  37. A circadian rhythm orchestrated by histone deacetylase 3 controls hepatic lipid metabolism.
    Science. 2011 Mar 11;331(6022):1315-9 PMID: 21393543
  38. Retinoic acid-related orphan receptor γ directly regulates neuronal PAS domain protein 2 transcription in vivo.
    Nucleic Acids Res. 2011 Jun;39(11):4769-82 PMID: 21317191
  39. Fatty acid synthesis in liver and adipose tissue of normal and genetically obese (ob/ob) mice during the 24-hour cycle.
    Biochem J. 1975 Aug;150(2):167-73 PMID: 1237298
  40. Epigenetic modifications and human disease.
    Nat Biotechnol. 2010 Oct;28(10):1057-68 PMID: 20944598
  41. Absence of the SRC-2 coactivator results in a glycogenopathy resembling Von Gierke's disease.
    Science. 2008 Nov 28;322(5906):1395-9 PMID: 19039140
  42. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity.
    Nature. 2009 Apr 23;458(7241):1056-60 PMID: 19262508
  43. Hepatic Hdac3 promotes gluconeogenesis by repressing lipid synthesis and sequestration.
    Nat Med. 2012 Jun;18(6):934-42 PMID: 22561686
  44. Rev-erbα and Rev-erbβ coordinately protect the circadian clock and normal metabolic function.
    Genes Dev. 2012 Apr 1;26(7):657-67 PMID: 22474260
  45. NPAS2: a gas-responsive transcription factor.
    Science. 2002 Dec 20;298(5602):2385-7 PMID: 12446832
  46. The histone methyltransferase MLL1 permits the oscillation of circadian gene expression.
    Nat Struct Mol Biol. 2010 Dec;17(12):1414-21 PMID: 21113167
  47. Identification of heme as the ligand for the orphan nuclear receptors REV-ERBalpha and REV-ERBbeta.
    Nat Struct Mol Biol. 2007 Dec;14(12):1207-13 PMID: 18037887
  48. Altered behavioral and metabolic circadian rhythms in mice with disrupted NAD+ oscillation.
    Aging (Albany NY). 2011 Aug;3(8):794-802 PMID: 21937766
  49. Epigenomics in environmental health.
    Front Genet. 2011 Nov 22;2:84 PMID: 22303378
  50. Energy sensing and regulation of gene expression in skeletal muscle.
    J Appl Physiol (1985). 2007 Feb;102(2):529-40 PMID: 17082363
  51. Histone lysine demethylase JARID1a activates CLOCK-BMAL1 and influences the circadian clock.
    Science. 2011 Sep 30;333(6051):1881-5 PMID: 21960634
  52. The structural basis of gas-responsive transcription by the human nuclear hormone receptor REV-ERBbeta.
    PLoS Biol. 2009 Feb 24;7(2):e43 PMID: 19243223
  53. Rhythmic histone acetylation underlies transcription in the mammalian circadian clock.
    Nature. 2003 Jan 9;421(6919):177-82 PMID: 12483227
  54. The meter of metabolism.
    Cell. 2008 Sep 5;134(5):728-42 PMID: 18775307
  55. Obesity and metabolic syndrome in circadian Clock mutant mice.
    Science. 2005 May 13;308(5724):1043-5 PMID: 15845877
  56. Rhythms of mammalian body temperature can sustain peripheral circadian clocks.
    Curr Biol. 2002 Sep 17;12(18):1574-83 PMID: 12372249
  57. Circadian rhythms persist without transcription in a eukaryote.
    Nature. 2011 Jan 27;469(7331):554-8 PMID: 21270895
  58. Entrainment of the circadian clock in the liver by feeding.
    Science. 2001 Jan 19;291(5503):490-3 PMID: 11161204
  59. Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus.
    Genes Dev. 2000 Dec 1;14(23):2950-61 PMID: 11114885
  60. Brain and muscle Arnt-like protein-1 (BMAL1), a component of the molecular clock, regulates adipogenesis.
    Proc Natl Acad Sci U S A. 2005 Aug 23;102(34):12071-6 PMID: 16093318
  61. Physiological significance of a peripheral tissue circadian clock.
    Proc Natl Acad Sci U S A. 2008 Sep 30;105(39):15172-7 PMID: 18779586
  62. Refeeding after fasting elicits insulin-dependent regulation of Per2 and Rev-erbα with shifts in the liver clock.
    J Biol Rhythms. 2011 Jun;26(3):230-40 PMID: 21628550
  63. Nuclear receptor corepressor and histone deacetylase 3 govern circadian metabolic physiology.
    Nature. 2008 Dec 18;456(7224):997-1000 PMID: 19037247
  64. Reciprocal regulation of haem biosynthesis and the circadian clock in mammals.
    Nature. 2004 Jul 22;430(6998):467-71 PMID: 15269772
  65. Circadian clock feedback cycle through NAMPT-mediated NAD+ biosynthesis.
    Science. 2009 May 1;324(5927):651-4 PMID: 19299583
  66. Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes.
    Nature. 2010 Jul 29;466(7306):627-31 PMID: 20562852
  67. Inactivation of hepatic Foxo1 by insulin signaling is required for adaptive nutrient homeostasis and endocrine growth regulation.
    Cell Metab. 2008 Jul;8(1):65-76 PMID: 18590693
  68. Circadian and light-induced transcription of clock gene Per1 depends on histone acetylation and deacetylation.
    Mol Cell Biol. 2004 Jul;24(14):6278-87 PMID: 15226430
  69. Circadian control of the NAD+ salvage pathway by CLOCK-SIRT1.
    Science. 2009 May 1;324(5927):654-7 PMID: 19286518
  70. Thiol-disulfide redox dependence of heme binding and heme ligand switching in nuclear hormone receptor rev-erb{beta}.
    J Biol Chem. 2011 Feb 11;286(6):4392-403 PMID: 21123168
  71. Signal transduction by heme-containing PAS-domain proteins.
    J Appl Physiol (1985). 2004 Feb;96(2):774-83 PMID: 14715687
  72. Deficient of a clock gene, brain and muscle Arnt-like protein-1 (BMAL1), induces dyslipidemia and ectopic fat formation.
    PLoS One. 2011;6(9):e25231 PMID: 21966465
  73. Activation of 5'-AMP-activated kinase with diabetes drug metformin induces casein kinase Iepsilon (CKIepsilon)-dependent degradation of clock protein mPer2.
    J Biol Chem. 2007 Jul 20;282(29):20794-8 PMID: 17525164
  74. Circadian regulator CLOCK is a histone acetyltransferase.
    Cell. 2006 May 5;125(3):497-508 PMID: 16678094
  75. Genetic and molecular analysis of the central and peripheral circadian clockwork of mice.
    Cold Spring Harb Symp Quant Biol. 2007;72:85-94 PMID: 18419265
  76. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1.
    Nature. 2005 Mar 3;434(7029):113-8 PMID: 15744310
  77. The role of the orphan nuclear receptor Rev-Erb alpha in adipocyte differentiation and function.
    Biochimie. 2005 Jan;87(1):21-5 PMID: 15733732
  78. Poly(ADP-ribose) polymerase 1 participates in the phase entrainment of circadian clocks to feeding.
    Cell. 2010 Sep 17;142(6):943-53 PMID: 20832105
  79. High-fat diet disrupts behavioral and molecular circadian rhythms in mice.
    Cell Metab. 2007 Nov;6(5):414-21 PMID: 17983587
  80. Coordinated transcription of key pathways in the mouse by the circadian clock.
    Cell. 2002 May 3;109(3):307-20 PMID: 12015981
  81. Nuclear receptor expression links the circadian clock to metabolism.
    Cell. 2006 Aug 25;126(4):801-10 PMID: 16923398
  82. Transactivation mechanisms of mouse clock transcription factors, mClock and mArnt3.
    Genes Cells. 2000 Sep;5(9):739-47 PMID: 10971655
  83. The circadian change of gluconeogenesis in the liver in vivo in fed rats.
    J Biochem. 1980 Oct;88(4):1009-13 PMID: 7451400
  84. Calorie restriction and the exercise of chromatin.
    Genes Dev. 2009 Aug 15;23(16):1849-69 PMID: 19608767
  85. The mammalian clock component PERIOD2 coordinates circadian output by interaction with nuclear receptors.
    Genes Dev. 2010 Feb 15;24(4):345-57 PMID: 20159955
  86. E3 ligases Arf-bp1 and Pam mediate lithium-stimulated degradation of the circadian heme receptor Rev-erb alpha.
    Proc Natl Acad Sci U S A. 2010 Jun 22;107(25):11614-9 PMID: 20534529
  87. AMPK regulates the circadian clock by cryptochrome phosphorylation and degradation.
    Science. 2009 Oct 16;326(5951):437-40 PMID: 19833968
  88. The mammalian circadian timing system: organization and coordination of central and peripheral clocks.
    Annu Rev Physiol. 2010;72:517-49 PMID: 20148687
  89. Cryptochromes mediate rhythmic repression of the glucocorticoid receptor.
    Nature. 2011 Dec 14;480(7378):552-6 PMID: 22170608
  90. Fat circadian biology.
    J Appl Physiol (1985). 2009 Nov;107(5):1629-37 PMID: 19470701
  91. Effects of fasting and re-feeding on the expression of Dec1, Per1, and other clock-related genes.
    J Biochem. 2006 Sep;140(3):401-8 PMID: 16873396
  92. The circadian rhythm of glucocorticoids is regulated by a gating mechanism residing in the adrenal cortical clock.
    Cell Metab. 2006 Aug;4(2):163-73 PMID: 16890544
  93. Cryptochrome mediates circadian regulation of cAMP signaling and hepatic gluconeogenesis.
    Nat Med. 2010 Oct;16(10):1152-6 PMID: 20852621
  94. Circadian rhythm transcription factor CLOCK regulates the transcriptional activity of the glucocorticoid receptor by acetylating its hinge region lysine cluster: potential physiological implications.
    FASEB J. 2009 May;23(5):1572-83 PMID: 19141540
  95. Resetting of circadian time in peripheral tissues by glucocorticoid signaling.
    Science. 2000 Sep 29;289(5488):2344-7 PMID: 11009419
  96. Histone acetyltransferase-dependent chromatin remodeling and the vascular clock.
    J Biol Chem. 2004 Feb 20;279(8):7091-7 PMID: 14645221
  97. Circadian cycling of the mouse liver transcriptome, as revealed by cDNA microarray, is driven by the suprachiasmatic nucleus.
    Curr Biol. 2002 Apr 2;12(7):540-50 PMID: 11937022
  98. CLOCK-mediated acetylation of BMAL1 controls circadian function.
    Nature. 2007 Dec 13;450(7172):1086-90 PMID: 18075593
  99. The polycomb group protein EZH2 is required for mammalian circadian clock function.
    J Biol Chem. 2006 Jul 28;281(30):21209-21215 PMID: 16717091
  100. The relationship between nutrition and circadian rhythms in mammals.
    Front Neuroendocrinol. 2007 Aug-Sep;28(2-3):61-71 PMID: 17451793
  101. Transcription factors and coactivators controlling nutrient and hormonal regulation of hepatic gluconeogenesis.
    Int J Biochem Cell Biol. 2012 Jan;44(1):33-45 PMID: 22004992
  102. Genomic convergence among ERRα, PROX1, and BMAL1 in the control of metabolic clock outputs.
    PLoS Genet. 2011 Jun;7(6):e1002143 PMID: 21731503
  103. Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism.
    Nucl Recept Signal. 2009;7:e003 PMID: 19381306
Article Info
Journal
Molecular cell
Abbr.
Mol Cell
ISSN
1097-4164
DOI
10.1016/j.molcel.2012.06.026
Published
2012-07-27
Pages
158-67
Language
English
Region
United States
NLM ID
9802571
PMCID
PMC3408602
Subset
IM
Grants
NIDDK NIH HHS · DK45586 · United States
NIDDK NIH HHS · R01 DK045586 · United States
NIDDK NIH HHS · RC1 DK086239 · United States
NIDDK NIH HHS · DK43806 · United States
NIDDK NIH HHS · R37 DK043806 · United States
External Links
PubMed source DOI: 10.1016/j.molcel.2012.06.026 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2