title: Oxyntomodulin regulates resetting of the liver circadian clock by food.
abstract: Circadian clocks coordinate 24-hr rhythms of behavior and physiology. In mammals, a master clock residing in the suprachiasmatic nucleus (SCN) is reset by the light-dark cycle, while timed food intake is a potent synchronizer of peripheral clocks such as the liver. Alterations in food intake rhythms can uncouple peripheral clocks from the SCN, resulting in internal desynchrony, which promotes obesity and metabolic disorders. Pancreas-derived hormones such as insulin and glucagon have been implicated in signaling mealtime to peripheral clocks. In this study, we identify a novel, more direct pathway of food-driven liver clock resetting involving oxyntomodulin (OXM). In mice, food intake stimulates OXM secretion from the gut, which resets liver transcription rhythms via induction of the core clock genes Per1 and 2. Inhibition of OXM signaling blocks food-mediated resetting of hepatocyte clocks. These data reveal a direct link between gastric filling with food and circadian rhythm phasing in metabolic tissues.
authors.affiliation: Circadian Rhythms Group, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
authors.forename: Dominic
authors.initials: D
authors.lastname: Landgraf
authors.affiliation: Circadian Rhythms Group, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Tsang
authors.affiliation: Circadian Rhythms Group, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
authors.forename: Alexei
authors.initials: A
authors.lastname: Leliavski
authors.affiliation: Chronophysiology Group, Medical Department I, University of Lübeck, Lübeck, Germany.
authors.forename: Christiane E
authors.initials: CE
authors.lastname: Koch
authors.affiliation: Circadian Rhythms Group, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
authors.forename: Johanna L
authors.initials: JL
authors.lastname: Barclay
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Canada.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Drucker
authors.affiliation: Circadian Rhythms Group, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
authors.forename: Henrik
authors.initials: H
authors.lastname: Oster
mesh_terms: D000818:Animals; D057906:Circadian Clocks / Q000187:drug effects* / Q000235:genetics; D002940:Circadian Rhythm / Q000187:drug effects* / Q000235:genetics; D004435:Eating / Q000187:drug effects / Q000502:physiology; D005215:Fasting; D005786:Gene Expression Regulation; D007328:Insulin / Q000096:biosynthesis / Q000378:metabolism; D000078790:Insulin Secretion; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008867:Microtomy; D053772:Oxyntomodulin / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D056950:Period Circadian Proteins / Q000235:genetics* / Q000378:metabolism; D017440:Photoperiod; D015398:Signal Transduction; D013493:Suprachiasmatic Nucleus / Q000187:drug effects / Q000502:physiology; D046509:Tissue Culture Techniques
chemical_list: D007328:Insulin; D053772:Oxyntomodulin; C539023:Per1 protein, mouse; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins
keywords: Per; biochemistry; cell biology; circadian clock; clock genes; food resetting; liver; mouse
references.citation: Nat Clin Pract Endocrinol Metab. 2005 Nov;1(1):22-31
references.pmid: 16929363
references.citation: Physiol Rev. 2005 Oct;85(4):1131-58
references.pmid: 16183909
references.citation: J Pharmacol Exp Ther. 2007 Jul;322(1):148-54
references.pmid: 17395766
references.citation: Nat Rev Genet. 2008 Oct;9(10):764-75
references.pmid: 18802415
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 30;105(39):15172-7
references.pmid: 18779586
references.citation: PLoS Comput Biol. 2008 Oct;4(10):e1000193
references.pmid: 18846204
references.citation: Gastroenterology. 2008 Dec;135(6):2096-106
references.pmid: 18809404
references.citation: Proc Natl Acad Sci U S A. 2009 Aug 11;106(32):13582-7
references.pmid: 19633195
references.citation: PLoS One. 2009;4(9):e6909
references.pmid: 19738906
references.citation: Obesity (Silver Spring). 2009 Nov;17(11):2100-2
references.pmid: 19730426
references.citation: Proc Natl Acad Sci U S A. 2009 Dec 15;106(50):21453-8
references.pmid: 19940241
references.citation: Annu Rev Physiol. 2010;72:517-49
references.pmid: 20148687
references.citation: Annu Rev Physiol. 2010;72:551-77
references.pmid: 20148688
references.citation: Scand J Work Environ Health. 2010 Mar;36(2):150-62
references.pmid: 20143038
references.citation: Nutr Res Rev. 2010 Jun;23(1):155-68
references.pmid: 20122305
references.citation: Physiol Rev. 2010 Jul;90(3):1063-102
references.pmid: 20664079
references.citation: J Biol Rhythms. 2011 Jun;26(3):230-40
references.pmid: 21628550
references.citation: PLoS One. 2011;6(8):e23709
references.pmid: 21901130
references.citation: Postgrad Med. 2011 Sep;123(5):106-15
references.pmid: 21904092
references.citation: Neuron. 2012 Apr 26;74(2):246-60
references.pmid: 22542179
references.citation: PLoS One. 2012;7(5):e37150
references.pmid: 22629359
references.citation: Sci Rep. 2012;2:439
references.pmid: 22666542
references.citation: Cell Metab. 2012 Jun 6;15(6):848-60
references.pmid: 22608008
references.citation: Science. 2000 Sep 29;289(5488):2344-7
references.pmid: 11009419
references.citation: Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3342-7
references.pmid: 17360649
references.citation: Endocrinology. 2013 Jan;154(1):127-39
references.pmid: 23183176
references.citation: Genes Dev. 2000 Dec 1;14(23):2950-61
references.pmid: 11114885
references.citation: Science. 2001 Jan 19;291(5503):490-3
references.pmid: 11161204
references.citation: Nucleic Acids Res. 2001 Jun 1;29(11):E51-1
references.pmid: 11376163
references.citation: Int J Obes Relat Metab Disord. 2001 Dec;25 Suppl 5:S42-7
references.pmid: 11840214
references.citation: Curr Biol. 2002 Apr 2;12(7):540-50
references.pmid: 11937022
references.citation: Endocr Regul. 2013 Jul;47(3):159-70
references.pmid: 23889486
references.citation: Curr Biol. 2014 Jun 2;24(11):1248-55
references.pmid: 24856209
references.citation: J Biol Chem. 2015 Jan 23;290(4):2189-97
references.pmid: 25480789
references.citation: Endocrinology. 2010 Mar;151(3):1019-29
references.pmid: 20080873
references.citation: Genes Dev. 2002 Oct 15;16(20):2633-8
references.pmid: 12381662
references.citation: Nucleic Acids Res. 2001 May 1;29(9):e45
references.pmid: 11328886
references.citation: Eur J Neurosci. 2002 Oct;16(8):1531-40
references.pmid: 12405967
references.citation: Pharmacol Rev. 2003 Mar;55(1):167-94
references.pmid: 12615957
references.citation: Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5339-46
references.pmid: 14963227
references.citation: J Biol Chem. 2004 May 7;279(19):20345-55
references.pmid: 14988413
references.citation: Annu Rev Genomics Hum Genet. 2004;5:407-41
references.pmid: 15485355
references.citation: Regul Pept. 1988 May;21(1-2):151-66
references.pmid: 2839871
references.citation: Endocrinology. 1988 Dec;123(6):2782-7
references.pmid: 3197645
references.citation: Cell. 1989 Nov 17;59(4):675-80
references.pmid: 2573431
references.citation: J Clin Endocrinol Metab. 1992 Jun;74(6):1405-9
references.pmid: 1592887
references.citation: Endocrinology. 1993 Aug;133(2):631-8
references.pmid: 8102095
references.citation: Endocrinology. 1994 May;134(5):2156-64
references.pmid: 8156917
references.citation: Nat Med. 1996 Nov;2(11):1254-8
references.pmid: 8898756
references.citation: Cell. 1997 Dec 26;91(7):1055-64
references.pmid: 9428527
references.citation: Cell. 1998 Jun 12;93(6):929-37
references.pmid: 9635423
references.citation: Mol Cell Endocrinol. 1998 Jun 25;141(1-2):179-86
references.pmid: 9723898
references.citation: Cell. 1999 Jan 22;96(2):271-90
references.pmid: 9988221