title: Liver-derived ketone bodies are necessary for food anticipation.
abstract: The circadian system has endowed animals with the ability to anticipate recurring food availability at particular times of day. As daily food anticipation (FA) is independent of the suprachiasmatic nuclei, the central pacemaker of the circadian system, questions arise of where FA signals originate and what role components of the circadian clock might play. Here we show that liver-specific deletion of Per2 in mice abolishes FA, an effect that is rescued by viral overexpression of Per2 in the liver. RNA sequencing indicates that Per2 regulates β-hydroxybutyrate (βOHB) production to induce FA leading to the conclusion that liver Per2 is important for this process. Unexpectedly, we show that FA originates in the liver and not in the brain. However, manifestation of FA involves processing of the liver-derived βOHB signal in the brain, indicating that the food-entrainable oscillator is not located in a single tissue but is of systemic nature.
authors.affiliation: Department of Biology, Unit of Biochemistry, University of Fribourg, Fribourg 1700, Switzerland.
authors.forename: Rohit
authors.initials: R
authors.lastname: Chavan
authors.affiliation: Department of Biology, Unit of Biochemistry, University of Fribourg, Fribourg 1700, Switzerland.
authors.forename: Céline
authors.initials: C
authors.lastname: Feillet
authors.affiliation: Department of Biology, Unit of Biochemistry, University of Fribourg, Fribourg 1700, Switzerland.
authors.forename: Sara S Fonseca
authors.initials: SS
authors.lastname: Costa
authors.affiliation: Department of Biology, Unit of Biochemistry, University of Fribourg, Fribourg 1700, Switzerland.
authors.forename: James E
authors.initials: JE
authors.lastname: Delorme
authors.affiliation: Department of Biology, Unit of Biochemistry, University of Fribourg, Fribourg 1700, Switzerland.
authors.forename: Takashi
authors.initials: T
authors.lastname: Okabe
authors.affiliation: Department of Biology, Unit of Biochemistry, University of Fribourg, Fribourg 1700, Switzerland.
authors.forename: Jürgen A
authors.initials: JA
authors.lastname: Ripperger
authors.affiliation: Department of Biology, Unit of Biochemistry, University of Fribourg, Fribourg 1700, Switzerland.
authors.forename: Urs
authors.identifier: http://orcid.org/0000-0002-0663-8676
authors.initials: U
authors.lastname: Albrecht
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000096:biosynthesis* / Q000378:metabolism; D000105:Acetyl Coenzyme A / Q000378:metabolism; D000818:Animals; D059031:Anticipation, Psychological / Q000502:physiology*; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D002940:Circadian Rhythm; D005247:Feeding Behavior; D005502:Food; D055879:Gene Knock-In Techniques; D055786:Gene Knockout Techniques; D007150:Immunohistochemistry; D007657:Ketone Bodies / Q000096:biosynthesis / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D056950:Period Circadian Proteins / Q000235:genetics*; D017423:Sequence Analysis, RNA; D015398:Signal Transduction
chemical_list: D007657:Ketone Bodies; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D000105:Acetyl Coenzyme A; D020155:3-Hydroxybutyric Acid
references.citation: Biol Proced Online. 2005;7:101-16
references.pmid: 16136228
references.citation: BMC Mol Biol. 2008;9:41
references.pmid: 18430226
references.citation: Bioinformatics. 2015 Jan 15;31(2):166-9
references.pmid: 25260700
references.citation: Trends Endocrinol Metab. 2014 Jan;25(1):42-52
references.pmid: 24140022
references.citation: Am J Physiol Regul Integr Comp Physiol. 2003 Jul;285(1):R57-67
references.pmid: 12649127
references.citation: J Clin Invest. 2003 Sep;112(6):892-901
references.pmid: 12975474
references.citation: Nat Genet. 1999 Sep;23(1):99-103
references.pmid: 10471508
references.citation: Nat Protoc. 2007;2(5):1236-47
references.pmid: 17546019
references.citation: Genes Dev. 2010 Feb 15;24(4):345-57
references.pmid: 20159955
references.citation: Elife. 2015;4:e06253
references.pmid: 25821984
references.citation: Neurosci Biobehav Rev. 1980 Summer;4(2):119-31
references.pmid: 6106914
references.citation: Bioinformatics. 2009 May 1;25(9):1105-11
references.pmid: 19289445
references.citation: Science. 2012 Oct 19;338(6105):349-54
references.pmid: 22936566
references.citation: Neurosci Res. 2005 Jun;52(2):166-73
references.pmid: 15893577
references.citation: Curr Biol. 2006 Oct 24;16(20):2016-22
references.pmid: 17055980
references.citation: Endocrinology. 2003 Sep;144(9):3749-56
references.pmid: 12933644
references.citation: Genesis. 2000 Nov-Dec;28(3-4):106-10
references.pmid: 11105051
references.citation: Proc Natl Acad Sci U S A. 2009 Aug 11;106(32):13582-7
references.pmid: 19633195
references.citation: Genes Dev. 2000 Dec 1;14(23):2950-61
references.pmid: 11114885
references.citation: Mol Metab. 2014 Jul 10;3(7):694-704
references.pmid: 25352998
references.citation: Endocrinology. 1974 Nov;95(5):1195-201
references.pmid: 4426285
references.citation: Nucleic Acids Res. 1995 Dec 25;23(24):5080-1
references.pmid: 8559668
references.citation: PLoS One. 2014;9(6):e99883
references.pmid: 24932636
references.citation: Cell Metab. 2014 Dec 2;20(6):991-1005
references.pmid: 25470547
references.citation: Behav Neural Biol. 1979 Mar;25(3):346-63
references.pmid: 464979
references.citation: J Biol Rhythms. 2001 Apr;16(2):100-4
references.pmid: 11302552
references.citation: J Neurosci. 2007 Mar 14;27(11):2890-5
references.pmid: 17360911
references.citation: Proc Natl Acad Sci U S A. 2009 Apr 21;106(16):6808-13
references.pmid: 19366674
references.citation: Nat Biotechnol. 2011 Jan;29(1):24-6
references.pmid: 21221095
references.citation: PLoS Biol. 2007 Feb;5(2):e34
references.pmid: 17298173
references.citation: Nature. 1999 Jul 8;400(6740):169-73
references.pmid: 10408444
references.citation: Annu Rev Neurosci. 2012;35:445-62
references.pmid: 22483041
references.citation: Neurosci Biobehav Rev. 1994 Summer;18(2):171-95
references.pmid: 8058212
references.citation: Nat Methods. 2012 Apr;9(4):357-9
references.pmid: 22388286
references.citation: Genesis. 2000 Feb;26(2):151-3
references.pmid: 10686615
references.citation: Genes Brain Behav. 2010 Jul;9(5):467-77
references.pmid: 20180860
references.citation: Annu Rev Physiol. 2010;72:551-77
references.pmid: 20148688
references.citation: Science. 2001 Jan 19;291(5503):490-3
references.pmid: 11161204
references.citation: Genome Res. 2003 Mar;13(3):476-84
references.pmid: 12618378
references.citation: Proc Natl Acad Sci U S A. 2012 Aug 28;109(35):14218-23
references.pmid: 22891330
references.citation: Science. 2003 Jul 18;301(5631):379-83
references.pmid: 12843397
references.citation: Cold Spring Harb Symp Quant Biol. 2007;72:95-104
references.pmid: 18419266
references.citation: Genome Biol. 2014;15(12):550
references.pmid: 25516281