title: Bmal1 and β-cell clock are required for adaptation to circadian disruption, and their loss of function leads to oxidative stress-induced β-cell failure in mice.
abstract: Circadian disruption has deleterious effects on metabolism. Global deletion of Bmal1, a core clock gene, results in β-cell dysfunction and diabetes. However, it is unknown if this is due to loss of cell-autonomous function of Bmal1 in β cells. To address this, we generated mice with β-cell clock disruption by deleting Bmal1 in β cells (β-Bmal1(-/-)). β-Bmal1(-/-) mice develop diabetes due to loss of glucose-stimulated insulin secretion (GSIS). This loss of GSIS is due to the accumulation of reactive oxygen species (ROS) and consequent mitochondrial uncoupling, as it is fully rescued by scavenging of the ROS or by inhibition of uncoupling protein 2. The expression of the master antioxidant regulatory factor Nrf2 (nuclear factor erythroid 2-related factor 2) and its targets, Sesn2, Prdx3, Gclc, and Gclm, was decreased in β-Bmal1(-/-) islets, which may contribute to the observed increase in ROS accumulation. In addition, by chromatin immunoprecipitation experiments, we show that Nrf2 is a direct transcriptional target of Bmal1. Interestingly, simulation of shift work-induced circadian misalignment in mice recapitulates many of the defects seen in Bmal1-deficient islets. Thus, the cell-autonomous function of Bmal1 is required for normal β-cell function by mitigating oxidative stress and serves to preserve β-cell function in the face of circadian misalignment.
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Jeongkyung
authors.initials: J
authors.lastname: Lee
authors.forename: Mousumi
authors.initials: M
authors.lastname: Moulik
authors.forename: Zhe
authors.initials: Z
authors.lastname: Fang
authors.forename: Pradip
authors.initials: P
authors.lastname: Saha
authors.forename: Fang
authors.initials: F
authors.lastname: Zou
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.forename: David L
authors.initials: DL
authors.lastname: Nelson
authors.forename: Ke
authors.initials: K
authors.lastname: Ma
authors.forename: David D
authors.initials: DD
authors.lastname: Moore
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Yechoor
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000222:Adaptation, Physiological / Q000502:physiology*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002940:Circadian Rhythm / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000235:genetics; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D006943:Hyperglycemia / Q000235:genetics; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000473:pathology / Q000502:physiology*; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000071246:Uncoupling Protein 2
chemical_list: D056930:ARNTL Transcription Factors; D000975:Antioxidants; C538961:Bmal1 protein, mouse; D007328:Insulin; D007473:Ion Channels; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D005947:Glucose
references.citation: Am J Epidemiol. 2007 Jan 15;165(2):175-83
references.pmid: 17071844
references.citation: J Biol Chem. 2004 Dec 3;279(49):51049-56
references.pmid: 15448158
references.citation: Biochem Biophys Res Commun. 2001 Mar 23;282(1):273-7
references.pmid: 11264003
references.citation: Aging (Albany NY). 2009 Dec 30;1(12):979-87
references.pmid: 20157581
references.citation: J Biol Chem. 2004 Dec 24;279(52):53988-93
references.pmid: 15485876
references.citation: J Cell Sci. 2010 Nov 15;123(Pt 22):3837-48
references.pmid: 21048160
references.citation: Endocrinology. 1999 Aug;140(8):3422-8
references.pmid: 10433196
references.citation: Genes Dev. 2006 Jul 15;20(14):1868-73
references.pmid: 16847346
references.citation: Cell. 1998 Jun 12;93(6):929-37
references.pmid: 9635423
references.citation: Genome Biol. 2002 Jun 18;3(7):RESEARCH0034
references.pmid: 12184808
references.citation: Cell. 2000 Dec 22;103(7):1009-17
references.pmid: 11163178
references.citation: J Gastrointest Surg. 1997 May-Jun;1(3):251-6; discussion 256
references.pmid: 9834355
references.citation: Free Radic Biol Med. 2011 Sep 15;51(6):1106-15
references.pmid: 21762777
references.citation: PLoS Biol. 2007 Feb;5(2):e34
references.pmid: 17298173
references.citation: Biochem Soc Trans. 2006 Nov;34(Pt 5):802-5
references.pmid: 17052202
references.citation: Dev Cell. 2009 Mar;16(3):358-73
references.pmid: 19289082
references.citation: Cell Metab. 2011 Feb 2;13(2):125-37
references.pmid: 21284980
references.citation: Endocr Rev. 2008 May;29(3):351-66
references.pmid: 18048763
references.citation: Diabetes. 2001 Jun;50(6):1302-10
references.pmid: 11375330
references.citation: Am J Ther. 2005 Nov-Dec;12(6):529-33
references.pmid: 16280646
references.citation: PLoS Med. 2011 Dec;8(12):e1001138
references.pmid: 22162952
references.citation: Cell. 2001 Jun 15;105(6):745-55
references.pmid: 11440717
references.citation: Cell. 2008 Sep 5;134(5):728-42
references.pmid: 18775307
references.citation: Cell Metab. 2006 Jun;3(6):417-27
references.pmid: 16753577
references.citation: PLoS One. 2012;7(8):e44237
references.pmid: 22952936
references.citation: Sci Transl Med. 2012 Apr 11;4(129):129ra43
references.pmid: 22496545
references.citation: Science. 2001 Jan 19;291(5503):490-3
references.pmid: 11161204
references.citation: Genes Dev. 2000 Dec 1;14(23):2950-61
references.pmid: 11114885
references.citation: Mol Cell Endocrinol. 2004 Oct 29;226(1-2):59-66
references.pmid: 15489006
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 30;105(39):15172-7
references.pmid: 18779586
references.citation: PLoS Med. 2011 Dec;8(12):e1001141
references.pmid: 22162955
references.citation: J Endocrinol. 2010 Nov;207(2):163-75
references.pmid: 20807727
references.citation: Diabetes Obes Metab. 2010 Oct;12 Suppl 2:141-8
references.pmid: 21029311
references.citation: Nature. 2010 Jul 29;466(7306):627-31
references.pmid: 20562852
references.citation: Diabetologia. 2011 Jan;54(1):120-4
references.pmid: 20890745
references.citation: Islets. 2010 Jul-Aug;2(4):225-35
references.pmid: 21099317
references.citation: Diabetologia. 1995 Mar;38(3):274-6
references.pmid: 7758872
references.citation: Diabetes. 2010 Dec;59(12):3090-8
references.pmid: 20802254
references.citation: Free Radic Biol Med. 1996;20(3):463-6
references.pmid: 8720919
references.citation: Proc Natl Acad Sci U S A. 2009 Mar 17;106(11):4453-8
references.pmid: 19255424
references.citation: J Biol Rhythms. 2011 Oct;26(5):423-33
references.pmid: 21921296
references.citation: Cell. 2002 May 3;109(3):307-20
references.pmid: 12015981
references.citation: Diabetes. 2002 Nov;51(11):3211-9
references.pmid: 12401712
references.citation: Cell. 2007 Aug 24;130(4):730-741
references.pmid: 17719549
references.citation: Islets. 2011 Nov-Dec;3(6):381-8
references.pmid: 22045262
references.citation: PLoS Biol. 2004 Nov;2(11):e377
references.pmid: 15523558
references.citation: Annu Rev Physiol. 2010;72:517-49
references.pmid: 20148687
references.citation: Endocrinology. 2006 Mar;147(3):1527-35
references.pmid: 16357046
references.citation: Curr Opin Pharmacol. 2006 Dec;6(6):615-9
references.pmid: 17045527
references.citation: Diabetes. 1999 Jul;48(7):1482-6
references.pmid: 10389858