title: Brd2 gene disruption causes "metabolically healthy" obesity: epigenetic and chromatin-based mechanisms that uncouple obesity from type 2 diabetes.
abstract: Disturbed body energy balance can lead to obesity and obesity-driven diseases such as Type 2 diabetes, which have reached an epidemic level. Evidence indicates that obesity-induced inflammation is a major cause of insulin resistance and Type 2 diabetes. Environmental factors, such as nutrients, affect body energy balance through epigenetic or chromatin-based mechanisms. As a bromodomain and external domain family transcription regulator, Brd2 regulates expression of many genes through interpretation of chromatin codes and participates in the regulation of body energy balance and immune function. In the severely obese state, Brd2 knockdown in mice prevented obesity-induced inflammatory responses, protected animals from insulin resistance, glucose intolerance and pancreatic beta cell dysfunction, and thus uncoupled obesity from diabetes. Brd2 provides an important model for investigation of the function of transcription regulators and the development of obesity and diabetes; it also provides a possible, innovative target to treat obesity and diabetes through modulation of the function of a chromatin code reader.
authors: IQuum Inc, Marlborough, MA 01752, USA.
authors: Fangnian
authors: F
authors: Wang
authors: Jude T
authors: JT
authors: Deeney
authors: Gerald V
authors: GV
authors: Denis
mesh_terms: D000818:Animals; D002843:Chromatin / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic / Q000502:physiology*; D006801:Humans; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D000092468:Bromodomain Containing Proteins
chemical_list: D002843:Chromatin; D017346:Protein Serine-Threonine Kinases; D014157:Transcription Factors; C098415:BRD2 protein, human; D000092468:Bromodomain Containing Proteins
references: Diabetes Res Clin Pract. 2010 Jan;87(1):4-14
references: 19896746
references: Metabolism. 2001 Dec;50(12):1499-504
references: 11735101
references: Diabetes. 2010 Nov;59(11):2980-8
references: 20724581
references: Cell. 2007 Feb 23;128(4):707-19
references: 17320508
references: Nat Rev Cancer. 2012 Jun 22;12(7):465-77
references: 22722403
references: Am J Physiol Regul Integr Comp Physiol. 2008 Feb;294(2):R528-38
references: 18032473
references: Diabetes Care. 1998 Feb;21(2):221-30
references: 9539986
references: Diabetologia. 1998 Oct;41(10):1241-8
references: 9794114
references: J Clin Invest. 1994 Jun;93(6):2590-9
references: 8200997
references: Diabetes Care. 2004 May;27(5):1047-53
references: 15111519
references: Nat Med. 2005 Feb;11(2):183-90
references: 15685173
references: J Immunol. 2009 Dec 1;183(11):7461-70
references: 19917698
references: FASEB J. 2012 May;26(5):1782-90
references: 22267336
references: Diabetes. 2009 Jan;58(1):185-93
references: 18984737
references: Behav Genet. 1997 Jul;27(4):325-51
references: 9519560
references: BMJ. 1989 Mar 4;298(6673):564-7
references: 2495113
references: Mol Cell Endocrinol. 2009 Jan 15;297(1-2):10-7
references: 19000735
references: J Immunol. 2006 Feb 1;176(3):1889-98
references: 16424220
references: Nat Struct Biol. 1999 Jul;6(7):601-4
references: 10404206
references: Dev Biol. 1986 Mar;114(1):161-9
references: 3007240
references: Cytokine. 2006 Feb 7;33(3):129-37
references: 16503147
references: Curr Opin Drug Discov Devel. 2009 Sep;12(5):659-65
references: 19736624
references: Lancet. 2011 Feb 12;377(9765):557-67
references: 21295846
references: Science. 2007 May 11;316(5826):889-94
references: 17434869
references: FASEB J. 2012 Mar;26(3):1131-41
references: 22131269
references: J Clin Endocrinol Metab. 2006 Aug;91(8):2906-12
references: 16735483
references: J Clin Invest. 1997 May 15;99(10):2416-22
references: 9153284
references: J Biol Chem. 2009 Feb 13;284(7):4439-50
references: 19074147
references: Arterioscler Thromb Vasc Biol. 2008 Jul;28(7):1304-10
references: 18420999
references: Sci Am. 2007 Sep;297(3):88-95
references: 17784629
references: Mol Cell Biol. 2009 Apr;29(8):2053-67
references: 19237535
references: Obesity (Silver Spring). 2008 Aug;16(8):1881-6
references: 18551117
references: Genes Dev. 1996 Feb 1;10(3):261-71
references: 8595877
references: Diabetes Care. 2011 Jan;34(1):210-5
references: 20937689
references: Arch Intern Med. 2008 Aug 11;168(15):1617-24
references: 18695075
references: N Engl J Med. 2008 Dec 11;359(24):2603-4
references: 19073980
references: Cytokine. 2007 Oct;40(1):1-16
references: 17981048
references: Int J Obes Relat Metab Disord. 1994 Aug;18(8):526-31
references: 7951471
references: Curr Opin Clin Nutr Metab Care. 2006 Jul;9(4):388-94
references: 16778567
references: J Biol Chem. 2010 Feb 26;285(9):6153-60
references: 20028977
references: Am J Physiol Endocrinol Metab. 2010 Sep;299(3):E506-15
references: 20570822
references: Diabetes. 2005 Aug;54(8):2277-86
references: 16046292
references: Nature. 1997 Oct 9;389(6651):610-4
references: 9335502
references: Discov Med. 2010 Dec;10(55):489-99
references: 21189220
references: Eur Cytokine Netw. 2006 Mar;17(1):4-12
references: 16613757
references: Diabetes. 2000 Dec;49(12):2208-11
references: 11118027
references: Protein Sci. 2008 Dec;17(12):2174-9
references: 18815416
references: Am J Physiol. 1998 Oct;275(4):R1374-9
references: 9756571
references: Diabetes. 1998 Jan;47(1):98-103
references: 9421381
references: J Lipid Res. 2005 Nov;46(11):2347-55
references: 16150820
references: Circulation. 2009 Oct 20;120(16):1640-5
references: 19805654
references: J Clin Endocrinol Metab. 2008 Dec;93(12):4633-42
references: 18782870
references: Diabetes. 2011 Jun;60(6):1688-98
references: 21515850
references: Obesity (Silver Spring). 2009 Dec;17(12):2254-7
references: 19478790
references: Obes Res. 2003 Nov;11(11):1325-32
references: 14627752
references: Mol Cell Biol. 2011 Jul;31(13):2641-52
references: 21555454
references: N Engl J Med. 2007 Jan 18;356(3):213-5
references: 17229948
references: J Clin Invest. 1996 Feb 15;97(4):1111-6
references: 8613535
references: Genes Dev. 2001 Dec 1;15(23):3208-16
references: 11731483
references: Diabetes Care. 2007 Jul;30 Suppl 2:S169-74
references: 17596467
references: Clin Sci (Lond). 1994 May;86(5):583-92
references: 7913431
references: J Biol Chem. 2005 Oct 28;280(43):36244-53
references: 16141209
references: J Clin Endocrinol Metab. 2003 Nov;88(11):5321-6
references: 14602768
references: Mol Cell. 2004 Jan 16;13(1):33-43
references: 14731392
references: J Clin Invest. 2003 Dec;112(12):1821-30
references: 14679177
references: Hypertension. 2008 Feb;51(2):383-92
references: 18086952
references: Int J Obes (Lond). 2010 Jan;34(1):29-40
references: 19752881
references: FASEB J. 1991 Jun;5(9):2237-42
references: 1860614
references: J Clin Endocrinol Metab. 2005 Jul;90(7):4145-50
references: 15855252
references: Cell. 1998 Mar 20;92(6):829-39
references: 9529258
references: FEBS Lett. 2010 Aug 4;584(15):3260-8
references: 20493850
references: Cell. 2006 Apr 21;125(2):315-26
references: 16630819
references: Lancet. 2005 Oct 1;366(9492):1197-209
references: 16198769
references: Endocrinology. 2011 Nov;152(11):4158-70
references: 21862610
references: Carcinogenesis. 2010 Jan;31(1):27-36
references: 19752007
references: Lancet. 1970 Mar 21;1(7647):582-4
references: 4190540
references: BMJ. 1995 Jul 15;311(6998):171-4
references: 7613432
references: J Biol Chem. 2009 May 8;284(19):12896-904
references: 19279000
references: J Clin Endocrinol Metab. 1997 Mar;82(3):739-44
references: 9062475
references: Am J Clin Nutr. 2008 Dec;88(6):1722S-1732S
references: 19064537
references: Nature. 1999 Jun 3;399(6735):491-6
references: 10365964
references: Arterioscler Thromb Vasc Biol. 2008 Sep;28(9):1654-9
references: 18566296
references: Am J Physiol Endocrinol Metab. 2001 May;280(5):E745-51
references: 11287357
references: J Biol Chem. 2010 Mar 5;285(10):7610-8
references: 20048151
references: Diabetologia. 2010 Jul;53(7):1461-71
references: 20383694
references: Genome Res. 2010 Apr;20(4):428-33
references: 20181961
references: Trends Biochem Sci. 1997 May;22(5):151-3
references: 9175470
references: BMJ. 1991 Oct 26;303(6809):1019-22
references: 1954451
references: Nat Genet. 2009 Dec;41(12):1319-24
references: 19898480
references: Science. 1993 Jan 1;259(5091):87-91
references: 7678183
references: Int J Obes (Lond). 2008 Sep;32(9):1373-9
references: 18626486
references: J Clin Invest. 2007 Sep;117(9):2621-37
references: 17717599
references: J Pediatr Endocrinol Metab. 2001 Sep-Oct;14(8):1085-91
references: 11592564
references: Obesity (Silver Spring). 2012 Jul;20(7):1372-8
references: 22395812
references: Nature. 2010 Dec 23;468(7327):1067-73
references: 20871596
references: Nucleic Acids Res. 1992 May 25;20(10):2603
references: 1350857
references: J Clin Endocrinol Metab. 2008 Oct;93(10):4075-9
references: 18682512
references: J Nutr. 1997 Sep;127(9):1917S-1922S
references: 9278582
references: Curr Opin Endocrinol Diabetes Obes. 2010 Oct;17(5):472-7
references: 20585247
references: Diabetes. 2006 Aug;55(8):2357-64
references: 16873701
references: Nature. 2010 Dec 23;468(7327):1119-23
references: 21068722
references: Biochem J. 2009 Dec 14;425(1):71-83
references: 19883376
references: Nat Med. 2001 Oct;7(10):1138-43
references: 11590438
references: J Clin Invest. 2006 Jul;116(7):1793-801
references: 16823477
references: Nat Genet. 2003 Mar;33 Suppl:245-54
references: 12610534
references: Obes Surg. 2008 Jun;18(6):648-51
references: 18392907
references: Proc Nutr Soc. 2012 May;71(2):276-83
references: 22390978
references: DNA Seq. 1992;2(4):203-10
references: 1352711
references: Am J Physiol Regul Integr Comp Physiol. 2010 Sep;299(3):R711-22
references: 20631295
references: J Biol Chem. 2007 Feb 9;282(6):4193-201
references: 17148447
references: Proc Natl Acad Sci U S A. 2009 Oct 6;106(40):17031-6
references: 19805069
references: Front Biosci. 2001 Aug 01;6:D1019-23
references: 11487477
references: Endocr Rev. 2006 Dec;27(7):710-18
references: 17122358
references: Cell. 2007 Feb 23;128(4):669-81
references: 17320505
references: Nature. 2007 Jun 28;447(7148):1116-20
references: 17515919
references: Mol Cell. 2008 Apr 11;30(1):51-60
references: 18406326
references: Metabolism. 1995 Sep;44(9 Suppl 3):12-4
references: 7674909
references: Mol Cell Biol. 2009 Mar;29(6):1575-91
references: 19114551
references: Asia Pac J Clin Nutr. 2009;18(2):280-4
references: 19713189
references: Gastroenterology. 2007 May;132(6):2169-80
references: 17498510
references: Expert Rev Mol Med. 2011 Sep 13;13:e29
references: 21933453
references: Circulation. 2005 Oct 25;112(17):2735-52
references: 16157765
references: Trends Mol Med. 2010 May;16(5):238-46
references: 20444648
references: Am J Clin Nutr. 1999 Feb;69(2):198-204
references: 9989680
references: Ann Surg. 2006 Nov;244(5):734-40
references: 17060766
references: Diabetologia. 1985 Jul;28(7):412-9
references: 3899825
references: Clin Perinatol. 2007 Dec;34(4):515-26, v
references: 18063102
references: Diabetes Care. 2008 Jul;31(7):1422-6
references: 18375420
references: Diabetologia. 1998 Dec;41(12):1516-22
references: 9867220
references: J Clin Invest. 2003 Dec;112(12):1796-808
references: 14679176
references: Curr Opin Lipidol. 2010 Feb;21(1):38-43
references: 19915462
references: N Engl J Med. 1995 Aug 10;333(6):343-7
references: 7609750