title: A predominant role for parenchymal c-Jun amino terminal kinase (JNK) in the regulation of systemic insulin sensitivity.
abstract: It has been established that c-Jun N-terminal kinase 1 (JNK1) is essential to the pathogenesis of insulin resistance and type 2 diabetes. Although JNK influences inflammatory signaling pathways, it remains unclear whether its activity in macrophages contributes to adipose tissue inflammation and ultimately to the regulation of systemic metabolism. To address whether the action of this critical inflammatory kinase in bone marrow-derived elements regulates inflammatory responses in obesity and is sufficient and necessary for the deterioration of insulin sensitivity, we performed bone marrow transplantation studies with wild type and JNK1-deficient mice. These studies illustrated that JNK1-deficiency in the bone marrow-derived elements (BMDE) was insufficient to impact macrophage infiltration or insulin sensitivity despite modest changes in the inflammatory profile of adipose tissue. Only when the parenchymal elements lacked JNK1 could we demonstrate a significant increase in systemic insulin sensitivity. These data indicate that while the JNK1 activity in BMDE is involved in metabolic regulation and adipose milieu, it is epistatic to JNK1 activity in the parenchymal tissue for regulation of metabolic homeostasis.
authors.affiliation: Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Sara N
authors.initials: SN
authors.lastname: Vallerie
authors.forename: Masato
authors.initials: M
authors.lastname: Furuhashi
authors.forename: Raquel
authors.initials: R
authors.lastname: Fucho
authors.forename: Gökhan S
authors.initials: GS
authors.lastname: Hotamisligil
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D016026:Bone Marrow Transplantation; D007249:Inflammation; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008055:Lipids / Q000737:chemistry; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
chemical_list: D007328:Insulin; D008055:Lipids; D014280:Triglycerides; D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8
references.citation: Can J Biochem Physiol. 1959 Aug;37(8):911-7
references.pmid: 13671378
references.citation: Nature. 2007 Jun 21;447(7147):959-65
references.pmid: 17554340
references.citation: Nature. 1997 Oct 9;389(6651):610-4
references.pmid: 9335502
references.citation: Science. 1993 Jan 1;259(5091):87-91
references.pmid: 7678183
references.citation: Nat Med. 2001 Jun;7(6):699-705
references.pmid: 11385507
references.citation: Nature. 2006 Apr 13;440(7086):944-8
references.pmid: 16612386
references.citation: Obesity (Silver Spring). 2007 Jun;15(6):1419-29
references.pmid: 17557979
references.citation: Nature. 2002 Nov 21;420(6913):333-6
references.pmid: 12447443
references.citation: J Clin Invest. 2003 Dec;112(12):1796-808
references.pmid: 14679176
references.citation: Proc Natl Acad Sci U S A. 2003 Jun 10;100(12):7265-70
references.pmid: 12756299
references.citation: Am J Physiol Cell Physiol. 2004 Jul;287(1):C200-8
references.pmid: 15013949
references.citation: Science. 2004 Oct 15;306(5695):457-61
references.pmid: 15486293
references.citation: Nature. 2006 Dec 14;444(7121):860-7
references.pmid: 17167474
references.citation: Cell Metab. 2005 Feb;1(2):107-19
references.pmid: 16054052
references.citation: J Biol Chem. 2003 Nov 14;278(46):45777-84
references.pmid: 12952969
references.citation: Science. 1996 Feb 2;271(5249):665-8
references.pmid: 8571133
references.citation: J Biol Chem. 2007 Aug 3;282(31):22765-74
references.pmid: 17550900
references.citation: Nat Med. 2007 Apr;13(4):455-62
references.pmid: 17351624
references.citation: Proc Natl Acad Sci U S A. 2006 Jul 11;103(28):10741-6
references.pmid: 16818881
references.citation: J Clin Invest. 2003 Dec;112(12):1821-30
references.pmid: 14679177
references.citation: Biochem Biophys Res Commun. 2006 Dec 1;350(4):1063-8
references.pmid: 17045576
references.citation: Diabetes. 1997 Sep;46(9):1526-31
references.pmid: 9287059
references.citation: J Biol Chem. 2002 Jan 11;277(2):1531-7
references.pmid: 11606564
references.citation: Biotechniques. 1994 Dec;17(6):1030-2
references.pmid: 7873170
references.citation: Cell Metab. 2007 Nov;6(5):386-97
references.pmid: 17983584
references.citation: J Biol Chem. 2000 Mar 24;275(12):9047-54
references.pmid: 10722755
references.citation: Nat Med. 2004 Oct;10(10):1128-32
references.pmid: 15448687
references.citation: J Clin Invest. 2000 Jul;106(2):171-6
references.pmid: 10903330
references.citation: Diabetes. 1997 Jan;46(1):3-10
references.pmid: 8971073
references.citation: J Biol Chem. 2002 Dec 13;277(50):48115-21
references.pmid: 12351658
references.citation: J Exp Med. 2001 Feb 5;193(3):317-28
references.pmid: 11157052
references.citation: Science. 2001 Aug 31;293(5535):1673-7
references.pmid: 11533494
references.citation: J Clin Invest. 2006 Jul;116(7):1793-801
references.pmid: 16823477
references.citation: J Clin Invest. 2007 Jun;117(6):1658-69
references.pmid: 17525798
references.citation: J Biol Chem. 2002 Aug 16;277(33):30010-8
references.pmid: 12011047
references.citation: Nature. 2007 Jun 28;447(7148):1116-20
references.pmid: 17515919
references.citation: J Biol Chem. 2004 Oct 29;279(44):45803-9
references.pmid: 15331609
references.citation: Cell. 2000 Oct 13;103(2):239-52
references.pmid: 11057897
references.citation: Nat Med. 2005 Feb;11(2):191-8
references.pmid: 15685170
references.citation: J Clin Invest. 2008 Jul;118(7):2640-50
references.pmid: 18551191
references.citation: Science. 2004 Nov 26;306(5701):1558-61
references.pmid: 15567863