A predominant role for parenchymal c-Jun amino terminal kinase (JNK) in the regulation of systemic insulin sensitivity.
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.
Vallerie
Sara N
SN
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts, United States of America.
Furuhashi
Masato
M
Fucho
Raquel
R
Hotamisligil
Gökhan S
GS
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
D007328:Insulin; D008055:Lipids; D014280:Triglycerides; D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8
Can J Biochem Physiol. 1959 Aug;37(8):911-7
13671378
Nature. 2007 Jun 21;447(7147):959-65
17554340
Nature. 1997 Oct 9;389(6651):610-4
9335502
Science. 1993 Jan 1;259(5091):87-91
7678183
Nat Med. 2001 Jun;7(6):699-705
11385507
Nature. 2006 Apr 13;440(7086):944-8
16612386
Obesity (Silver Spring). 2007 Jun;15(6):1419-29
17557979
Nature. 2002 Nov 21;420(6913):333-6
12447443
J Clin Invest. 2003 Dec;112(12):1796-808
14679176
Proc Natl Acad Sci U S A. 2003 Jun 10;100(12):7265-70
12756299
Am J Physiol Cell Physiol. 2004 Jul;287(1):C200-8
15013949
Science. 2004 Oct 15;306(5695):457-61
15486293
Nature. 2006 Dec 14;444(7121):860-7
17167474
Cell Metab. 2005 Feb;1(2):107-19
16054052
J Biol Chem. 2003 Nov 14;278(46):45777-84
12952969
Science. 1996 Feb 2;271(5249):665-8
8571133
J Biol Chem. 2007 Aug 3;282(31):22765-74
17550900
Nat Med. 2007 Apr;13(4):455-62
17351624
Proc Natl Acad Sci U S A. 2006 Jul 11;103(28):10741-6
16818881
J Clin Invest. 2003 Dec;112(12):1821-30
14679177
Biochem Biophys Res Commun. 2006 Dec 1;350(4):1063-8
17045576
Diabetes. 1997 Sep;46(9):1526-31
9287059
J Biol Chem. 2002 Jan 11;277(2):1531-7
11606564
Biotechniques. 1994 Dec;17(6):1030-2
7873170
Cell Metab. 2007 Nov;6(5):386-97
17983584
J Biol Chem. 2000 Mar 24;275(12):9047-54
10722755
Nat Med. 2004 Oct;10(10):1128-32
15448687
J Clin Invest. 2000 Jul;106(2):171-6
10903330
Diabetes. 1997 Jan;46(1):3-10
8971073
J Biol Chem. 2002 Dec 13;277(50):48115-21
12351658
J Exp Med. 2001 Feb 5;193(3):317-28
11157052
Science. 2001 Aug 31;293(5535):1673-7
11533494
J Clin Invest. 2006 Jul;116(7):1793-801
16823477
J Clin Invest. 2007 Jun;117(6):1658-69
17525798
J Biol Chem. 2002 Aug 16;277(33):30010-8
12011047
Nature. 2007 Jun 28;447(7148):1116-20
17515919
J Biol Chem. 2004 Oct 29;279(44):45803-9
15331609
Cell. 2000 Oct 13;103(2):239-52
11057897
Nat Med. 2005 Feb;11(2):191-8
15685170
J Clin Invest. 2008 Jul;118(7):2640-50
18551191
Science. 2004 Nov 26;306(5701):1558-61
15567863