Inducible nitric oxide synthase deficiency in myeloid cells does not prevent diet-induced insulin resistance.
Recent findings denote an important contribution of macrophage inflammatory pathways in causing obesity-related insulin resistance. Inducible nitric oxide synthase (iNOS) is activated in proinflammatory macrophages and modestly elevated in insulin-responsive tissues. Although the benefits of systemic iNOS inhibition in insulin-resistant models have been demonstrated, the role of macrophage iNOS in metabolic disorders is not clear. In the current work, we used bone marrow transplantation (BMT) to generate mice with myeloid iNOS deficiency [iNOS BMT knockout (KO)]. Interestingly, disruption of iNOS in myeloid cells did not protect mice from high-fat diet-induced obesity and insulin resistance. When mice were treated with the iNOS inhibitor, N6-(1-Iminoethyl)-L-lysine hydrochloride (L-NIL), we observed a significant and comparable improvement of glucose homeostasis and insulin sensitivity in both wild-type and iNOS BMT KO mice. We further demonstrated that absence of iNOS in primary macrophages did not affect acute TLR4 signaling pathways and had only a modest and mixed effect on inflammatory gene expression. With respect to TNFalpha treatment, iNOS KO macrophages showed, if anything, a greater inflammatory response. In summary, we conclude that iNOS inhibition in tissues other than myeloid cells is responsible for the beneficial effects in obesity/insulin resistance.
Lu
Min
M
Department of Medicine, University of California, San Diego, California 92093, USA.
Li
PingPing
P
Pferdekamper
Jan
J
Fan
WuQiang
W
Saberi
Maziyar
M
Schenk
Simon
S
Olefsky
Jerrold M
JM
D000818:Animals; D015153:Blotting, Western; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D004041:Dietary Fats / Q000009:adverse effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007150:Immunohistochemistry; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D008239:Lysine / Q000031:analogs & derivatives / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000201:enzymology / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D009765:Obesity / Q000139:chemically induced / Q000235:genetics
D004041:Dietary Fats; D004791:Enzyme Inhibitors; C090663:N(6)-(1-iminoethyl)lysine; D052247:Nitric Oxide Synthase Type II; D008239:Lysine
J Biol Chem. 2005 Apr 8;280(14):14203-11
15805118
Nat Med. 2009 Aug;15(8):930-9
19633656
J Leukoc Biol. 2007 Mar;81(3):580
17332374
FEMS Immunol Med Microbiol. 2007 Dec;51(3):443-52
17903207
Int J Obes Relat Metab Disord. 2003 Dec;27 Suppl 3:S53-5
14704746
N Engl J Med. 2006 Nov 9;355(19):2003-11
17093251
Am J Physiol Endocrinol Metab. 2006 Sep;291(3):E476-82
16638822
Diabetes. 2008 Dec;57(12):3239-46
18829989
Am J Physiol Cell Physiol. 2006 Jun;290(6):C1477-86
16381800
Nat Med. 2001 Oct;7(10):1138-43
11590438
J Biol Chem. 2004 May 14;279(20):20767-74
14985344
Circulation. 2005 Mar 22;111(11):1448-54
15781756
Clin Sci (Lond). 2006 Oct;111(4):275-80
16803456
Nature. 2006 Dec 14;444(7121):860-7
17167474
J Lipid Res. 2005 Jan;46(1):135-42
15466365
Diabetes. 2005 May;54(5):1340-8
15855318
J Lipid Res. 2004 Sep;45(9):1640-8
15231849
Circ Res. 2009 Jul 2;105(1):99-107
19478200
FASEB J. 2002 Mar;16(3):327-42
11874982
J Clin Invest. 2008 Sep;118(9):2992-3002
18769626
Am J Physiol Endocrinol Metab. 2006 Jun;290(6):E1068-77
16380391
J Toxicol Environ Health A. 2003 Jun 13;66(11):995-1013
12775513
Med Electron Microsc. 2004 Mar;37(1):16-28
15057601
Eur J Pharmacol. 1995 Dec 29;294(2-3):703-12
8750736
Nat Med. 2009 Aug;15(8):914-20
19633658
J Biol Chem. 2006 Mar 24;281(12):7727-36
16418168
Cell Metab. 2008 Oct;8(4):301-9
18840360
Diabetes. 2005 Apr;54(4):959-67
15793233
J Endocrinol. 2004 Jun;181(3):419-27
15171690
Mol Cell Biol. 2000 Jul;20(13):4699-707
10848596
Sci STKE. 2004 Nov 02;2004(257):pe52
15523044
Cell Metab. 2007 Nov;6(5):386-97
17983584
J Clin Invest. 2007 Oct;117(10):2877-88
17823662
Ann N Y Acad Sci. 1959 Sep 25;82:420-30
13833973
Physiol Rev. 2007 Jan;87(1):315-424
17237348
J Med Chem. 2002 Apr 11;45(8):1686-9
11931623
Diabetes. 2008 Aug;57(8):1999-2011
18458147
Cell Metab. 2009 Nov;10(5):419-29
19883619
J Biol Chem. 2005 Mar 4;280(9):7511-8
15632167
J Leukoc Biol. 2007 Mar;81(3):579; discussion 580
17332373
Cell Metab. 2008 Jun;7(6):496-507
18522831