title: Inducible nitric oxide synthase deficiency in myeloid cells does not prevent diet-induced insulin resistance.
abstract: 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.
authors.affiliation: Department of Medicine, University of California, San Diego, California 92093, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Lu
authors.forename: PingPing
authors.initials: P
authors.lastname: Li
authors.forename: Jan
authors.initials: J
authors.lastname: Pferdekamper
authors.forename: WuQiang
authors.initials: W
authors.lastname: Fan
authors.forename: Maziyar
authors.initials: M
authors.lastname: Saberi
authors.forename: Simon
authors.initials: S
authors.lastname: Schenk
authors.forename: Jerrold M
authors.initials: JM
authors.lastname: Olefsky
mesh_terms: 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
chemical_list: D004041:Dietary Fats; D004791:Enzyme Inhibitors; C090663:N(6)-(1-iminoethyl)lysine; D052247:Nitric Oxide Synthase Type II; D008239:Lysine
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