scholarly journals Targeted Disruption of Inducible Nitric Oxide Synthase Protects Against Aging, S-Nitrosation, and Insulin Resistance in Muscle of Male Mice

Diabetes ◽  
2012 ◽  
Vol 62 (2) ◽  
pp. 466-470 ◽  
Author(s):  
E. R. Ropelle ◽  
J. R. Pauli ◽  
D. E. Cintra ◽  
A. S. da Silva ◽  
C. T. De Souza ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Insulin Resistance ◽  
Nitric Oxide Synthase ◽  
Inducible Nitric Oxide Synthase ◽  
Male Mice ◽  
Targeted Disruption ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

Testosterone production in mice lacking inducible nitric oxide synthase expression is sensitive to restraint stress

2007 ◽  
Vol 292 (2) ◽  
pp. E615-E620 ◽  
Author(s):  
Ben A. Weissman ◽  
Chantal M. Sottas ◽  
Ping Zhou ◽  
Costantino Iadecola ◽  
Matthew P. Hardy
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Inducible Nitric Oxide Synthase ◽  
Restraint Stress ◽  
Immobilization Stress ◽  
Male Mice ◽  
Wild Type ◽  
Basal Plasma ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

Immobilization stress (IMO) induces a rapid increase in glucocorticoid secretion [in rodents, corticosterone CORT)] and this is associated with decreased circulating testosterone (T) levels. Nitric oxide (NO), a reactive free radical and neurotransmitter, has been reported to be produced at higher rates in tissues such as brain during stress. The biosynthesis of T is also known to be dramatically suppressed by NO. Specifically, the inducible isoform of nitric oxide synthase (iNOS) was directly implicated in this suppression. To assess the respective roles of CORT and NO in stress-mediated inhibition of T production, adult wild-type (WT) and inducible nitric oxide synthase knockout (iNOS−/−) male mice were evaluated. Animals of each genotype were assigned to either basal control or 3-h IMO groups. Basal plasma and testicular T levels were equivalent in both genotypes, whereas testicular weights of mutant mice were significantly higher compared with WT animals. Exposure to 3-h IMO increased plasma CORT and decreased T concentrations in mice of both genotypes. Testicular T levels were also affected by stress in WT and mutant males, being sharply reduced in both genotypes. However, the concentrations of nitrite and nitrate, the stable metabolites of NO measured in testicular extracts, did not differ between control and stressed WT and iNOS−/− mice. These results support the hypothesis that CORT, but not NO, is a plausible candidate to mediate rapid stress-induced suppression of Leydig cell steroidogenesis.

scholarly journals Inducible Nitric Oxide Synthase Deficiency in Myeloid Cells Does Not Prevent Diet-Induced Insulin Resistance

2010 ◽  
Vol 24 (7) ◽  
pp. 1413-1422 ◽  
Author(s):  
Min Lu ◽  
PingPing Li ◽  
Jan Pferdekamper ◽  
WuQiang Fan ◽  
Maziyar Saberi ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Insulin Resistance ◽  
Nitric Oxide Synthase ◽  
Inducible Nitric Oxide Synthase ◽  
Myeloid Cells ◽  
Mixed Effect ◽  
Insulin Resistant ◽  
Oxide Synthase ◽  
Inos Inhibition ◽  
Inducible Nitric Oxide

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 TNFα 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.

Inducible nitric oxide synthase plays a role in LPS-induced hyperglycemia and insulin resistance

2002 ◽  
Vol 282 (2) ◽  
pp. E386-E394 ◽  
Author(s):  
Hiroki Sugita ◽  
Masao Kaneki ◽  
Eriko Tokunaga ◽  
Michiko Sugita ◽  
Chieko Koike ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Insulin Resistance ◽  
Nitric Oxide Synthase ◽  
Inducible Nitric Oxide Synthase ◽  
Glycogen Phosphorylase ◽  
Hepatic Glucose Output ◽  
Hepatic Glucose ◽  
Glucose Output ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

The molecular mechanisms underlying endotoxin-induced insulin resistance remain unclear. Endotoxin or lipopolysaccharide (LPS) injection is a potent stimulator of inducible nitric oxide synthase (iNOS). This study in rats, using the specific iNOS inhibitor aminoguanidine, investigated the role of iNOS in endotoxin-induced hyperglycemia and insulin resistance. LPS injection led to hyperglycemia, insulin resistance, and increased iNOS protein expression and activity. Aminoguanidine prevented LPS-induced hyperglycemia without affecting insulin levels or iNOS expression. Aminoguanidine attenuated the LPS-induced insulin resistance, reflected by the requirement for a higher glucose infusion rate to maintain euglycemia during a hyperinsulinemic clamp study. Aminoguanidine completely blocked the LPS-elevated hepatic glucose output and also inhibited LPS-induced increases in hepatic glycogen phosphorylase activities and phospho enolpyruvate carboxykinase (PEPCK) mRNA expression, key enzymes for glycogenolysis and gluconeogenesis, respectively. Thus, these data demonstrate an important role for iNOS in LPS-induced insulin resistance, evidenced by the attenuation of LPS-induced hyperglycemia and reversal of increased hepatic glucose output by aminoguanidine. The protective effect of aminoguanidine on insulin resistance is probably by attenuation of hepatic glucose output via its inhibition of key enzymes for glycogenolysis and gluconeogenesis, including glycogen phosphorylase and PEPCK.

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