Lack of Inducible Nitric Oxide Synthase Prevents Lipid-Induced Skeletal Muscle Insulin Resistance Without Attenuating Cytokine Level

Abstract

Abstract. We examined whether deletion of inducible nitric oxide synthase (iNOS) could prevent lipid infusion-induced insulin resistance in iNOS-knockout and wild-type mice with the in vivo euglycemic-hyperinsulinemic clamp technique. Plasma NO metabolites were increased in lipid-infused wild-type mice, while they were not increased in iNOS-knockout mice. Plasma tumor necrosis factor-α levels were increased in both wild-type and iNOS-knockout by lipid-infusion. Lipid infusion reduced glucose infusion rate (GIR) and whole body glucose uptake in wild-type mice, whereas iNOS-knockout mice displayed comparable GIR and whole body glucose uptake compared with the control. In the gastrocnemius, lipid infusion decreased glucose uptake and glycolysis that were accompanied with increased phosphorylation of c-Jun N-terminal kinase and reduced phosphorylation of phosphoinositide 3-kinases and serine/threonine kinase Akt. However, lipid infusion did not affect glucose uptake or phosphorylation of these proteins in iNOS-knockout mice. The mRNA levels of inflammatory cytokines were also increased in the gastrocnemis of wild-type and iNOS-knockout mice by lipid infusion. Nitrotyrosine level in the gastrocnemius was increased in lipid-infused wild-type mice but it was not increased in iNOS-knockout mice. These results suggest that lack of iNOS prevents lipid infusion-induced skeletal muscle insulin resistance without attenuating cytokine levels.

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

“…Genetic, pharmacological, and physiological iNOS inhibition reduced IRβ, IRS-1, and Akt S -nitrosation and increased insulin signaling in old mice. Our results reinforce the idea that iNOS plays a crucial role in inducing insulin resistance, as previously shown in different animal models such as diet-, lipopolysaccharide-, and lipid-induced skeletal muscle insulin resistance (3,13,15,16). …”

iNOS inhibitor, L-NIL, reverses burn-induced glycogen synthase kinase-3β activation in skeletal muscle of rats

“…2C). Our results are in line with a recent study that lipid infusion decreases basal Akt/PKB phosphorylation in skeletal muscle of wild-type, but not iNOS knockout, mice [22]. Based on previous studies [17, 20], one can speculate that nitrosative protein modifications, such as S-nitrosylation and tyrosine nitration, may be possibly involved in iNOS-mediated decreases in phosphorylation of Akt/PKB.…”

AMP-activated protein kinase (AMPK)α2 plays a role in determining the cellular fate of glucose in insulin-resistant mouse skeletal muscle

“…This was associated with reduced AMPKα2 activity in skeletal muscle and, as seen by others, increased skeletal muscle iNOS levels [46]. Infusion of Intralipid is sufficient to induce inflammatory markers in plasma [10] and skeletal muscle [47] of overnight fasted C57BL/6J mice. Indeed, Tnf α (also known as Tnf ) expression increased in skeletal muscle after as little as 30 min of Intralipid [47].…”

“…In skeletal muscle, iNOS abundance is enhanced in obesity and type 2 diabetes [8, 9]. Deletion of iNOS improves insulin sensitivity [8, 10] and intracellular insulin signalling [11] in animal models of insulin resistance. In cell cultures, reduced AMPKα activation is associated with enhanced iNOS production [12], whereas pharmacological activation of AMPKα reduces iNOS levels [12, 13].…”