Abstract
Recent studies have implicated inhibitor of kappaB kinase (IKK) in mediating fatty acid (FA)-induced insulin resistance. How IKK causes these effects is unknown. The present study addressed the role of nuclear factor kappaB (NFkappaB), the distal target of IKK activity, in FA-induced insulin resistance in L6 myotubes, an in vitro skeletal muscle model. A 6-h exposure of myotubes to the saturated FA palmitate reduced insulin-stimulated glucose uptake by approximately 30%, phosphatidylinositol-3 kinase and protein kinase B phosphorylation by approximately 40%, and stimulated inhibitor of kappaBalpha degradation and the nuclear translocation of NFkappaB. On the other hand, the Omega-3 polyunsaturated FA linolenate neither induced insulin resistance nor promoted nuclear localization of NFkappaB. Supporting the hypothesis that IKK acts through NFkappaB to cause insulin resistance, the IKK inhibitors acetylsalicylate and parthenolide prevented FA-induced reductions in insulin-stimulated glucose uptake and NFkappaB nuclear translocation. Most importantly, NFkappaB SN50, a cell-permeable peptide that inhibits NFkappaB nuclear translocation downstream of IKK, was sufficient to prevent palmitate-induced reductions in insulin-stimulated glucose uptake. Acetylsalicylate, but not NFkappaB SN50, prevented FA effects on phosphatidylinositol-3 kinase activity and protein kinase B phosphorylation. We conclude that FAs induce insulin resistance and activates NFkappaB in L6 cells. Furthermore, inhibition of NFkappaB activation, indirectly by preventing IKK activation or directly by inhibiting NFkappaB nuclear translocation, prevents the detrimental effects of palmitate on the metabolic actions of insulin in L6 myotubes.
Highlights
Insulin resistance is a hallmark of obesity/type 2 diabetes
The present study addressed the role of nuclear factor B (NFB), the distal target of IKK activity, in fatty acid (FA)-induced insulin resistance in L6 myotubes, an in vitro skeletal muscle model
Palmitate and Linoleate, but Not the ⍀-3 Polyunsaturated FA Linolenate, Induce Insulin Resistance and Stimulate the Nuclear Translocation of NFB in L6 Myotubes—We first determined the effects of fatty acids on insulin sensitivity and NFB nuclear translocation in L6 myotubes
Summary
The pathogenesis of insulin resistance is poorly understood, dyslipidemia has been proposed as a candidate mechanism Supporting this hypothesis are observations that plasma and tissue lipid levels are inversely correlated with insulin sensitivity [1, 2], that reduced availability of lipids improves insulin sensitivity [3,4,5,6], that a short-term lipid/ fatty acid infusion can induce insulin resistance (6 –11), and that lipid metabolites such as diacylglycerol and ceramide can inhibit insulin signaling [6, 12,13,14,15]. Inhibition of nuclear translocation of NFB by three independent methods blocks the effects of palmitate on insulin action One of these inhibitors blocks NFB nuclear translocation downstream of IKK activation and IB degradation, demonstrating that NFB activation is an important mechanism of lipid-induced insulin resistance in L6 myotubes
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