Conditional disruption of IκB kinase 2 fails to prevent obesity-induced insulin resistance

Abstract

The inhibitor of NF-kappaB (IkappaB) kinases (IKK1[alpha] and IKK2[beta]), the catalytic subunits of the IKK complex, phosphorylate IkappaB proteins on serine residues, targeting them for degradation and thus activating the transcription factor NF-kappaB. More recently, IKK2 has been implicated in mediation of insulin resistance caused by obesity, lipid infusion, and TNF-alpha stimulation, since salicylate and aspirin, known inhibitors of IKK activity, can reverse insulin resistance in obese mouse models. To further genetically elucidate the role of IKK2 in obesity-mediated insulin resistance, we have conditionally inactivated the mouse IKK2 gene in adult myocytes by Cre-loxP-mediated recombination in vivo. We have investigated the development of obesity-induced insulin resistance in muscle-specific IKK2 knockout mice and mice exhibiting a 50% reduction of IKK2 expression in every tissue and have found that, after gold thioglucose treatment, wild-type and mutant mice developed obesity to a similar extent. Surprisingly, no difference in obesity-induced insulin resistance was detectable, either at a physiological or at a molecular level. Moreover, impaired glucose tolerance resulting from a high-fat diet occurred to the same degree in control and IKK2 mutant mice. These data argue against a substantial role for muscular IKK2 in mediating obesity-induced insulin resistance in these models in vivo.

Aspirin attenuates insulin resistance in muscle of diet-induced obese rats by inhibiting inducible nitric oxide synthase production and S-nitrosylation of IRβ/IRS-1 and Akt

“…Gene-and diet-induced obesity are associated with enhanced IKKβ activity in liver, which may induce serine phosphorylation of IRS-1, preventing its tyrosine phosphorylation by insulin [8,24]. However, in muscle, data on the importance of IKKβ activation in the development of insulin resistance remain conflicting [25]. Another mechanism by which aspirin could prevent insulin resistance induced by obesity is through inhibition of JNK, another serine kinase associated with serine-phosphorylation of IRS-1 and therefore with insulin resistance.…”

siRNA-Mediated Reduction of Inhibitor of Nuclear Factor-κB Kinase Prevents Tumor Necrosis Factor-α–Induced Insulin Resistance in Human Skeletal Muscle

“…Heterozygous IKK␤ ϩ/Ϫ mice fed a high-fat diet or intergressed on an obese ob/ob mice background were protected against the development of insulin resistance (3). Conversely, mice with either skeletal muscle-specific IKK␤ knockout or a separate cohort of heterozygous IKK␤ ϩ/Ϫ were not protected against gold thioglucose-induced obesity or dietary-induced metabolic abnormalities (46). The reason for the differences noted between these animal models is unknown, but the differences could be strain specific or related to undefined experimental differences.…”

From physical inactivity to immobilization: Dissecting the role of oxidative stress in skeletal muscle insulin resistance and atrophy

“…However, caution must be taken when generalizing these mechanisms to skeletal muscle. Muscle-specific JNK or IKKβ deficient mice were not protected against obesity-induced insulin resistance [154,155]. In addition, overactivation of NF-κB and IKKβ in skeletal muscle does not lead to insulin resistance [156].…”