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

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Abstract

The inhibitor of NF-κB (IκB) kinases (IKK1[α] and IKK2[β]), the catalytic subunits of the IKK complex, phosphorylate IκB proteins on serine residues, targeting them for degradation and thus activating the transcription factor NF-κB. More recently, IKK2 has been implicated in mediation of insulin resistance caused by obesity, lipid infusion, and TNF-α 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.

Authors

Mathias Röhl, Manolis Pasparakis, Stephanie Baudler, Julia Baumgartl, Dinesh Gautam, Marion Huth, Rossana De Lorenzi, Wilhelm Krone, Klaus Rajewsky, Jens C. Brüning