Comments for:
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
Inappropriate title
Submitter: Steven E Shoelson | steven.shoelson@joslin.harvard.edu
Joslin Diabetes Center
Published February 10, 2004
The title of the recent JCI article “Conditional disruption of IkB kinase 2 fails to prevent obesity-induced insulin resistance” is misleading. Although the title does not make this clear, the manuscript primarily characterizes mice that lack IKKb in muscle, created using conventional Cre-Lox technology. It would be fair to conclude from their data that the mice lack a demonstrable phenotype. But the authors have not abolished IKKb activity in other tissues that have obvious roles in insulin resistance. Debate in science is always healthy, but exaggerated claims may divert attention from important areas of research. This is especially problematic in this case because the research is at the mechanistic intersection between three of the biggest epidemics facing humanity – obesity, insulin resistance/type 2 diabetes, and the metabolic syndrome.
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ISSN: 0021-9738 (print), 1558-8238 (online)