Conditional disruption of IkappaB kinase 2 fails to prevent obesity-induced insulin resistance.
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.
Röhl
Mathias
M
Klinik II und Poliklinik für Innere Medizin der Universität zu Köln and Center for Molecular Medicine Cologne, Germany.
Pasparakis
Manolis
M
Baudler
Stephanie
S
Baumgartl
Julia
J
Gautam
Dinesh
D
Huth
Marion
M
De Lorenzi
Rossana
R
Krone
Wilhelm
W
Rajewsky
Klaus
K
Brüning
Jens C
JC
D000818:Animals; D006051:Aurothioglucose / Q000378:metabolism; D051550:I-kappa B Kinase; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D051379:Mice; D018482:Muscle, Skeletal / Q000201:enzymology / Q000378:metabolism; D009765:Obesity / Q000201:enzymology* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
D007328:Insulin; D006051:Aurothioglucose; D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse