Activation of the classical I kappa B kinases (IKK alpha and IKK beta) was previously shown to contribute to obesity-induced inflammation and insulin resistance. Using knockout mice, we investigated whether the related isoform IKK epsilon plays a similar metabolic role. IKK epsilon(-/-) mice had reduced body weight, leptin levels, as well as higher insulin sensitivity when kept on chow diet. However, inflammatory parameters, measured in liver, adipose tissue and plasma, were either unaltered or showed a trend toward up-regulation (liver NF-kappa B activity, TNF alpha and IL-1 beta expression). Chronic feeding of a high fat diet induced equal obesity and insulin resistance, and similarly induced inflammatory markers, in IKK epsilon(-/-) and wild-type mice, indicating that under high caloric conditions the inflammatory and metabolic effects of IKK epsilon deficiency were overridden. Taken together, our data indicate that IKK epsilon does not have general pro-inflammatory properties in liver and adipose tissue, and suggest that reduced adiposity is the primary mechanism for improved insulin sensitivity in IKK epsilon(-/-) mice on chow diet. (C) 2011 Elsevier Inc. All rights reserved.