Deficiency of IKKε inhibits inflammation and induces cardiac protection in high-fat diet-induced obesity in mice

Immune response and metabolic regulation have been recognized as a central homeostatic mechanism, the dysfunction of which can trigger a cluster of chronic metabolic disorders, particularly obesity, type II diabetes and cardiovascular disease. Serine/threonine kinase I kappa B kinase (IKK) epsilon is a multifunctional regulator that participates in immune regulation, cell proliferation and transformation, and oncogenesis. In the present study, we investigated the role of IKK epsilon in cardiovascular disorders using murine models of apolipoprotein E-deficient [ApoE(-/-)] mice and ApoE/IKK epsilon double-knockout [ApoE(-/-)/IKK epsilon(-/-)]mice, which were fed a normal diet (ND) and high-fat diet (HFD) for 12 weeks, respectively. Results of this study showed that mouse obesity correlated in vivo with an increased expression of IKK epsilon. Additionally, chronic low-grade inflammation in cardiac tissue was evident in ApoE(-/-) mice, but was markedly reduced in ApoE(-/-)/IKK epsilon(-/-) mice. However, serum lipid levels in the ApoE(-/-) mice group were not significantly higher than those of the ApoE(-/-)/IKK epsilon(-/-) group. Furthermore, immunofluorescence and western blot analysis demonstrated evident increases in the expression of nuclear factor-kappa B (NF-kappa B) pathway components and downstream factors in the ApoE(-/-) mice group, while these increases were blocked in the ApoE(-/-)/IKK epsilon(-/-) group. Taken together, these data indicate that deficiency of IKK epsilon prevented obesity and inflammatory response in the murine hearts in ApoE(-/-) and ApoE(-/-)/IKK epsilon(-/-) mice fed an ND and HFD, respectively, suggesting that IKKe may play a role in HFD-induced inflammation in hearts of obese mice and may serve as a novel target for the treatment of a variety of metabolism-associated cardiovascular diseases.