IKKβ links vascular inflammation to obesity and atherosclerosis

I kappa B kinase beta (IKK beta), a central coordinator of inflammatory responses through activation of NF-kappa B, has been implicated in vascular pathologies, but its role in atherogenesis remains elusive. Here, we demonstrate that IKK beta functions in smooth muscle cells (SMCs) to regulate vascular inflammatory responses and atherosclerosis development. IKK beta deficiency in SMCs driven by a SM22Cre-IKK beta-flox system rendered low density lipoprotein receptor-null mice resistant to vascular inflammation and atherosclerosis induced by high-fat feeding. Unexpectedly, IKK beta-deficient mice were also resistant to diet-induced obesity and metabolic disorders. Cell lineage analysis revealed that SM22Cre is active in primary adipose stromal vascular cells and deficiency of IKK beta diminished the ability of these cells to differentiate, leading to accumulation of adipocyte precursor cells in adipose tissue. Mechanistically, reduction of IKK beta expression or pharmacological inhibition of IKK beta inhibited proteasome-mediated beta-catenin ubiquitination and degradation in murine preadipocytes, resulting in elevated beta-catenin levels and impaired adipocyte differentiation. Further, chronic treatment of mice with a potent IKK beta inhibitor decreased adipogenesis and ameliorated diet-induced obesity. Our findings demonstrate a pivotal role of IKK beta in linking vascular inflammation to atherosclerosis and adipose tissue development, and provide evidence for using appropriate IKK beta inhibitors in the treatment of obesity and metabolic disorders.