IKKβ links vascular inflammation to obesity and atherosclerosis

Yipeng Sui, Se Hyung Park, Jinxian Xu, Sébastien Monette, Robert N. Helsley, Seong Su Han, Changcheng Zhou

Research output: Contribution to journalArticlepeer-review

60 Scopus citations

Abstract

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

Original languageEnglish (US)
Pages (from-to)869-886
Number of pages18
JournalJournal of Experimental Medicine
Volume211
Issue number5
DOIs
StatePublished - May 2014

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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