Abstract 270: IκB Kinase β Signaling in Adipose Progenitor Cells Promotes Obesity and Metabolic Disorders

Abstract

Objective: Obesity is associated with a state of chronic low-grade inflammation that is a major contributor to diabetes and cardiovascular diseases. IκB kinase β (IKKβ), a central coordinator of inflammation through activation of NF-κB, has been implicated in the pathogenesis of obesity-associated metabolic disorders. However, the role of IKKβ in adipose tissue development and metabolism remains elusive. We have recently revealed a potential role of IKKβ in the regulation of adipocyte differentiation. This study aims to investigate the impact of adipose progenitor cell IKKβ deficiency in diet-induced obesity and metabolic disorders. Approach and Results: To determine the role of IKKβ in adipose tissue development, we selectively deleted IKKβ in the white adipose lineage. This was attained by using a PDGFRβ-Cre/IKKβ-loxP system. Cell lineage analysis confirmed that PDGFRβ-Cre is active in primary adipose stromal vascular (SV) cells and PDGFRβ-positive SV cells had higher adipogenic potential than did PDGFRβ-negative cells. PDGFRβ-Cre-mediated IKKβ deletion diminished the ability of SV cells to differentiate into adipocytes. By analyzing mice that selectively lacked IKKβ in the white adipose lineage, we found that deficiency of IKKβ protected mice from high-fat diet-induced obesity. Moreover, IKKβ deficient mice had decreased plasma proinflammatory cytokine levels and enhanced insulin sensitivity. Mechanistically, IKKβ deficiency inhibited proteasome-mediated β-catenin ubiquitination and degradation in adipose SV cells, causing an accumulation of nuclear β-catenin protein levels and impaired adipocyte differentiation. Consistently, CRISPR-mediated IKKβ deletion in murine 3T3-L1 preadipocytes also increased nuclear β-catenin protein levels and blocked 3T3-L1 cell differentiation. Conclusions: Our results establish IKKβ as an important regulator of adipogenesis and adipose tissue development. Overnutrition-mediated IKKβ activation may serve as an initial signal that triggers adipose progenitor cell differentiation in response to consumption of a high-fat diet. Inhibition of IKKβ may present as a novel therapeutic approach to combat obesity and diabetes.