Abstract 612: Targeting I κ B Kinase β in Adipocyte Lineage Cells for Treatment of Obesity and Metabolic Dysfunctions

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 identified as a potential therapeutic target for the treatment of obesity-associated metabolic dysfunctions. We recently revealed a novel role of IKKβ in adipogenesis and demonstrated that IKKβ functions in adipocyte precursor cells to regulate adipose tissue development. In this study, we used pharmacological and genetic approaches to explore the therapeutic potential of targeting IKKβ signaling in adipocyte lineage cells for treatment of obesity and metabolic dysfunctions. Approach and Results: We first evaluated an antisense oligonucleotide (ASO) inhibitor of IKKβ and found that IKKβ ASO ameliorated diet-induced metabolic dysfunctions in mice. Interestingly, IKKβ ASO also targeted IKKβ in adipocyte precursor cells, leading to inhibited adipocyte differentiation and reduced adiposity in high-fat (HF)-fed mice. Consistently, CRISPR/Cas9-mediated genomic deletion of IKKβ or pharmacological inhibition of IKKβ inhibited E3 ubiquitin ligase-mediated β-catenin ubiquitination and degradation in murine and human adipocyte precursor cells, resulting in elevated Wnt signaling and impaired adipocyte differentiation. To further elucidate the role of adipose progenitor IKKβ signaling in diet-induced obesity, we generated mice that selectively lack IKKβ in the white adipose lineage and confirmed the essential role of IKKβ in mediating adipocyte differentiation in vivo . Deficiency of IKKβ decreased HF-elicited adipogenesis in addition to reducing inflammation and protected mice from diet-induced obesity and insulin resistance. Conclusions: Our findings establish IKKβ as a pivotal regulator of adipogenesis and suggest that overnutrition-mediated IKKβ activation serves as an initial signal that triggers adipose progenitor cell differentiation in response to HF-feeding. Inhibition of IKKβ with antisense therapy may present as a novel therapeutic approach to combat obesity and metabolic dysfunctions.