IKKß and Wnt/ß-Catenin Signaling Interaction Regulates Adipogenesis and Osteogenesis in Mesenchymal Stem Cells of Nonhuman Primates and Humans

Abstract

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. We recently demonstrated that IKKβ also functions in adipose progenitors to regulate adipogenesis and adipose tissue development in mice. Deficiency of IKKβ in adipose progenitors decreased high-fat (HF)-elicited adipogenesis and protected mice from diet-induced adiposity and insulin resistance. Here we report that IKKβ can regulate both adipogenesis and osteogenesis in mesenchymal stem cells (MSCs) of non-human primates (Macaca fascicularis) and humans. Activation or overexpression of IKKβ increased adipocyte differentiation but inhibited osteoblast differentiation of MSCs isolated from adipose tissue and bone marrow of macaques and humans. By contrast, IKKβ loss of function decreased adipogenesis and increased osteogenesis in macaque and human MSCs. Mechanistically, IKKβ can directly interact with Wnt/β-catenin signaling and phosphorylate β-catenin at serine-33, -37 and -45, leading to its ubiquitination and degradation. Inhibition of canonical Wnt/β-catenin signaling then contributed to the increased adipogenesis and decreased osteogenesis in MSCs. Our findings demonstrate IKKβ as a key molecule that regulates MSC differentiation, and provide a connection between IKKβ and Wnt/β-catenin signaling which may lead to new insights into the pathogenesis of obesity and osteoporosis. Disclosure Y. Sui: None. S. Park: None. P.A. Kern: None. R. Temel: Research Support; Self; Ionis Pharmaceuticals, Inc., Regulus Therapeutics Inc.. Stock/Shareholder; Self; Merck & Co., Inc., Ionis Pharmaceuticals, Inc., Resverlogix Corp.. C. Zhou: None.