Role of IKKβ in obesity and atherosclerosis

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 DESCRIPTION (provided by applicant): Obesity is associated with a state of chronic inflammation that is thought to be a major contributor to diabetes and atherosclerosis. Many inflammatory pathways that contribute to the development of insulin resistance and atherosclerosis are regulated by IKKβ/NF-κB signaling. However, the role of IKKβ in metabolic disorders and atherosclerosis remains elusive. Our initial studies showed that IKKβ deficiency (driven by a SM22Cre-IKKβ- flox system) in smooth muscle cells (SMCs) rendered mice resistant to the development of diet-induced obesity, metabolic disorders, and atherosclerosis. We made the novel finding that SM22 is expressed in primary adipose stromal vascular (SV) cells and IKKβ positively regulates adipogenesis, indicating that chronic inflammation might be an important initial trigger for the adipocyte differentiation in response to high-fat diet consumption. Our central hypothesis is that IKKβ is essential for adipogenesis and atherogenesis, and that high-fat diet-induced IKKβ activation promotes adipocyte differentiation and adipose inflammation, leading to increased obesity, insulin resistance, and atherosclerosis. Three specific aims are proposed: (1) Define the role of IKKβ in the regulation of murine and human adipocyte differentiation in response to overnutrition; (2) Determine the contribution of adipocyte IKKβ to the development of obesity-associated insulin resistance and atherosclerosis; and (3) Determine the impact of pharmacological inhibition of IKKβ by antisense oligonucleotides on diet-induced obesity and atherosclerosis. The proposed studies will define the role of IKKβ in adipogenesis and atherogenesis and will reveal a critical link between overnutrition, inflammation, and cardiometabolic disease. Our studies will also provide strong evidence for use of appropriate IKKβ inhibitors as an innovative therapeutic strategy to treat obesity and cardiometabolic disease.