Role of IKKB in obesity and atherosclerosis

This is an R01 application intended to test the hypothesis that IKKâ is a critical regulator of adipogenesis and atherogenesis, and that overnutrition-induced activation of IKKâ promotes adipocyte differentiation, adipocyte inflammation and atherosclerosis. 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 IKKâ/NF-êB signaling. However, the role of IKKâ in metabolic disorders and atherosclerosis remains elusive. Our initial studies showed that IKKâ deficiency (driven by an SM22Cre-IKKâ-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 IKKâ positively regulates adipogenesis, indicating that chronic inflammation might be an important initial trigger for the adipocyte differentiation in response to high-fat diet consumption. Three specific aims are proposed: (1) Define the role of IKKâ in the regulation of murine and human adipocyte differentiation in response to overnutrition; (2) Determine the effect of adipocyte IKKâ deficiency on the development of obesity-associated insulin resistance and atherosclerosis; and (3) Determine the impact of pharmacological inhibition of IKKâ by ASO on diet-induced obesity and associated atherosclerosis. The proposed studies will define the role of IKKâ in diet-induced adipose tissue growth, adipocyte inflammation and insulin resistance and will reveal a critical link between overnutrition, inflammation, and metabolic disorders. Our studies will also provide strong evidence for use of appropriate IKKâ inhibitors as an innovative therapeutic strategy to treat obesity and metabolic disorders.