The role of IKKB in linking obesity to adipose tissue inflammation and adipogene

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The goal of this project is to investigate the role of IKB kinase beta (IKKB), a central coordinator of innate immunity and inflammation through activation of NF-KB, in linking obesity to adipose tissue inflammation and adipogenesis. Obesity is associated with a state of chronic low-grade inflammation that has been considered to be a major contributor to diabetes and atherosclerosis. The transcriptional factor NF-KB is a primary mediator of inflammatory pathways that are linked to the development of obesity-associated insulin resistance and atherosclerosis. IKKB is the predominant catalytic subunit ofthe IKK complex that is required for canonical activation of NF-KB by inflammatory mediators. Given the defined role of IKKB in regulating NF-KB-mediated inflammation in several cell types, it is unclear whether IKKB contributes to obesity-induced inflammation in adipocytes. In the proposed studies, we will define the role of adipocyte-derived IKKB in high fat (HF) diet-induced obesity, adipose inflammation and insulin resistance. In preliminary studies during Phase I support of this project, we also defined the role of smooth muscle cell (SMC) IKKB in the development of obesity-associated atherosclerosis in LDL receptor (LDLR) deficient mice. To delete IKKB in SMCs, we used SM22-Cre transgenic male mice carrying floxed IKKB alleles that were mated to female LDLR-/- mice carrying floxed IKKB alleles. During the course of these studies, we made the novel finding that deficiency of IKKB in SMCs rendered mice resistant to the development of diet-induced obesity. Preliminary results demonstrate that SM22 is expressed in primary adipose stromal/vascular (SV) cells, consistent with recent reports that SM22-Cre is active in mesenchymal stem cells (MSCs) that give rise to adipose tissue. Notably, SV cells from SMC IKKB-deficient mice exhibited impaired adipogenic potential. These results implicate a previously unrecognized role of IKKB in the regulation of adipogenesis. The central hypothesis of this proposal is that HF-diet induced activation of IKKB promotes adipocyte differentiation, adipocyte inflammation, and insulin resistance. In the proposed studies, we will define mechanisms for IKKB-mediated regulation of adipogenesis. We will also define the effect of adipocyte IKKB deficiency on the development of obesity, adipose inflammation, and insulin resistance in response to a HF diet. The proposed studies will elucidate new aspects of adipocyte biology and metabolic control and may lead to novel therapeutic targets for obesity and diabetes.