The goal of this project is to investigate the role of IKB kinase beta (IKK), a central coordinator of innate immunity and inflammation through activation of NF-?B, 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-?B is a primary mediator of inflammatory pathways that are linked to the development of obesity-associated insulin resistance and atherosclerosis. IKK is the predominant catalytic subunit of the IKK complex that is required for canonical activation of NF-?B by inflammatory mediators. Given the defined role of IKK in regulating NF-?B-mediated inflammation in several cell types, it is unclear whether IKK contributes to obesity-induced inflammation in adipocytes. In the proposed studies, we will define the role of adipocyte-derived IKK 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) IKK in the development of obesity-associated atherosclerosis in LDL receptor (LDLR) deficient mice. To delete IKK in SMCs, we used SM22-Cre transgenic male mice carrying floxed IKK alleles that were mated to female LDLR-/- mice carrying floxed IKK alleles. During the course of these studies, we made the novel finding that deficiency of IKK 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 IKK-deficient mice exhibited impaired adipogenic potential. These results implicate a previously unrecognized role of IKK in the regulation of adipogenesis. The central hypothesis of this proposal is that HF-diet induced activation of IKK promotes adipocyte differentiation, adipocyte inflammation, and insulin resistance. In the proposed studies, we will define mechanisms for IKK-mediated regulation of adipogenesis. We will also define the effect of adipocyte IKK 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.
Obesity is a rapidly growing epidemic representing a serious threat to the health of the population in almost every country around the world. There is an urgent need to understand the mechanisms underlying the diet induced obesity and associated metabolic disorders. The proposed study will investigate a novel mechanism that links over nutrition and obesity.
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