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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
5P20GM103527-07
Application #
8733723
Study Section
Special Emphasis Panel (ZGM1-TWD-Y)
Project Start
Project End
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
7
Fiscal Year
2014
Total Cost
$262,567
Indirect Cost
$87,567
Name
University of Kentucky
Department
Type
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
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