Normal AT remodeling requires a balance between the synthesis and degradation of a complex network of extracellular matrix (ECM) proteins. Disruption of this balance, as observed in obesity, can lead to AT fibrosis and inflammation. We have reported that oncostatin M (OSM), a gp130 cytokine, is produced by AT macrophages and up-regulated in mouse and human obesity. Our data demonstrate that adipocyte-specific knockout of the OSM-specific receptor (OSMR) in mice leads to insulin resistance, glucose intolerance, and increased pro-fibrotic and pro-inflammatory gene expression in visceral AT. The proposed aims will test the overall hypothesis that that loss of adipocyte OSMR signaling disrupts normal adipose tissue homeostasis and promotes AT fibrosis and insulin resistance. Importantly, Dr. Elks will learn and implement new methods in transgenic mouse generation and phenotyping, molecular biology, and the biochemical assessment and imaging of the AT-ECM that are necessary for her independence as an investigator. Pennington Biomedical Research Center will provide an ideal learning environment for Dr. Elks to successfully complete the proposed aims and objectives. The training in this research project will also provide a basis for future projects to assess alterations in AT-ECM biology and adipocyte metabolism in metabolic diseases, and to apply findings to the development of novel therapies for insulin resistance and obesity, which is Dr. Elks' long-term research goal. The PI has assembled an outstanding mentoring team of experienced investigators and collaborators who will all provide their guidance and expertise to help her achieve independence.
Obesity, defined as fat (adipose) tissue excess, is a primary contributor to type 2 diabetes and a major healthcare burden. As obesity develops, adipose tissue becomes dysfunctional and often leads to additional metabolically unfavorable effects. The proposed research is relevant to public health because it will: 1) examine novel factors regulating adipose tissue function, and 2) provide understanding on how these factors can contribute to metabolic disorders
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