Grants and Contracts Details
The prevalence of obesity in the United States is increasing at epidemic proportions, with an estimated prevalence of 30 %. Obesity is the most common risk factor for type 2 diabetes and subsequent cardiovascular disease. Obese adipose tissue is characterized by the infiltration of macrophages and the secretion of inflammatory cytokines which have recently been identified as an important source of inflammation. There is increasing evidence that this cytokine-induced chronic state of low-grade inflammation is closely involved in the pathogenesis of insulin resistance and associated complications such as atherosclerosis. Cell-mediated immunity, migration and recruitment of monocytes/macrophages into tissues and subsequent cytokine secretion are dependent on the expression of Osteopontin (OPN), an adhesion molecule and important component of cellular immunity and inflammation. Our preliminary studies demonstrate that OPN plasma levels and mRNA in adipose tissue increase during the development of obesity. Interestingly, particularly macrophages within obese adipose tissue express high levels of OPN. We observed further OPN-deficient mice are protected from adipose tissue inflammation and insulin resistance during diet-induced obesity. Based on these findings, the central hypothesis of this proposal is that OPN regulates macrophage infiltration into adipose tissue leading to the development of insulin resistance. To test this hypothesis we propose: 1) To determine the regulation of macrophage infiltration into adipose tissue by OPN; 2) To determine the relative contribution of OPN derived from hematopoetic cells to adipose tissue inflammation; and 3) To determine the role of OPN for the development of insulin resistance during diet-induced obesity. These experiments may ultimately identify OPN as an important link between adipose tissue-derived inflammatory processes, insulin resistance and the premature development of atherosclerosis.
|Effective start/end date||7/1/07 → 6/30/08|
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