Insulin resistance is a condition associated with a cluster of abnormalities including hypertension, glucose intolerance, hypertriglyceridemia, obesity and premature coronary artery disease. Understanding the molecular basis of the link between insulin resistance and these pathological states has been a difficult task. Elevated plasma levels of free fatty acids are a common hallmark of insulin resistance. Cytoplasmic fatty acid binding proteins (FABP) are small cytoplasmic proteins that bind a variety of fatty acids and are expressed in a tightly regulated, tissue specific manner. Proposed functions of cytoplasmic FABP include trapping and trafficking of fatty acids within cells and cell signaling. Targeted disruption of the aP2 allele has been shown to uncouple obesity and insulin resistance, indicating an important role for aP2 in the insulin resistance. Preliminary studies indicate that aP2 promotes atherosclerosis and macrophage foam cell formation in apoE deficient mice. Mall, a closely related FABP, is also expressed by adipocytes and macrophages and is up-regulated in aP2 deficient mice. The goal of this project is to investigate the impact of aP2 and mall-deficiency on insulin resistance and atherosclerosis. To this end, murine bone marrow transplantation will be used to generate mice chimeric for aP2 and or mall expression by macrophages and or adipocytes allowing the investigation of the relative cell-specific contributions of expression of these genes to atherosclerosis and insulin resistance. Finally, in vitro studies will investigate the role of aP2 and mall in macrophage foam cell formation. By providing new insights into the link between insulin resistance and atherosclerosis, these studies may lead to new therapeutic approaches to diabetes and coronary artery disease.
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