Objectives: The goal of this proposal is to determine the role of PSGL-1 in mediating visceral adipose tissue inflammation. The results of these studies may uncover novel therapeutic targets to reduce the vascular comorbidities associated with the obesity epidemic. Research Plan: To assess the role of PSGL-1 deficiency on the development of visceral adipose tissue inflammation, mouse models of genetic and diet-induced obesity will be used. In vitro models will address the mechanisms by which PSGL-1 regulates endothelial adhesion molecule expression. Finally, a novel model of inflammatory fat will be used to determine the specific effect of PSGL-1 in mediating the effects of visceral inflammatory fat on atherosclerosis. Methods: The strategy to accomplish the objectives will be to use transgenic mouse models and in vitro assays to explore mediators of fat inflammation and the vascular risk associated with inflammatory fat.
Aim 1 will determine the effect of PSGL-1 deficiency on adipose tissue macrophage infiltration in mouse models of genetic and diet-induced obesity.
Aim 2 will determine mechanisms by which PSGL-1 induces expression of endothelial selectins and MCP-1 in obesity.
Aim 3 will determine the effect of PSGL-1 neutralization on atherosclerosis induced by inflammatory visceral adipose tissue. Clinical Relevance: Atherosclerosis is the most common underlying cause of morbidity and mortality in the United States veteran population. Although some therapies targeting cholesterol are proving to be useful in preventing complications of atherosclerosis such as myocardial infarction and stroke, these complications are still commonplace and predicted to increase in the near future due to the obesity epidemic. Links between obesity and vascular risk remain to be elucidated, however several recent clinical studies have suggested that visceral adiposity is largely responsible for obesity-associated vascular risk. Whether visceral adipose tissue is a marker or mediator of vascular risk is unclear. Experimental models of obesity have demonstrated marked differences between visceral and subcutaneous fat in terms of adipocytokine expression and leukocyte infiltration. We have recently demonstrated that inflammatory visceral adipose tissue is sufficient to accelerate atherosclerosis in mice, in the absence of diabetes. Thus, identification of factors that promote visceral fat inflammation and/or mediate the increased vascular risk associated with visceral fat inflammation will be useful in designing therapies aimed at reducing the vascular risk associated with central obesity. Potential Impact on Veterans Health Care: By uncovering the mechanism(s) by which visceral adiposity affects vacular disease, new therapies can be developed and applied to the obese veteran population at risk for complications of atherosclerosis. Reducing the morbidities associated with vascular disease, such as myocardial infarction and stroke, will have a major beneficial effect on the health of the veteran population.
Project Narrative Obesity is epidemic in the US and having an adverse impact on cardiovascular morbidity and mortality. Recent clinical studies have demonstrated that the macrovascular risk associated with obesity is due to excess visceral adiposity. Our hypothesis is that inflammation in fat is responsible for the vascular risk associated with obesity. Identification of the cellular and molecular mediators of fat inflammation may lead to novel therapeutic agents aimed at reducing the risk of myocardial infarction and stroke in an overweight population.
