Hemostatic Gene Expression and Vascular Disease in Obesity: Insights from Studies of Genetically Obese Mice

Abstract

IntroductionObesity is a major public health problem in Western societies with substantial economic consequences. In the United States alone, over 30% of the population is defined as clinically obese, and thereby, are subject to increased risk for obesity-associated disorders, including cardiovascular disease (CVD), hypertension, insulin resistance, and non-insulin dependent diabetes mellitus (NIDDM).1,2 In spite of the magnitude of this problem, the molecular changes in obesity that promote these conditions are far from resolved. The fact that human obesity is a polygenic disorder with complex environmental and behavioral characteristics has made obesity research one of the more difficult areas of investigation in the medical sciences.1,3 However, recent studies of genetically obese mice and rats have produced breakthroughs in several areas of obesity-related research, primarily because obesity in these animals appears to be monogenic (i.e., to result from mutations in single genes). In this regard, five different genes, all mapped to different chromosomal locations, have been shown to cause distinct syndromes of spontaneous obesity with severe insulin resistance in mice.3 These include the obese (ob), diabetes (db), tubby (tub), lethal yellow (Ay) and fat (fat) mutations. Genes encoding intercellular adhesion molecule 1 (ICAM-1) and the leukocyte integrin αmβ2 (MAC-1) also have been implicated in the regulation of adipose tissue mass.4 These animal studies, together with studies of cultured adipocytes, have provided fundamental new information about the factors and cells that may be responsible for the altered hemostatic balance leading to increased cardiovascular risk in obesity/NIDDM.In this chapter, we summarize our studies on plasminogen activator inhibitor 1 (PAI-1), tissue factor, and transforming growth factor (TGF)-β expression in obesity, using genetically obese mice as a model. These studies emphasize the key role played by the adipocyte, a cell whose numbers, size, and metabolic activity are grossly altered in obesity/NIDDM. They also implicate multiple cytokines, hormones, and growth factors in the abnormal expression of these and perhaps other hemostatic genes by adipocytes in obesity/NIDDM (Fig. 1). These studies emphasize the key role played by tumor necrosis factor (TNF)-α in the expression of hemostatic genes in this disorder.