Regulation of tissue factor gene expression in obesity

Altered expression of proteins of the fibrinolytic and coagulation cascades in obesity may contribute to the cardiovascular risk associated with this condition. In spite of this, the zymogenic nature of some of the molecules and the presence of variable amounts of activators, inhibitors, and cofactors that alter their activity have made it difficult to accurately monitor changes in the activities of these proteins in tissues where they are synthesized. Thus, as a first approach to determine whether tissue factor (TF) expression is altered in obesity, this study examined changes in TF mRNA in various tissues from lean and obese (ob/ob and db/db) mice. TF gene expression was elevated in the brain, lung, kidney, heart, liver, and adipose tissues of both ob/ob and db/db mice compared with their lean counterparts. In situ hybridization analysis indicated that TF mRNA was elevated in bronchial epithelial cells in the lung, in myocytes in the heart, and in adventitial cells lining the arteries including the aortic wall. Obesity is associated with insulin resistance and hyperinsulinemia, and administration of insulin to lean mice induced TF mRNA in the kidney, brain, lung, and adipose tissue. These observations suggest that the hyperinsulinemia associated with insulin-resistant states, such as obesity and noninsulin-dependent diabetes mellitus, may induce local TF gene expression in multiple tissues. The elevated TF may contribute to the increased risk of atherothrombotic disease that accompanies these conditions.