The Adipocyte and Hemostatic Balance in Obesity

Abstract

P lasminogen activator inhibitor 1 is the primary physiological inhibitor of plasminogen activation in vivo, and elevations in plasma PAI-1 appear to compromise normal fibrin clearance mechanisms and promote thrombosis. PAI-1 is dramatically upregulated in obesity, a complex condition associated with increased risk for myocardial infarction, accelerated atherosclerosis, hypertension, glucose intolerance, insulin resistance, hyperinsulinemia, and NIDDM. In spite of the apparent link between elevated PAI-1 levels and thrombotic disease, little is known about the origin of this plasma inhibitor in obesity/NIDDM or about the signals that control its biosynthesis. Potential insights into the underlying molecular events have come from recent studies of genetically obese mice and of cultured adipocytes. These studies are reviewed here.* They emphasize the key role played by the adipocyte, a cell whose numbers, size, and metabolic activity are grossly altered in obesity/NIDDM. They also suggest that multiple cytokines, hormones, and growth factors may be involved, and they raise the possibility that the abnormal expression of other hemostatic genes by adipocytes in obesity/NIDDM may also contribute to the cardiovascular complications of this disorder. In this regard, our preliminary studies indicate that TF gene expression is elevated in the adipose tissues of the obese mouse. Properties of PAI-1PAI-1 appears to be the primary physiological inhibitor of plasminogen activation in blood, since it is the only PAI found complexed with single-chain tissue-type PA in carefully collected human plasma, and the second-order rate constant for its interaction with tissue-type PA and urokinase-type PA (Ϸ3.5ϫ10 7 [mol/L] Ϫ1 ⅐ s Ϫ1 ) is at least two orders of magnitude higher than that of other PAIs. [1][2][3][4] The normal concentration of PAI-1 protein in human plasma ranges from 6 to 80 ng/mL with a geometric mean at 24 ng/mL, whereas that of tissuetype PA is 5 to 10 ng/mL. Abnormalities in the concentration of PAI-1 are frequently associated with vascular disease. For example, the inhibitor is elevated in a variety of thrombotic conditions, including myocardial infarction and deep venous thrombosis. Elevated PAI-1 also correlates with thrombosis in animal models, and transgenic mice that overexpress PAI-1 have been reported to develop venous thrombosis. 5 On the other hand, the absence of PAI-1 in humans leads to life-long bleeding problems presumably resulting from the development of a hyperfibrinolytic state, and disruption of the PAI-1 gene in mice is also associated with a mild hyperfibrinolytic state as manifested by increased resistance to endotoxin-induced thrombosis. 5 Finally, neutralizing plasma PAI-1 activity with specific antibodies or by the use of PAI-1 inhibitors 4,6 enhances spontaneous or tissue-type PA-mediated thrombolysis. These observations emphasize that imbalances in the PA/PAI-1 ratio are likely to promote either thrombosis or bleeding. As summarized in the next section, this balance is severely disturbed ...

Effects of tumor necrosis factor alpha on leptin secretion and gene expression: relationship to changes of glucose metabolism in isolated rat adipocytes

“…This is supported by reports that adipose tissue can synthesize and secrete several factors 44 capable of modulating leptin secretion, including TGF-b. 44,45 However, research efforts have largely overlooked the fact that TNF-a and TGF-b, like leptin, are expressed in the adipose tissue of not only obese rodents, but also pre-obese, normal and lean rodents. 44 Thus, how molecules such as TNF-a, TGF-b, leptin and insulin interact to modulate adipocyte physiology in homeostasis and in the pathogenesis of obesity remains unde®ned.…”

Fat poetry: a kingdom for PPARγ

“…The circulating levels of PAI1 are correlated with obesity and insulin resistance, and thus predict future risk of type 2 diabetes and cardiovascular disease [106,107]. The adipose tissue is thought to be an important contributor to the elevated plasmatic PAI1 concentrations in obesity [108,109], but the mechanisms underlying the association between PAI1 levels and the disturbances found in the metabolic syndrome are not well understood. However, inhibition of fibrinolysis by PAI1 might be responsible for the high incidence of cardiovascular diseases, which is a feature of this syndrome [110].…”

Relationship between metabolic syndrome and platelet responsiveness to leptin in overweight and obese patients

“…[1][2][3] Additionally, altered hemostatic balance also may contribute to the excess risk of acute cardiovascular events in obese individuals. 4,5 Leptin, the product of the ob gene, 6 is a protein secreted mainly by the adipose tissue, which signals the size of energy stores to the central nervous system modulating the activity of hypothalamic centers involved in the regulation of food intake and energy balance. 7 Although leptin's major role seems to be in the regulation of body weight and energy metabolism, several evidences suggest that this hormone could be involved in other pathophysiological mechanisms, such as immune function, angiogenesis, bone formation and fertility, and the expression of leptin receptor has been demonstrated in a variety of tissues.…”