Skurk, T. & Hauner, H. Obesity and impaired fibrinolysis: role of adipose production of plasminogen activator inhibitor-1. Int. J. Obes. Relat. Metab. Disord. 28, 1357-1364

Technische Universität München, München, Bavaria, Germany
International Journal of Obesity (Impact Factor: 5). 12/2004; 28(11):1357-64. DOI: 10.1038/sj.ijo.0802778
Source: PubMed


Obesity is the central promoter of the metabolic syndrome which also includes disturbed fibrinolysis in addition to hypertension, dyslipidaemia and impaired glucose tolerance/type 2 diabetes mellitus. Plasminogen activator inhibitor-1 (PAI-1) is the most important endogenous inhibitor of tissue plasminogen activator and uro-plasminogen activator, and is a main determinant of fibrinolytic activity. There is now compelling evidence that obesity and, in particular, an abdominal type of body fat distribution are associated with elevated PAI-1 antigen and activity levels. Recent studies established that PAI-1 is expressed in adipose tissue. The greater the fat cell size and the adipose tissue mass, the greater is the contribution of adipose production to circulating PAI-1. Experimental data show that visceral adipose tissue has a higher capacity to produce PAI-1 than subcutaneous adipose tissue. Studies in human adipocytes indicate that PAI-1 synthesis is upregulated by insulin, glucocorticoids, angiotensin II, some fatty acids and, most potently, by cytokines such as tumour necrosis factor-alpha and transforming growth factor-beta, whereas catecholamines reduce PAI-1 production. Interestingly, pharmacological agents such as thiazolidinediones, metformin and AT(1)-receptor antagonists were found to reduce adipose expression of PAI-1. In addition, weight loss by dietary restriction or comprehensive lifestyle modification is effective in lowering PAI-1 plasma levels. In conclusion, impaired fibrinolysis in obesity is probably also due to an increased expression of PAI-1 in adipose tissue. An altered function of the endocrine system and an impaired auto-/paracrine function at the fat cell levels may mediate this disturbance of the fibrinolytic system and thereby increase the risk for cardiovascular disease..

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    • "MCP-1 expression is increased in the adipose tissue of obese individuals and the overexpression of MCP-1 in murine adipose tissue leads to macrophage recruitment and insulin resistance (Kanda et al., 2006; Tateya, Tamori, Kawaguchi, Kanda, & Kasuga, 2010). The increase in the secretion of MCP-1 and PAI-1 has an ominous impact on the progression of atherogenesis (Aiello et al., 1999; Skurk & Hauner, 2004). As an early instigator of obesity-associated metabolic syndrome , increased oxidative stress and pro-inflammatory cytokine production in accumulated fat should be an important target for the development of new therapies. "

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    • "From 1951 to 2003, the percentage of body fat increased from 11.0% to 16.2% for males and from 17.4% to 22.2% for females (Olds, 2009). This increase poses a health threat because many adipokines secreted by body fat (e.g., tumor necrosis factor a) set the stage for cardiometabolic diseases (e.g., hypertension, nonalcoholic fatty liver disease; Fay, 2004; Hutley & Prins, 2005; Pi-Sunyer, 2006; Skurk & Hauner, 2004). As fat mass increases, the secretion of cardiometabolic deleterious adipokines and the amount of atherogenic lipoprotein particles also increase (Burns, Hannon, Brusseau, Shultz, & Eisenman, 2013; Iwashima et al., 2011; Pou et al., 2007; Weiss & Caprio, 2005). "
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    • "As a consequence, clots/matrices in chronic wounds obtain an altered composition and structure, as compared to those in acute wounds [47], [48], no longer support re-epithelialisation and granulation tissue formation, and therefore have to be removed. However, elevated levels of pro-inflammatory mediators, like TNF-α and C5a, in chronic wounds may lead to enhanced production of the fibrinolysis inhibitor PAI-1 [49], [50] as is reported for obese and diabetic patients [26], [27]. PAI-1 binds to and inactivates uPA and tPA which results in impaired lysis of clots and fibrin cuffs [26], [51]. "
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