Functional role of the fibrinolytic system in development of adipose tissue

Development of obesity is associated with extensive modifications in adipose tissue involving adipogenesis, angiogenesis and extracellular matrix proteolysis. The fibrinolytic (plasminogen/plasmin) system contributes to these processes. The main physiological inhibitor of the fibrinolytic system, plasminogen activator inhibitor-1 (PAI-1), is expressed in murine and human adipose tissues, and high PAI-1 levels predispose to thrombotic complications. The potential role of PAI-1 in development of adipose tissue remains, however, enigmatic. We have used nutritionally induced obesity models in wild-type and transgenic mice to study the role of the fibrinolytic system in the development of obesity. Our main findings are: 1) Obesity is associated with markedly enhanced plasma levels of PAI-1; 2) The effect of PAI-1 on in vivo adipose tissue development is concentration-dependent; 3) PAI-1 does not play a significant role in adipogenesis but may affect angiogenesis; 4). Tissue-type plasminogen activator (t-PA), the main target of PAI-1, impairs adipose tissue development; 5) PAI-1 contributes to the deleterious effect of obesity on the outcome of thrombotic ischemic stroke; and 6) The use of synthetic low Mr inhibitors of PAI-1 may have the potential to reduce obesity. These studies thus support a role for fibrinolytic activity and suggest that its modulation may allow to affect development of adipose tissue.