| Research Abstract |
Obese patients are at risk for development of cardiovascular disease, which can in part be explained by disturbances in the haemostatic and fibrinolytic systems. Recently, it has been demonstrated that the adipocyte itself is able to produce a primary fibrinolytic inhibitor, PAI-1, possibly accounting for the elevated PAI-1 levels in obesity. We hypothesized that leptin receptor signal transduction pathway might regulate PAI-1 gene expression in adipocytes, which could be activated by leptin secreted from these cells. Administration of recombinant leptin to ob/ob genetic obese mice not only caused reduction of plasma levels of PAI-1 but also repression of PAI-1 gene expression in abdominal fat, subcutaneous fat tissues, and lung tissue after 6 hr and 24 hr treatments. Cotransfection of 3T3-L1 preadipocyte with 5-PAI-1/Luc reporter and leptin expression vectors revealed that PAI-1 promoter activities were repressed in a dose-dependent manner. These results suggested that exogenous addition of leptin caused repression of PAI-1 expression in vivo and in vitro. Adipocytes express at least two kinds of leptin receptors ; long-and short-form. To identify the leptin receptor (LepR) involved in repression of PAI-1 gene expression, 3T3-L1 preadipocyte were transfected with leptin, and either short-or long-form LepR expression vectors, and then luciferase activities were measured after 48-hr incubation. Transfection in combination with leptin and short-form LepR expression vectors reduced PAI-1 gene transcriptional activities to 70〜75% of control value, while the transcriptional activities were up-regulated 1.8〜2 fold by transfection with leptin and long-form LepR expression vectors. These results suggested that decreased PAI-1 gene expression by leptin treatment was due to the short-form LepR signaling-mediated mechanisms.
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