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Plasminogen activator inhibitor-1 modulates adipocyte differentiation
Departments of 1 Pathology, 2 Medicine, and 4 Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee; and 3 Laboratory for Pharmaceutical Biology and Phytopharmacology, Katholieke Universiteit Leuven, Leuven, Belgium Submitted 29 December 2004 ; accepted...
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Published in: | American journal of physiology: endocrinology and metabolism 2006-01, Vol.290 (1), p.E103-E113 |
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Main Authors: | , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
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Online Access: | Get full text |
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Summary: | Departments of 1 Pathology, 2 Medicine, and 4 Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee; and 3 Laboratory for Pharmaceutical Biology and Phytopharmacology, Katholieke Universiteit Leuven, Leuven, Belgium
Submitted 29 December 2004
; accepted in final form 29 July 2005
Increased plasminogen activator inhibitor-1 (PAI-1) is linked to obesity and insulin resistance. However, the functional role of PAI-1 in adipocytes is unknown. This study was designed to investigate effects and underlying mechanisms of PAI-1 on glucose uptake in adipocytes and on adipocyte differentiation. Using primary cultured adipocytes from PAI-1 +/+ and PAI-1 / mice, we found that PAI-1 deficiency promoted adipocyte differentiation, enhanced basal and insulin-stimulated glucose uptake, and protected against tumor necrosis factor- -induced adipocyte dedifferentiation and insulin resistance. These beneficial effects were associated with upregulated glucose transporter 4 at basal and insulin-stimulated states and upregulated peroxisome proliferator-activated receptor- (PPAR ) and adiponectin along with downregulated resistin mRNA in differentiated PAI-1 / vs. PAI-1 +/+ adipocytes. Similarly, inhibition of PAI-1 with a neutralizing anti-PAI-1 antibody in differentiated 3T3-L1 adipocytes further promoted adipocyte differentiation and glucose uptake, which was associated with increased expression of transcription factors PPAR , CCAAT enhancer-binding protein- (C/EBP ), and the adipocyte-selective fatty acid-binding protein aP2, thus mimicking the phenotype in PAI-1 / primary adipocytes. Conversely, overexpression of PAI-1 by adenovirus-mediated gene transfer in 3T3-L1 adipocytes inhibited differentiation and reduced PPAR , C/EBP , and aP2 expression. This was also associated with a decrease in urokinase-type plasminogen activator mRNA expression, decreased plasmin activity, and increased collagen I mRNA expression. Collectively, these results indicate that absence or inhibition of PAI-1 in adipocytes protects against insulin resistance by promoting glucose uptake and adipocyte differentiation via increased PPAR expression. We postulate that these PAI-1 effects on adipocytes may, at least in part, be mediated via modulation of plasmin activity and extracellular matrix components.
plasminogen activator inhibitor-1; peroxisome proliferator-activated receptor- ; adipocyte differentiation; glucose uptake; insulin resistance
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ISSN: | 0193-1849 1522-1555 |
DOI: | 10.1152/ajpendo.00605.2004 |