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1 Department of Pathology, Vanderbilt University School of Medicine, Nashville, TN, USA
2 Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
3 Department of Pathology, Vanderbilt University School of Medicine, Nashville, TN, USA; Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
4 Laboratory for Pharmaceutical Biology and Phytopharmacology, Katholieke Universiteit Leuven, Leuven, Belgium
5 Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA
* To whom correspondence should be addressed. E-mail: lijun.ma{at}vanderbilt.edu.
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-
(TNF-)-induced adipocyte de-differentiation and insulin resistance. These beneficial effects were associated with upregulated glucose transporter 4 (GLUT4) 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 PPARCCAAT-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 (uPA) 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.
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