title: Plasminogen activator inhibitor-1 modulates adipocyte differentiation.
abstract: 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-alpha-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-gamma (PPARgamma) 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 PPARgamma, CCAAT enhancer-binding protein-alpha (C/EBPalpha), 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 PPARgamma, C/EBPalpha, 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 PPARgamma 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.
authors.affiliation: Department of Pathology, Vanderbilt University School of Medicine, Nashville, TN 37232-2561, USA.
authors.forename: Xiubin
authors.initials: X
authors.lastname: Liang
authors.forename: Talerngsak
authors.initials: T
authors.lastname: Kanjanabuch
authors.forename: Su-Li
authors.initials: SL
authors.lastname: Mao
authors.forename: Chuan-Ming
authors.initials: CM
authors.lastname: Hao
authors.forename: Yi-Wei
authors.initials: YW
authors.lastname: Tang
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Declerck
authors.forename: Alyssa H
authors.initials: AH
authors.lastname: Hasty
authors.forename: David H
authors.initials: DH
authors.lastname: Wasserman
authors.forename: Agnes B
authors.initials: AB
authors.lastname: Fogo
authors.forename: Li-Jun
authors.initials: LJ
authors.lastname: Ma
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D052242:Adiponectin / Q000235:genetics; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D024042:Collagen Type I / Q000235:genetics; D050556:Fatty Acid-Binding Proteins / Q000378:metabolism; D005341:Fibrinolysin / Q000378:metabolism; D015870:Gene Expression / Q000235:genetics; D005947:Glucose / Q000378:metabolism / Q000493:pharmacokinetics; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D052243:Resistin / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics
chemical_list: D052242:Adiponectin; D000911:Antibodies, Monoclonal; D022763:CCAAT-Enhancer-Binding Protein-alpha; D024042:Collagen Type I; D050556:Fatty Acid-Binding Proteins; D051275:Glucose Transporter Type 4; D007328:Insulin; D047495:PPAR gamma; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D052243:Resistin; C051321:SERPINE1 protein, human; C495693:Slc2a4 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator; D005947:Glucose