title: Prevention of obesity and insulin resistance in mice lacking plasminogen activator inhibitor 1.
abstract: Increased plasminogen activator inhibitor 1 (PAI-1) has been linked to not only thrombosis and fibrosis but also to obesity and insulin resistance. Increased PAI-1 levels have been presumed to be consequent to obesity. We investigated the interrelationships of PAI-1, obesity, and insulin resistance in a high-fat/high-carbohydrate (HF) diet-induced obesity model in wild-type (WT) and PAI-1-deficient mice (PAI-1(-/-)). Obesity and insulin resistance developing in WT mice on an HF diet were completely prevented in mice lacking PAI-1. PAI-1(-/-) mice on an HF diet had increased resting metabolic rates and total energy expenditure compared with WT mice, along with a marked increase in uncoupling protein 3 mRNA expression in skeletal muscle, likely mechanisms contributing to the prevention of obesity. In addition, insulin sensitivity was enhanced significantly in PAI-1(-/-) mice on an HF diet, as shown by euglycemic-hyperinsulinemic clamp studies. Peroxisome proliferator-activated receptor (PPAR)-gamma and adiponectin mRNA, key control molecules in lipid metabolism and insulin sensitivity, were maintained in response to an HF diet in white adipose tissue in PAI-1(-/-) mice, contrasting with downregulation in WT mice. This maintenance of PPAR-gamma and adiponectin may also contribute to the observed maintenance of body weight and insulin sensitivity in PAI-1(-/-) mice. Treatment in WT mice on an HF diet with the angiotensin type 1 receptor antagonist to downregulate PAI-1 indeed inhibited PAI-1 increases and ameliorated diet-induced obesity, hyperglycemia, and hyperinsulinemia. PAI-1 deficiency also enhanced basal and insulin-stimulated glucose uptake in adipose cells in vitro. Our data suggest that PAI-1 may not merely increase in response to obesity and insulin resistance, but may have a direct causal role in obesity and insulin resistance. Inhibition of PAI-1 might provide a novel anti-obesity and anti-insulin resistance treatment.
authors.affiliation: Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Li-Jun
authors.initials: LJ
authors.lastname: Ma
authors.forename: Su-Li
authors.initials: SL
authors.lastname: Mao
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Taylor
authors.forename: Talerngsak
authors.initials: T
authors.lastname: Kanjanabuch
authors.forename: YouFei
authors.initials: Y
authors.lastname: Guan
authors.forename: YaHua
authors.initials: Y
authors.lastname: Zhang
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Brown
authors.forename: Larry L
authors.initials: LL
authors.lastname: Swift
authors.forename: Owen P
authors.initials: OP
authors.lastname: McGuinness
authors.forename: David H
authors.initials: DH
authors.lastname: Wasserman
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Vaughan
authors.forename: Agnes B
authors.initials: AB
authors.lastname: Fogo
mesh_terms: D052242:Adiponectin; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D002153:Calorimetry, Indirect; D002352:Carrier Proteins / Q000235:genetics; D004195:Disease Models, Animal; D015309:Glucose Clamp Technique; D006946:Hyperinsulinism; D007328:Insulin / Q000008:administration & dosage / Q000494:pharmacology; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins; D007473:Ion Channels; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins; D009765:Obesity / Q000097:blood / Q000235:genetics / Q000517:prevention & control*; D017395:Plasminogen Activator Inhibitor 1 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D014158:Transcription, Genetic; D014280:Triglycerides / Q000097:blood / Q000378:metabolism; D000071256:Uncoupling Protein 1; D015430:Weight Gain
chemical_list: D052242:Adiponectin; D001786:Blood Glucose; D002352:Carrier Proteins; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D007473:Ion Channels; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D017395:Plasminogen Activator Inhibitor 1; D011506:Proteins; D012333:RNA, Messenger; D014280:Triglycerides; D000071256:Uncoupling Protein 1