14747283

pubmed:Citation

2

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.

eng

AIM

MEDLINE

0012-1797

Print

NLM

336-46

pubmed-meshheading:14747283-Adiponectin, pubmed-meshheading:14747283-Animals, pubmed-meshheading:14747283-Blood Glucose, pubmed-meshheading:14747283-Calorimetry, Indirect, pubmed-meshheading:14747283-Carrier Proteins, pubmed-meshheading:14747283-Disease Models, Animal, pubmed-meshheading:14747283-Glucose Clamp Technique, pubmed-meshheading:14747283-Hyperinsulinism, pubmed-meshheading:14747283-Insulin, pubmed-meshheading:14747283-Insulin Resistance, pubmed-meshheading:14747283-Intercellular Signaling Peptides and Proteins, pubmed-meshheading:14747283-Ion Channels, pubmed-meshheading:14747283-Male, pubmed-meshheading:14747283-Membrane Proteins, pubmed-meshheading:14747283-Mice, pubmed-meshheading:14747283-Mice, Knockout, pubmed-meshheading:14747283-Mitochondrial Proteins, pubmed-meshheading:14747283-Obesity, pubmed-meshheading:14747283-Plasminogen Activator Inhibitor 1, pubmed-meshheading:14747283-Polymerase Chain Reaction, pubmed-meshheading:14747283-Proteins, pubmed-meshheading:14747283-RNA, Messenger, pubmed-meshheading:14747283-Transcription, Genetic, pubmed-meshheading:14747283-Triglycerides, pubmed-meshheading:14747283-Weight Gain

Prevention of obesity and insulin resistance in mice lacking plasminogen activator inhibitor 1.

Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't