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Diabetes 53:336-346, 2004
© 2004 by the American Diabetes Association, Inc.
Prevention of Obesity and Insulin Resistance in Mice Lacking Plasminogen Activator Inhibitor 1
1 Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee
2 Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
3 Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee
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)-
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- 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.
Address correspondence and reprint requests to Agnes B. Fogo, MD, MCN C3310, Department of Pathology, Vanderbilt University Medical Center, 21st and Garland Ave., Nashville, TN 37232-2561. E-mail: agnes.fogo{at}vanderbilt.edu
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