Prevention of Obesity and Insulin Resistance in Mice Lacking Plasminogen Activator Inhibitor 1
Prevention of Obesity and Insulin Resistance in Mice Lacking Plasminogen Activator Inhibitor 1 Li-Jun Ma 1 , Su-Li Mao 1 , Kevin L. Taylor 1 , Talerngsak Kanjanabuch 1 , YouFei Guan 2 , YaHua Zhang 2 , Nancy J. Brown 2 , Larry L. Swift 1 , Owen P. McGuinness 3 , David H. Wasserman 3 , Douglas E. Vau...
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Veröffentlicht in: | Diabetes (New York, N.Y.) N.Y.), 2004-02, Vol.53 (2), p.336-346 |
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Zusammenfassung: | Prevention of Obesity and Insulin Resistance in Mice Lacking Plasminogen Activator Inhibitor 1
Li-Jun Ma 1 ,
Su-Li Mao 1 ,
Kevin L. Taylor 1 ,
Talerngsak Kanjanabuch 1 ,
YouFei Guan 2 ,
YaHua Zhang 2 ,
Nancy J. Brown 2 ,
Larry L. Swift 1 ,
Owen P. McGuinness 3 ,
David H. Wasserman 3 ,
Douglas E. Vaughan 2 and
Agnes B. Fogo 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
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
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)-γ
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-γ 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 u |
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ISSN: | 0012-1797 1939-327X |
DOI: | 10.2337/diabetes.53.2.336 |