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Publication
Prevention of obesity and insulin resistance in mice lacking plasminogen
activator inhibitor 1.
Authors Ma LJ, Mao SL, Taylor KL, Kanjanabuch T, Guan Y, Zhang Y, Brown NJ, Swift LL,
McGuinness OP, Wasserman DH, Vaughan DE, Fogo AB
Submitted By Agnes Fogo on 11/6/2007
Status Published
Journal Diabetes
Year 2004
Date Published 2/1/2004
Volume : Pages 53 : 336 - 346
PubMed Reference 14747283
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.








Genes
SymbolDescription
Pparaperoxisome proliferator activated receptor alpha
Ppargperoxisome proliferator activated receptor gamma
Serpine1serine (or cysteine) proteinase inhibitor, clade E (nexin, plasminogen activator inhibitor type 1), member 1
Serpine2serine (or cysteine) proteinase inhibitor, clade E (nexin, plasminogen activator inhibitor type 1), member 2
Adipoqadiponectin, C1Q and collagen domain containing

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