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Prevention of obesity and insulin resistance in mice lacking plasminogen activator inhibitor 1.
Diabetes 2004; 53(2):336-46D

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+Show Affiliations

Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

14747283

Citation

Ma, Li-Jun, et al. "Prevention of Obesity and Insulin Resistance in Mice Lacking Plasminogen Activator Inhibitor 1." Diabetes, vol. 53, no. 2, 2004, pp. 336-46.
Ma LJ, Mao SL, Taylor KL, et al. Prevention of obesity and insulin resistance in mice lacking plasminogen activator inhibitor 1. Diabetes. 2004;53(2):336-46.
Ma, L. J., Mao, S. L., Taylor, K. L., Kanjanabuch, T., Guan, Y., Zhang, Y., ... Fogo, A. B. (2004). Prevention of obesity and insulin resistance in mice lacking plasminogen activator inhibitor 1. Diabetes, 53(2), pp. 336-46.
Ma LJ, et al. Prevention of Obesity and Insulin Resistance in Mice Lacking Plasminogen Activator Inhibitor 1. Diabetes. 2004;53(2):336-46. PubMed PMID: 14747283.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Prevention of obesity and insulin resistance in mice lacking plasminogen activator inhibitor 1. AU - Ma,Li-Jun, AU - Mao,Su-Li, AU - Taylor,Kevin L, AU - Kanjanabuch,Talerngsak, AU - Guan,YouFei, AU - Zhang,YaHua, AU - Brown,Nancy J, AU - Swift,Larry L, AU - McGuinness,Owen P, AU - Wasserman,David H, AU - Vaughan,Douglas E, AU - Fogo,Agnes B, PY - 2004/1/30/pubmed PY - 2004/4/2/medline PY - 2004/1/30/entrez SP - 336 EP - 46 JF - Diabetes JO - Diabetes VL - 53 IS - 2 N2 - 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. SN - 0012-1797 UR - https://www.unboundmedicine.com/medline/citation/14747283/Prevention_of_obesity_and_insulin_resistance_in_mice_lacking_plasminogen_activator_inhibitor_1_ L2 - http://diabetes.diabetesjournals.org/cgi/pmidlookup?view=long&pmid=14747283 DB - PRIME DP - Unbound Medicine ER -