On the role of plasminogen activator inhibitor-1 in adipose tissue development and insulin resistance in mice

OBJECTIVES: To investigate the role of plasminogen activator inhibitor-1 (PAI-1) in adipose tissue development and insulin metabolism. METHODS: Aged male wild-type (WT) or transgenic mice with adipose tissue overexpression of PAI-1 (45-55 weeks) in 50% C57Bl/6: 50% Friend Virus B-strain (FVB) genetic background, kept on normal chow, were used without or with administration of a synthetic low molecular weight PAI-1 inhibitor (PAI-039) to the food (1 mg g(-1)) for 4 weeks. RESULTS: The PAI-1 transgenic mice showed somewhat lower body weight and adipose tissue mass than WT mice, whereas fasting insulin levels were higher. Glucose and insulin tolerance tests did not reveal significant differences between both genotypes. Addition of PAI-039 to the food did not significantly affect total body fat, weight of the isolated s.c. and gonadal fat territories or their adipocyte size and blood vessel composition in either genotype. Fasting glucose levels and glucose tolerance tests were, for both genotypes, comparable with those without inhibitor treatment. Insulin levels and insulin tolerance tests in WT, but not in PAI-1 transgenic mice, suggested a higher insulin sensitivity after inhibitor treatment (insulin level 30 min after glucose injection of 2.0 +/- 0.17 ng mL(-1) vs. 3.2 +/- 0.48 ng mL(-1) without inhibitor treatment; P = 0.028). CONCLUSIONS: In this model, overexpression of PAI-1 moderately impaired adipose tissue formation without affecting glucose or insulin tolerance. Administration of a synthetic PAI-1 inhibitor for 4 weeks did not affect adipose tissue development in WT or PAI-1 transgenic mice, but induced a higher insulin sensitivity in WT mice.