An increased plasma plasminogen activator inhibitor-1 (PAI-1) level is a risk factor for myocardial infarction, particularly when associated with visceral obesity. Although the link between PAI-1 and obesity is well documented, little is known about the physiological relevance of PAI-1 production by adipose tissue. Therefore, we have compared adipose tissue development and insulin resistance plasma parameters in PAI-1-deficient mice (PAI-1(-/-)) and wild-type littermates (PAI-1(+/+)) in a model of nutritionally induced obesity. After 17 weeks of consuming a high-fat diet (HFD), PAI-1(+/+) mice showed marked obesity, with a 52% increase in body weight compared with mice that were kept on a standard fat diet (P<0.0001). This weight gain was accompanied by adipocyte hypertrophy and an increase in the number of stroma cells in the gonadal fat pad, expressed as stroma cells/adipocytes (0.67+/-0.05 versus 0.43+/-0. 02; P<0.001). In plasma, the HFD induced a marked increase in PAI-1 antigen (5.1+/-0.56 versus 2+/-0.22 ng/mL; P<0.001), fasting insulinemia (1.1+/-0.21 versus 0.21+/-0.04 ng/mL; P<0.001), and glycemia (7.4+/-0.5 versus 5+/-0.3 mmol/L; P<0.001), whereas plasma triglyceride levels were not affected. When we compared PAI-1(-/-) and PAI-1(+/+) mice on the HFD, PAI-1(-/-) mice gained weight faster than did PAI-1(+/+) mice, with a significant difference in body weight between 3 and 8 weeks of the diet (32+/-1.7 versus 26+/-1.6 g at 6 weeks; P<0.05). After 17 weeks of the HFD, its effect on weight gain and the number and size of adipocytes was similar in PAI-1(+/+) and PAI-1(-/-) mice. By contrast, the increase in the number of stroma cells presented by PAI-1(+/+) mice was not observed in PAI-1(-/-) mice. In obese PAI-1(-/-) mice, tissue-type PA activity and antigen levels in the gonadal fat pad were significantly higher than in obese PAI-1(+/+) mice (230+/-50 versus 47+/-20 arbitrary units/g, P<0.01; 40+/-13 versus 17+/-13 ng/g, P<0.05, respectively), whereas urokinase-type PA activity and antigen levels were similar in both groups. In plasma, nonobese PAI-1(-/-) mice displayed 62% higher insulin levels (P<0.05) than did PAI-1(+/+) mice. Obese PAI-1(-/-) mice displayed 68% higher triglyceride levels (P<0.01) and 21% lower glucose levels (P<0.05) than did PAI-1(+/+) mice. These data support an effect of PAI-1 on weight gain and adipose tissue cellularity in the induction of obesity in mice. Moreover, PAI-1 influences glucidolipidic metabolism. The elevated expression of PAI-1 observed in human obesity could be involved in mechanisms that control adipose tissue development.