Influence of PAI-1 on adipose tissue growth and metabolic parameters in a murine model of diet-induced obesity

An increased plasma plasminogen activator inhibitor-1 (PAI-I) level is a ri sk factor for myocardial infarction, particularly when associated with visc eral obesity. Although the link between PAI-I and obesity is well documente d, 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-I-/-) a nd wild-type littermates (PAI-1(+/+)) in a model of nutritionally induced o besity. 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 mic e chat were kept on a standard fat diet (P<0.0001). This weight gain was ac companied 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 incr ease in PAI-1 antigen (5.1+/-0.56 versus 2+/-0.22 ng/mL P<0.001), fasting i nsulinemia (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 w ere not affected. When we compared PAI-1(-/-) and PAI-1(+/+) mice on the HF D, PAI-1(-/-) mice gained weight faster than did PAI-1(+/+) mice, with a si gnificant 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-I-/- mice. By contrast, the increase in the number of st roma cells presented by PAI-1(+/+) mice was not observed in PAI-1(-/-) mice , In obese PAT-1(-/-) mice, tissue-type PA activity and antigen levels in t he gonadal fat pad were significantly higher than in obese PAT-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 di splayed 62% higher insulin levels (P<0.05) than did PAI-1(+/+) mice. Obese PAX-I-/- mice displayed 68% higher triglyceride levels (P<0.01) and 21% low er 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 induct ion of obesity in mice. Moreover, PAI-1 influences glucidolipidic metabolis m. The elevated expression of PAI-1 observed in human obesity could, be inv olved in mechanisms that control adipose tissue development.