Disruption of the plasminogen activator inhibitor‐1 gene reduces the adiposity and improves the metabolic profile of genetically obese and diabetic ob/ob mice

• Published in: The FASEB journal 2001-08, Vol.15 (10), p.1840-1842
• Main Authors: Schäfer, Katrin, Fujisawa, Kazuhiku, Konstantinides, Stavros, Loskutoff, David J.
• Format: Article
• Language: English
• Subjects: Adipose Tissue - metabolism; animal models; Animals; Body Composition; Diabetes Mellitus - metabolism; gene disruption; Gene Expression; Hyperglycemia - etiology; Hyperglycemia - prevention & control; Hyperinsulinism - etiology; Hyperinsulinism - prevention & control; insulin resistance; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; obesity; Obesity - complications; Obesity - metabolism; Plasminogen Activator Inhibitor 1 - deficiency; Plasminogen Activator Inhibitor 1 - genetics; Plasminogen Activator Inhibitor 1 - physiology; tumor necrosis factor α; Tumor Necrosis Factor-alpha - genetics
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.00-0750fje

ABSTRACT Elevated levels of plasma and adipose tissue plasminogen activator inhibitor‐1 (PAI‐1) are observed frequently in obese humans and rodents. In this report, genetically obese (ob/ob) mice lacking the PAI‐1 gene (PAI‐1−/−) were generated and then used to test the hypothesis that the presence of PAI‐1 promotes the hyperglycemia, hyperinsulinemia, and insulin resistance associated with obesity. Both wild‐type (WT) ob/ob and PAI‐1−/− ob/ob mice developed substantial adiposity compared with their lean counterparts. However, the PAI‐1−/− ob/ob mice weighed significantly less than the WT ob/ob mice, and their hyperglycemia and hyperinsulinemia improved significantly. Although intraperitoneal glucose administration resulted in a dramatic increase in serum insulin levels in WT ob/ob mice, the increase in PAI‐1−/−ob/ob mice was relatively small. Reverse transcription polymerase chain reaction assays and in situ hybridization studies demonstrated that tumor necrosis factor α (TNF‐α) mRNA expression increased significantly in the adipose tissue of WT ob/ob mice at most ages tested. However, it was not increased, or only mildly increased, in the adipose tissue of the PAI‐1−/− ob/ob mice. The concentration and rate of secretion of TNF‐α protein in adipose tissue from PAI‐1−/− ob/ob mice also were significantly lower compared with their WT ob/ob counterparts as shown by immunohistochemistry and ELISA. These results suggest that PAI‐1 contributes to the development of the characteristic hyperglycemia and hyperinsulinemia associated with murine obesity, possibly by facilitating increased adipose tissue TNF‐α gene expression.