Abstract 719: Identification of Insulin Receptor Substrate Proteins Mediating PAI-1 Production in IRS-1 Null Mice
Obesity is associated with dysfunctional insulin receptor substrate (IRS)-1 pathway and compensatory hyperinsulinemia. Insulin can stimulate production of plasminogen activator inhibitor (PAI)-1, the physiologic inhibitor of fibrinolysis, in adipocytes. Because hypofibrinolysis by PAI-1 confers cardiovascular risk, role of IRS-1-mediated signaling in PAI-1 expression was elucidated in IRS-1 knockout (KO) mice. PAI-1 mRNA was increased by 10-fold in adipose tissue of IRS-1 KO (P<0.001). Abdominal adipocyes isolated from IRS-1 KO released 11-fold more PAI-1 to the conditioned media (P<0.001), indicating increased PAI-1 production in IRS-1 KO. IRS-2 was barely detectable in abdominal adipose tissue of IRS-1 KO. In contrast, IRS-3 was increased by 60% in IRS-1 KO, suggesting that IRS-3-mediated pathway was compensating for the lack of IRS-1 in adipose tissue. PAI-1 mRNA was increased in IRS-1 heart and perivascular fibrosis was persistently augmented, suggesting that PAI-1 can contribute to coronary arterial remodeling. In IRS-1 KO cardiac expressions of IRS-2 and p85, a substrate of IRS-2, were increase by 2.7 and 2.4 fold over control and active JNK1 was increased by 1.36 fold and active JNK2 was increased by 2.18 fold, suggesting the presence of compensatory IRS-2-mediated pathway. Thus, impaired IRS-1 mediated signaling can be compensated by diverse alternative pathways in IRS-1 KO. These alternative pathways may contribute to persistent PAI-1 expression and hypofibrinlysis in the setting of hyperinsulinemia in obesity.