A Noncanonical Role for Plasminogen Activator Inhibitor Type 1 in Obesity-Induced Diabetes

Obesity is a major risk factor for type 2 diabetes because of chronic hepatic inflammation and resultant insulin resistance. Hepatocyte growth factor (HGF) is responsible for resetting hepatic homeostasis after injury following activation by urokinase-type plasminogen activator (u-PA; encoded by the PLAU gene). Plasminogen activator inhibitor type-1 (PAI-1; encoded by the SERPINE1 gene), a u-PA inhibitor and antifibrinolytic agent, is often elevated in obesity and is linked to cardiovascular events. We hypothesized that, in addition to its role in preventing fibrinolysis, elevated PAI-1 inhibits HGF's activation by u-PA and the resultant anti-inflammatory and hepatoprotective properties. Wild-type and PAI-1 knockout (KO) mice on a high-fat diet both became significantly heavier than lean controls; however, the obese KO mice demonstrated improved glucose metabolism compared with wild-type mice. Obese KO mice also exhibited an increase in conversion of latent single-chain HGF to active two-chain HGF, coinciding with an increase in the phosphorylation of HGF receptor, MET, as well as dampened inflammation. These results strongly suggest that, in addition to its other functions, PAI-mediated inhibition of HGF activation prohibits the resolution of inflammation in the context of obesity-induced type 2 diabetes.