Deficiency of urokinase plasminogen activator delays the development of diet-induced obesity and associated metabolic pathologies.

Obesity is a global health issue that contributes to many pathologies such as metabolic dysfunction-associated steatotic liver disease (MASLD), hypercholesterolemia, insulin resistance and dysregulation of coagulation and fibrinolysis that ultimately increases the risk of cardiovascular diseases. Recent studies suggest a reciprocal role of coagulation and fibrinolytic proteins regulating the development of obesity and associated pathologies. Current studies in our lab indicate that plasmin, the main fibrinolytic protease, exacerbates high-fat diet (HFD)-induced metabolic abnormalities without impacting weight gain. However, the impact of pathways upstream of plasminogen activation on diet-induced obesity (DIO) and metabolic pathologies remains unclear. To determine the role of urokinase plasminogen activator (uPA), which converts plasminogen to plasmin, in DIO and metabolic sequalae, wildtype (Plau+/+) and uPA-deficient mice (Plau-/-) were challenged with a low-fat diet (LFD) or HFD. Plau-/- mice were initially protected from HFD-induced weight gain, but had similar weights compared to Plau+/+ mice by the end of 20 weeks. Consistently, compared to HFD-fed Plau+/+ mice, HFD-fed Plau-/- mice had significantly reduced levels of hepatic triglycerides after 14 weeks, but not after 20 weeks. However, HFD-fed Plau-/- mice maintained the smaller liver mass and reduced circulating level of alanine aminotransferase, a marker of hepatocellular damage, compared to HFD-fed Plau+/+ mice after 20 weeks. HFD-fed Plau-/- mice also performed significantly better than HFD-fed Plau+/+ mice in glucose and insulin tolerance tests. Our findings indicate that uPA deficiency protects against the initial development of obesity and associated pathologies, but not against prolonged HFD challenge.