Together, these data provide support for a pathway in which the increase in hepatocyte PAI-1 in obesity, mediated at least in part by suppression of Rev-Erbα, activates an LRP1/PKA/p-CREB/PLAT pathway that lessens the magnitude of the PAI-1–mediated decrease in fibrinolysis in obesity. Here, SERPINE1 is linked to obesity due to melanocortin 4 receptor deficiency.