To test the functional significance of the increase in liver tPA in obesity, we silenced hepatocyte tPA in obese mice using hepatocyte-specific shRNA (AAV8-H1-shPlat) (13), titrating the dosage of the virus to lower hepatic Plat close to the level in lean mice, but not lower (Figure 1A). Here, PLAT is linked to obesity due to melanocortin 4 receptor deficiency.