SMAD3 and Glucose intolerance: In addition, exposure of the cells to palmitate increases SMAD3 levels and causes a robust elevation in the expression of its target gene SERPINE1 and its encoded protein plasminogen activator inhibitor 1 (PAI-1), with this effect prevented by leptomycin B. Consistent with this, Gdf15−/− mice fed a high-fat diet (HFD) show increased glucose intolerance and elevated levels of SMAD3 and PAI-1 in their skeletal muscle compared to HFD-fed wild-type (WT) mice.