Cilostazol increases 3T3-L1 preadipocyte differentiation with improved glucose uptake associated with activation of peroxisome proliferator-activated receptor-γ transcription

In the present study, we assessed that cilostazol stimulates differentiation of 3T3-L1 fibroblasts into adipocytes, and to improve insulin sensitivity in conjunction with PPARγ transcriptional activity. Upon treatment of COS-7 cells and human umbilical vein endothelial cells (HUVECs) with cilostazol (10 and 30 μM), endogenous PPARγ transcriptional activity was significantly elevated in both cells as did rosiglitazone (10 μM), and these effects were suppressed by 5 μM GW9662, an antagonist of PPARγ activity. Cilostazol-induced 3T3-L1 fibroblast differentiation into adipocytes in concert with increases in expression of PPARγ responsive genes such as CCAAT enhancer binding protein α (C-EBPα), aP2, which were accompanied by increased adiponectin and decreased resistin expressions as did rosiglitazone. These variables were strongly suppressed by GW9662, indicative of a PPARγ-mediated signaling. GLUT4 protein expression and glucose uptake were significantly elevated by cilostazol as was by rosiglitazone, which were also attenuated by GW9662, indicative of improvement of insulin sensitivity. Signaling pathways involved in the cilostazol-stimulated PPARγ transcription activity in HUVECs included phosphatidylinositol 3-kinase (PI3-kinase)/AKT. Taken together, it is suggested that cilostazol increases differentiation of 3T3-L1 fibroblasts into adipocytes, and improves insulin sensitivity by stimulating PPARγ transcription.