Cilostazol increases 3T3-L1 preadipocyte differentiation with improved glucose uptake associated with activation of peroxisome proliferator-activated receptor-gamma 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 PPARgamma transcriptional activity. Upon treatment of COS-7 cells and human umbilical vein endothelial cells (HUVECs) with cilostazol (10 and 30 microM), endogenous PPARgamma transcriptional activity was significantly elevated in both cells as did rosiglitazone (10 microM), and these effects were suppressed by 5 microM GW9662, an antagonist of PPARgamma activity. Cilostazol-induced 3T3-L1 fibroblast differentiation into adipocytes in concert with increases in expression of PPARgamma responsive genes such as CCAAT enhancer binding protein alpha (C-EBPalpha), aP2, which were accompanied by increased adiponectin and decreased resistin expressions as did rosiglitazone. These variables were strongly suppressed by GW9662, indicative of a PPARgamma-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 PPARgamma 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 PPARgamma transcription.
Park
So Youn
SY
Department of Pharmacology, College of Medicine, Pusan National University, Seo-Gu, Busan, Republic of Korea.
Lee
Jeong Hyun
JH
Kim
Ki Young
KY
Kim
Eun Kyoung
EK
Yun
Sung Ji
SJ
Kim
Chi Dae
CD
Lee
Won Suk
WS
Hong
Ki Whan
KW
D041721:3T3-L1 Cells; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D019556:COS Cells; D002454:Cell Differentiation; D002522:Chlorocebus aethiops; D000077407:Cilostazol; D005347:Fibroblasts / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D051379:Mice; D047495:PPAR gamma / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D000077154:Rosiglitazone; D013777:Tetrazoles / Q000494:pharmacology*; D045162:Thiazolidinediones / Q000494:pharmacology
C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D010726:Phosphodiesterase Inhibitors; C495693:Slc2a4 protein, mouse; D013777:Tetrazoles; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D005947:Glucose; D000077407:Cilostazol