Anti-adipogenesis by 6-thioinosine is mediated by downregulation of PPAR gamma through JNK-dependent upregulation of iNOS

作者：Lee Jongsung; Jung Eunsun; Lee Jienny; Huh Sungran; Kim Young Soo; Kim Yong Woo; Kim Yeong Shik; Park Deokhoon

来源：Cellular and Molecular Life Sciences, 2010, 67(3): 467-481.

DOI：10.1007/s00018-009-0196-y

• 3T3-L1 adipocytes
• Adipocyte differentiation
• iNOS
• JNK
• PPAR gamma

Adipocyte dysfunction is associated with the development of obesity. This study shows that 6-thioinosine inhibits adipocyte differentiation. The mRNA levels of PPAR gamma and C/EBP alpha, but not C/EBP beta and delta, were reduced by 6-thioinosine. Moreover, the mRNA levels of PPAR gamma target genes (LPL, CD36, aP2, and LXR alpha) were down-regulated by 6-thioinosine. We also demonstrated that 6-thioinosine inhibits the transactivation activity and the mRNA level of PPAR gamma. Additionally, attempts to elucidate a possible mechanism underlying the 6-thioinosine-mediated effects revealed that 6-thioinosine induced iNOS gene expression without impacting eNOS expression, and that this was mediated through activation of AP-1, especially, JNK. In addition, 6-thioinosine was found to operate upstream of MEKK-1 in JNK activation signaling. Taken together, these findings suggest that the inhibition of adipocyte differentiation by 6-thioinosine occurs primarily through the reduced expression of PPAR gamma, which is mediated by upregulation of iNOS via the activation of JNK.

• 出版日期2010-2