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

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/EBPalpha, but not C/EBPbeta and delta, were reduced by 6-thioinosine. Moreover, the mRNA levels of PPAR gamma target genes (LPL, CD36, aP2, and LXRalpha) 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.

Citation

Jongsung Lee, Eunsun Jung, Jienny Lee, Sungran Huh, Young-Soo Kim, Yong-Woo Kim, Yeong Shik Kim, Deokhoon Park. Anti-adipogenesis by 6-thioinosine is mediated by downregulation of PPAR gamma through JNK-dependent upregulation of iNOS. Cellular and molecular life sciences : CMLS. 2010 Feb;67(3):467-81

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PMID: 19941061

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