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.
Lee
Jongsung
J
Biospectrum Life Science Institute, Gunpo City, Gyunggi Do 435-833, Republic of Korea.
Jung
Eunsun
E
Lee
Jienny
J
Huh
Sungran
S
Kim
Young-Soo
YS
Kim
Yong-Woo
YW
Kim
Yeong Shik
YS
Park
Deokhoon
D
D041721:3T3-L1 Cells; D050156:Adipogenesis / Q000187:drug effects*; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D048728:MAP Kinase Kinase Kinase 1 / Q000378:metabolism; D051379:Mice; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology; D013868:Thioinosine / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
D000873:Anthracenes; D000964:Antimetabolites, Antineoplastic; D022763:CCAAT-Enhancer-Binding Protein-alpha; D047495:PPAR gamma; D014409:Tumor Necrosis Factor-alpha; C432165:pyrazolanthrone; D013868:Thioinosine; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D048031:JNK Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1