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

Abstract

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.

Nitric oxide balances osteoblast and adipocyte lineage differentiation via the JNK/MAPK signaling pathway in periodontal ligament stem cells

“…Several studies have reported that JNK activity is specifically required for the initial stage of differentiation events of adipocytes and may act with a positive impact in adipogenesis differentiation [ 34 , 35 ]. Conversely, results from other studies have suggested that JNK activity may have the opposite effect on adipogenesis [ 36 – 38 ]. In our study, we found that, in both adipogenic and osteogenic differentiation processes, NO increased the phosphorylation of JNK/MAPK, and then p-JNK transportation to the nucleus induced the expression of osteogenic transcription factors and repressed the expression of adipogenic transcription factors, thus increasing osteogenesis and reducing adipogenesis.…”

IGFBP2 enhances adipogenic differentiation potentials of mesenchymal stem cells from Wharton's jelly of the umbilical cord via JNK and Akt signaling pathways

“…Moreover, the anti-adipogenesis effect of 6-thioinosine was mediated by decreased expression of PPARγ through JNK pathway. Loss of JNK1 activity resulted in resistance to high-fat diet-induced obesity in vivo [ 50 , 51 ]. In addition, Akt was also essential for inducing PPARγ and adipogenic differentiation; depletion of Akt impaired adipogenesis in mice [ 39 – 41 ].…”

PPARs: Protectors or Opponents of Myocardial Function?

“…PPAR γ is detected in several tissues and it is upregulated by various factors, such as C/EBPs [ 38 , 39 ], estrogen [ 40 ], MEK/ERK signaling [ 41 ], c-Fos [ 42 ], TGF- β [ 43 ], Smad1 [ 44 ], p38 kinase, early growth-response factor-1 (Egr-1) [ 45 ], polyunsaturated fatty acids [ 19 , 46 , 47 ], the orphan nuclear receptor ROR α [ 48 ], the zinc-finger protein Zfp423 [ 49 ], and vitamin E [ 50 ]. Downregulation of PPAR γ is mediated by multiple factors including LPS [ 51 , 52 ], JNK [ 53 – 55 ], TNF α [ 56 – 59 ], IL-11 [ 58 ], CCAAT/enhancer-binding protein homologous protein (CHOP) [ 60 ], retinoic acid [ 33 , 61 ], estrogen receptor- (ER-) α [ 62 ], the JAK/STAT pathway [ 23 , 38 , 39 ], interferon-gamma [ 51 , 63 ], leptin [ 64 ], angiotensin II [ 26 ], fasting [ 65 ], and androgens [ 66 ]. Krüppel-like factors (KLFs) have also been shown to affect PPAR γ and lipid metabolism in different ways.…”