Ceramide inhibits insulin-stimulated Akt phosphorylation through activation of Rheb/mTORC1/S6K signaling in skeletal muscle

Chang Ting Hsieh, Jen Hua Chuang, Wen Chin Yang, Yi Yin, Yenshou Lin

研究成果: 雜誌貢獻文章

22 引文 斯高帕斯(Scopus)


Ceramide is a negative regulator of insulin activity. At the molecular level, it causes a decrease in insulin-stimulated Akt Ser473 phosphorylation in C2C12 myotubes. Interestingly, we found that the phosphorylation of S6K at Thr389 was increased under the same conditions. Utilizing both rapamycin to inhibit mTORC1 activity and shRNA to knock down Rheb, we demonstrated that the decrease in Akt Ser473 phosphorylation stimulated by insulin after C2-ceramide incubation can be prevented. The mechanism by which C2-ceramide impairs signaling would seem to involve a negative feedback of activated S6K via phosphorylation of insulin receptor substrate-1 at Ser636/639, since S6K inhibitor can block this phenomenon. Finally, rapamycin treatment was found not to affect C2-ceramide-induced PKCζ activation, suggesting that the pathway revealed in this study is parallel to the one involving PKCζ activation. We proposed a novel pathway/mechanism involving Rheb/mTORC1/S6K signaling to explain how C2-ceramide impairs insulin signaling via Akt phosphorylation. The existence of multiple pathways involved in insulin signaling impairment by C2-ceramide treatment implies that different strategies might be needed to ameliorate insulin resistance caused by C2-ceramide.

頁(從 - 到)1400-1408
期刊Cellular Signalling
出版狀態已發佈 - 2014 七月


ASJC Scopus subject areas

  • Cell Biology