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, Yen-Shou Lin

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1400-1408
Number of pages9
JournalCellular Signalling
Volume26
Issue number7
DOIs
Publication statusPublished - 2014 Jan 1

Fingerprint

Ceramides
Skeletal Muscle
Phosphorylation
Insulin
Sirolimus
Insulin Receptor Substrate Proteins
Skeletal Muscle Fibers
Small Interfering RNA
Insulin Resistance
mechanistic target of rapamycin complex 1
N-acetylsphingosine

Keywords

  • C2-ceramide
  • Insulin resistance
  • MTORC1
  • MTORC2
  • Myotubes

ASJC Scopus subject areas

  • Cell Biology

Cite this

Ceramide inhibits insulin-stimulated Akt phosphorylation through activation of Rheb/mTORC1/S6K signaling in skeletal muscle. / Hsieh, Chang Ting; Chuang, Jen Hua; Yang, Wen Chin; Yin, Yi; Lin, Yen-Shou.

In: Cellular Signalling, Vol. 26, No. 7, 01.01.2014, p. 1400-1408.

Research output: Contribution to journalArticle

Hsieh, Chang Ting ; Chuang, Jen Hua ; Yang, Wen Chin ; Yin, Yi ; Lin, Yen-Shou. / Ceramide inhibits insulin-stimulated Akt phosphorylation through activation of Rheb/mTORC1/S6K signaling in skeletal muscle. In: Cellular Signalling. 2014 ; Vol. 26, No. 7. pp. 1400-1408.
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