Submitted to: Molecular Endocrinology
Publication Type: Peer reviewed journal
Publication Acceptance Date: 5/13/2004
Publication Date: 5/13/2004
Citation: Gao, Z., Zhang, X., Zuberi, A., Hwang, D.H., Quon, M.J., Lefevre, M., Ye, J. Inhibition of insulin sensitivity by free fatty acids requires activation of multiple serine kinases in 3t3-l1 adipocytes. Molecular Endocrinology 18:2024-2034, (2004). Interpretive Summary:
Technical Abstract: Insulin receptor substrate (IRS) has been suggested as a molecular target of free fatty acids (FFAs) for insulin resistance. However, the signaling pathways by which FFAs lead to the inhibition of IRS function remain to be established. In this study, we explored FFA- signaling pathway that contributes to IRS-1 serine phosphorylation and degradation in adipocytes and in dietary obese mice. We observed that linoleic acid resulted in a reduction in insulin-induced glucose uptake in 3T3-L1 adipocytes. This mimics insulin resistance induced by high-fat-diet in C57BL/J mice. The reduction is associated with a decrease in IRS-1 protein abundance. IRS-1 decrease was proceeded by IRS-1 (Ser307) phosphorylation, which was associated with activation of serine kinases IKK and JNK. IKK and JNK were activated by linoleic acid and IRS-1 degradation was reduced by inhibition of the two kinases. We demonstrate that PKC0 is expressed in adipocytes. PKC0 was activated by fatty acids in 3T3-L1 adipocytes as indicated by its phosphorylation status, and in fat tissue as indicated by its protein expression level. Activation of PKC0 contributes to IKK and JNK activation as inhibition of PKCO by calphostin C blocked activation of the latter kinases. Inhibition of PKCO or IKK plus JNK by chemical nhibitors resulted in protection of IRS-1 function and insulin sensitivity in 3T3-L1 adipocytes. These data suggest that: (1) activation of PKC0 contributes to IKK and JNK activation by FFAs; (2) IKK and JNK mediate PKC0 signals for IRS-1 serine phosphorylation and degradation; (3) this molecular mechanism may be responsible for insulin resistance associated with hyperlipidemia.