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Inhibition of insulin sensitivity by free fatty acids requires activation of multiple serine kinases in 3T3-L1 adipocytes.
Mol Endocrinol. 2004 Aug; 18(8):2024-34.ME

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 the FFA-signaling pathway that contributes to serine phosphorylation and degradation of IRS-1 in adipocytes and in dietary obese mice. Linoleic acid, an FFA used in this study, resulted in a reduction in insulin-induced glucose uptake in 3T3-L1 adipocytes. This mimics insulin resistance induced by high-fat diet in C57BL/6J mice. The reduction in glucose uptake is associated with a decrease in IRS-1, but not IRS-2 or GLUT4 protein abundance. Decrease in IRS-1 protein was proceeded by IRS-1 (serine 307) phosphorylation that was catalyzed by serine kinases inhibitor kappaB kinase (IKK) and c-JUN NH2-terminal kinase (JNK). IKK and JNK were activated by linoleic acid and inhibition of the two kinases led to prevention of IRS-1 reduction. We demonstrate that protein kinase C (PKC) theta is expressed in adipocytes. In 3T3-L1 adipocytes and fat tissue, PKCtheta was activated by fatty acids as indicated by its phosphorylation status, and by its protein level, respectively. Activation of PKCtheta contributes to IKK and JNK activation as inhibition of PKCtheta by calphostin C blocked activation of the latter kinases. Inhibition of either PKCtheta or IKK plus JNK by chemical inhibitors resulted in protection of IRS-1 function and insulin sensitivity in 3T3-L1 adipocytes. These data suggest that: 1) activation of PKCtheta contributes to IKK and JNK activation by FFAs; 2) IKK and JNK mediate PKCtheta signals for IRS-1 serine phosphorylation and degradation; and 3) this molecular mechanism may be responsible for insulin resistance associated with hyperlipidemia.

Authors+Show Affiliations

Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, Louisiana 70808, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

15143153

Citation

Gao, Zhanguo, et al. "Inhibition of Insulin Sensitivity By Free Fatty Acids Requires Activation of Multiple Serine Kinases in 3T3-L1 Adipocytes." Molecular Endocrinology (Baltimore, Md.), vol. 18, no. 8, 2004, pp. 2024-34.
Gao Z, Zhang X, Zuberi A, et al. Inhibition of insulin sensitivity by free fatty acids requires activation of multiple serine kinases in 3T3-L1 adipocytes. Mol Endocrinol. 2004;18(8):2024-34.
Gao, Z., Zhang, X., Zuberi, A., Hwang, D., Quon, M. J., Lefevre, M., & Ye, J. (2004). Inhibition of insulin sensitivity by free fatty acids requires activation of multiple serine kinases in 3T3-L1 adipocytes. Molecular Endocrinology (Baltimore, Md.), 18(8), 2024-34.
Gao Z, et al. Inhibition of Insulin Sensitivity By Free Fatty Acids Requires Activation of Multiple Serine Kinases in 3T3-L1 Adipocytes. Mol Endocrinol. 2004;18(8):2024-34. PubMed PMID: 15143153.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of insulin sensitivity by free fatty acids requires activation of multiple serine kinases in 3T3-L1 adipocytes. AU - Gao,Zhanguo, AU - Zhang,Xiaoying, AU - Zuberi,Aamir, AU - Hwang,Daniel, AU - Quon,Michael J, AU - Lefevre,Michael, AU - Ye,Jianping, Y1 - 2004/05/13/ PY - 2004/5/15/pubmed PY - 2005/1/27/medline PY - 2004/5/15/entrez SP - 2024 EP - 34 JF - Molecular endocrinology (Baltimore, Md.) JO - Mol. Endocrinol. VL - 18 IS - 8 N2 - 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 the FFA-signaling pathway that contributes to serine phosphorylation and degradation of IRS-1 in adipocytes and in dietary obese mice. Linoleic acid, an FFA used in this study, resulted in a reduction in insulin-induced glucose uptake in 3T3-L1 adipocytes. This mimics insulin resistance induced by high-fat diet in C57BL/6J mice. The reduction in glucose uptake is associated with a decrease in IRS-1, but not IRS-2 or GLUT4 protein abundance. Decrease in IRS-1 protein was proceeded by IRS-1 (serine 307) phosphorylation that was catalyzed by serine kinases inhibitor kappaB kinase (IKK) and c-JUN NH2-terminal kinase (JNK). IKK and JNK were activated by linoleic acid and inhibition of the two kinases led to prevention of IRS-1 reduction. We demonstrate that protein kinase C (PKC) theta is expressed in adipocytes. In 3T3-L1 adipocytes and fat tissue, PKCtheta was activated by fatty acids as indicated by its phosphorylation status, and by its protein level, respectively. Activation of PKCtheta contributes to IKK and JNK activation as inhibition of PKCtheta by calphostin C blocked activation of the latter kinases. Inhibition of either PKCtheta or IKK plus JNK by chemical inhibitors resulted in protection of IRS-1 function and insulin sensitivity in 3T3-L1 adipocytes. These data suggest that: 1) activation of PKCtheta contributes to IKK and JNK activation by FFAs; 2) IKK and JNK mediate PKCtheta signals for IRS-1 serine phosphorylation and degradation; and 3) this molecular mechanism may be responsible for insulin resistance associated with hyperlipidemia. SN - 0888-8809 UR - https://www.unboundmedicine.com/medline/citation/15143153/Inhibition_of_insulin_sensitivity_by_free_fatty_acids_requires_activation_of_multiple_serine_kinases_in_3T3_L1_adipocytes_ L2 - https://academic.oup.com/mend/article-lookup/doi/10.1210/me.2003-0383 DB - PRIME DP - Unbound Medicine ER -