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This version published online on May 13, 2004
Molecular Endocrinology, doi:10.1210/me.2003-0383
Molecular Endocrinology Vol. 0, No. 2004 200303831-
doi:10.1210/me.2003-0383
Copyright © 2004 by the Endocrine Society.
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Submitted on October 1, 2003
Accepted on May 7, 2004

Inhibition of Insulin Sensitivity by Free Fatty Acids Requires Activation of Multiple Serine Kinases in 3T3-L1 Adipocytes

ZHANGUO GAO, XIAOYING ZHANG, AAMIR ZUBERI, DANIEL HWANG, MICHAEL J. QUON, MICHAEL LEFEVRE, and JIANPING YE*

Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana 70808; Western Human Nutrition Research Center and Department of Nutrition, University of California, Davis, CA 95616; Diabetes Unit, National Center for Complementary and Alternative Medicine, NIH, Bethesda, MD 20892-1755

* To whom correspondence should be addressed. E-mail: yej{at}pbrc.edu.

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 serine phosphorylation and degradation of IRS-1 in adipocytes and in dietary obese mice. Linoleic acid, a free fatty acid 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 (Ser307) phosphorylation that was catalyzed by serine kinases IKK and 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 PKC{theta} is expressed in adipocytes. In 3T3-L1 adipocytes and fat tissue, PKC{theta} was activated by fatty acids as indicated by its phosphorylation status, and by its protein level, respectively. Activation of PKC{theta} contributes to IKK and JNK activation as inhibition of PKC{theta} by calphostin C blocked activation of the latter kinases. Inhibition of either PKC{theta} 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 PKC{theta} contributes to IKK and JNK activation by FFAs; (2) IKK and JNK mediate PKC{theta} signals for IRS-1 serine phosphorylation and degradation; (3) this molecular mechanism may be responsible for insulin resistance associated with hyperlipidemia.




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