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J. Biol. Chem., Vol. 278, Issue 12, 10297-10303, March 21, 2003
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From the Department of Biochemistry and Molecular Biology and the
§ Department of Biology, Colorado State University, Fort
Collins, Colorado 80523-1870 and the Multiple studies suggest that lipid oversupply to
skeletal muscle contributes to the development of insulin resistance,
perhaps by promoting the accumulation of lipid metabolites capable of inhibiting signal transduction. Herein we demonstrate that exposing muscle cells to particular saturated free fatty acids (FFAs), but not
mono-unsaturated FFAs, inhibits insulin stimulation of Akt/protein
kinase B, a serine/threonine kinase that is a central mediator of
insulin-stimulated anabolic metabolism. These saturated FFAs
concomitantly induced the accumulation of ceramide and diacylglycerol, two products of fatty acyl-CoA that have been shown to accumulate in
insulin-resistant tissues and to inhibit early steps in insulin signaling. Preventing de novo ceramide synthesis negated
the antagonistic effect of saturated FFAs toward Akt/protein kinase B. Moreover, inducing ceramide buildup recapitulated and augmented the
inhibitory effect of saturated FFAs. By contrast, diacylglycerol
proved dispensable for these FFA effects. Collectively these results
identify ceramide as a necessary and sufficient intermediate linking
saturated fats to the inhibition of insulin signaling.
A Role for Ceramide, but Not Diacylglycerol, in the Antagonism of
Insulin Signal Transduction by Saturated Fatty Acids*
,, Department of
Pharmacology and Toxicology, University of Kansas,
Lawrence, Kansas 66045
*
This work was supported by National Institutes of Health
(NIH) Grants R01-DK58784 (to S. A. S.), DK59749 (to R. T. D.), and R21-DK60676 (to G. L. F.), a Career Development Award from the American Diabetes Association (to S. A. S.), a Career Development Award from the Juvenile Diabetes Research Foundation (to R. T. D.), a
Beginning Grant-in-aid from the American Heart Association (to
S. A. S.), and a Basil O'Connor Starter Scholar's Award from the
March of Dimes (to S. A. S.).The costs of publication of this article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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