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J. Biol. Chem., Vol. 282, Issue 17, 12583-12589, April 27, 2007

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Key Role for Ceramides in Mediating Insulin Resistance in Human Muscle Cells^*

Laura Pickersgill¹, Gary J. Litherland, Andrew S. Greenberg, Mark Walker, and Stephen J. Yeaman²

From the Institute of Cell & Molecular Biosciences and Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom and the Obesity and Metabolism Laboratory, Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts 02111-1524

Elevated non-esterified fatty acids, triglyceride, diacylglycerol, and ceramide have all been associated with insulin resistance in muscle. We set out to investigate the role of intramyocellular lipid metabolites in the induction of insulin resistance in human primary myoblast cultures. Muscle cells were subjected to adenovirus-mediated expression of perilipin or incubated with fatty acids for 18 h, prior to insulin stimulation and measurement of lipid metabolites and rates of glycogen synthesis. Adenovirus-driven perilipin expression lead to significant accumulation of triacylglycerol in myoblasts, without any detectable effect on insulin sensitivity, as judged by the ability of insulin to stimulate glycogen synthesis. Similarly, incubation of cells with the monounsaturated fatty acid oleate resulted in triacylglycerol accumulation without inhibiting insulin action. By contrast, the saturated fatty acid palmitate induced insulin resistance. Palmitate treatment caused less accumulation of triacylglycerol than did oleate but also induced significant accumulation of both diacylglycerol and ceramide. Insulin resistance was also caused by cell-permeable analogues of ceramide, and palmitate-induced resistance was blocked in the presence of inhibitors of de novo ceramide synthesis. Oleate co-incubation completely prevented the insulin resistance induced by palmitate. Our data are consistent with ceramide being the agent responsible for insulin resistance caused by palmitate exposure. Furthermore, the triacylglycerol derived from oleate was able to exert a protective role in sequestering palmitate, thus preventing its conversion to ceramide.

Received for publication, December 5, 2006 , and in revised form, February 26, 2007.

^* This work was supported partly by Wellcome Trust Grant 066495/Z/01/A, National Institutes of Health Grant IH DK50647 and United States Department of Agriculture-Agricultural Research Service Co-operative Agreement 58 1950-4-401. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by a Biotechnology and Biological Sciences Research Council Co-operative Award in Science Engineering studentship in collaboration with Xcellsyz Ltd. Present address: Unilever Colworth, Sharnbrook, Bedford MK44 1LQ, UK.

² To whom correspondence should be addressed. Tel.: 44-191-222-7433; Fax: 44-191-222-7424; E-mail: S.J.Yeaman{at}ncl.ac.uk.

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