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Key role for ceramides in mediating insulin resistance in human muscle cells

Lookup NU author(s): Dr Laura Rush, Dr Gary Litherland, Professor Mark Walker, Emeritus Professor Steve Yeaman

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Abstract

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. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc.

Publication metadata

Author(s): Pickersgill L, Litherland GJ, Greenberg AS, Walker M, Yeaman SJ

Publication type: Article

Publication status: Published

Journal: Journal of Biological Chemistry

Year: 2007

Volume: 282

Issue: 17

Pages: 12583-12589

Print publication date: 27/04/2007

ISSN (print): 0021-9258

ISSN (electronic): 1083-351X

Publisher: American Society for Biochemistry and Molecular Biology, Inc.

URL: http://dx.doi.org/10.1074/jbc.M611157200

DOI: 10.1074/jbc.M611157200

PubMed id: 17337731

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