Skip to main content
ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Publications at this Location » Publication #211426
Title: Key Role for Ceramides in Mediating Insulin Resistance in Human Muscle Cells

Author
item PICKERSGILL, LAURA - INST. OF CELL & MOL. SCI
item LITHERLAND, GARY - INST. OF CELL & MOL. SCI
item Greenberg, Andrew
item WALKER, MARK - INST. OF CELL & MOL. SCI
item YEAMAN, STEPHEN - INST. OF CELL & MOL. SCI

Submitted to: Journal of Biological Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/26/2007
Publication Date: 4/27/2007
Citation: Pickersgill, L., Litherland, G.J., Greenberg, A.S., Walker, M., Yeaman, S.J. 2007. Key Role for Ceramides in Mediating Insulin Resistance in Human Muscle Cells. Journal of Biological Chemistry. 282(17):12583-12589.

Interpretive Summary: Elevated levels of fatty acids have been associated with insulin resistance in muscle. Due to this fact, we set out to investigate the role of lipid metabolites in the onset of insulin resistance in human muscle cell cultures. The muscle cells were subjected to either expression of the protein perilipin or incubated with fatty acids. In both cases the muscle cells were subjected to these environments prior to insulin stimulation and measurement of lipid metabolites and rates of glycogen synthesis. Perilipin expression leads to significant accumulation of the fatty acid triacylglycerol in muscle cells without any detectable effect on insulin sensitivity. Similarly, incubation of cells with the fatty acid oleate resulted in triacylglycerol accumulation without inhibiting insulin action. By contrast, the fatty acid palmitate induced insulin resistance and caused less accumulation of triacylglycerol than did oleate, but also induced significant accumulation of both fatty acids diacylglycerol and ceramide. 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 protective role in sequestering palmitate, thus preventing its conversion to ceramide.

Technical 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 18h, prior to insulin stimulation and measurement of lipid metabolites and rates of glycogen synthesis. Adenovirus-driven perilipin expression leads 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 mono-unsaturated 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 protective role in sequestering palmitate, thus preventing its conversion to ceramide.