Inhibition of De Novo Ceramide Synthesis Reverses Diet-Induced Insulin Resistance and Enhances Whole-Body Oxygen Consumption
- John R. Ussher1,
- Timothy R. Koves2,
- Virgilio J.J. Cadete1,
- Liyan Zhang1,
- Jagdip S. Jaswal1,
- Suzanne J. Swyrd,
- David G. Lopaschuk1,
- Spencer D. Proctor3,
- Wendy Keung1,
- Deborah M. Muoio2 and
- Gary D. Lopaschuk1
- 1Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, Department of Pediatrics, University of Alberta, Edmonton, Canada;
- 2Sarah W. Stedman Nutrition and Metabolism Center, Department of Medicine, Duke University, Durham, North Carolina;
- 3Metabolic and Cardiovascular Diseases Laboratory, Alberta Institute for Human Nutrition, University of Alberta, Edmonton, Canada.
- Corresponding author: Gary Lopaschuk, .
OBJECTIVE It has been proposed that skeletal muscle insulin resistance arises from the accumulation of intramyocellular lipid metabolites that impede insulin signaling, including diacylglycerol and ceramide. We determined the role of de novo ceramide synthesis in mediating muscle insulin resistance.
RESEARCH DESIGN AND METHODS Mice were subjected to 12 weeks of diet-induced obesity (DIO), and then treated for 4 weeks with myriocin, an inhibitor of serine palmitoyl transferase-1 (SPT1), the rate-limiting enzyme of de novo ceramide synthesis.
RESULTS After 12 weeks of DIO, C57BL/6 mice demonstrated a doubling in gastrocnemius ceramide content, which was completely reversed (141.5 ± 15.8 vs. 94.6 ± 10.2 nmol/g dry wt) via treatment with myriocin, whereas hepatic ceramide content was unaffected by DIO. Interestingly, myriocin treatment did not alter the DIO-associated increase in gastrocnemius diacyglycerol content, and the only correlation observed between lipid metabolite accumulation and glucose intolerance occurred with ceramide (R = 0.61). DIO mice treated with myriocin showed a complete reversal of glucose intolerance and insulin resistance which was associated with enhanced insulin-stimulated Akt and glycogen synthase kinase 3β phosphorylation. Furthermore, myriocin treatment also decreased intramyocellular ceramide content and prevented insulin resistance development in db/db mice. Finally, myriocin-treated DIO mice displayed enhanced oxygen consumption rates (3,041 ± 124 vs. 2,407 ± 124 ml/kg/h) versus their control counterparts.
CONCLUSIONS Our results demonstrate that the intramyocellular accumulation of ceramide correlates strongly with the development of insulin resistance, and suggests that inhibition of SPT1 is a potentially promising target for the treatment of insulin resistance.
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See accompanying commentary, p. 2351.
- Received August 31, 2009.
- Accepted May 5, 2010.
- © 2010 by the American Diabetes Association.
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