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Regulation of glucose homeostasis and insulin action by ceramide acyl-chain length: A beneficial role for very long-chain sphingolipid species

Abstract

In a recent study, we showed that in response to high fat feeding C57BL/6, 129X1, DBA/2 and FVB/N mice all developed glucose intolerance, while BALB/c mice displayed minimal deterioration in glucose tolerance and insulin action. Lipidomic analysis of livers across these five strains has revealed marked strain-specific differences in ceramide (Cer) and sphingomyelin (SM) species with high-fat feeding; with increases in C16-C22 (long-chain) and reductions in C>22 (very long-chain) Cer and SM species observed in the four strains that developed HFD-induced glucose intolerance. Intriguingly, the opposite pattern was observed in sphingolipid species in BALB/c mice. These strain-specific changes in sphingolipid acylation closely correlated with ceramide synthase 2 (CerS2) protein content and activity, with reduced CerS2 levels/activity observed in glucose intolerant strains and increased content in BALB/c mice. Overexpression of CerS2 in primary mouse hepatocytes induced a specific elevation in very long-chain Cer, but despite the overall increase in ceramide abundance, there was a substantial improvement in insulin signal transduction, as well as decreased ER stress and gluconeogenic markers. Overall our findings suggest that very long-chain sphingolipid species exhibit a protective role against the development of glucose intolerance and hepatic insulin resistance.

Type Journal
ISBN 0006-3002 (Print) 0006-3002 (Linking)
Authors Montgomery, M. K.; Brown, S. H.; Lim, X. Y.; Fiveash, C. E.; Osborne, B.; Bentley, N. L.; Braude, J. P.; Mitchell, T. W.; Coster, A. C.; Don, A. S.; Cooney, G. J.; Schmitz-Peiffer, C.; Turner, N.;
Publisher Name BBA-MOL BASIS DIS
Published Date 2016-11-01 00:00:00
Published Volume 1861
Published Issue 11
Published Pages 1828-1839
URL http://www.ncbi.nlm.nih.gov/pubmed/27591968
Status Published in-print