Title

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

RIS ID

110303

Publication Details

Montgomery, M. K., Brown, S. H. J., Lim, X. Y., Fiveash, C. E., Osborne, B., Bentley, N. L., Braude, J. P., Mitchell, T. W., Coster, A. C. F., Don, A. S., Cooney, G. J., Schmitz-Peiffer, C. & Turner, N. (2016). Regulation of glucose homeostasis and insulin action by ceramide acyl-chain length: A beneficial role for very long-chain sphingolipid species. Biochimica Et Biophysica Acta-molecular And Cell Biology Of Lipids, 1861 (11), 1828-1839.

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 revealedmarked strain-specific differences in ceramide (Cer) and sphingomyelin (SM)specieswith high-fat feeding;with increases in C16-C22 (long-chain) and reductions in C N 22 (very long-chain) Cer and SM species observed in the four strains that developed HFDinduced 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.

Grant Number

ARC/LE0989078

Grant Number

ARC/FT110100249

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