Regulation of glucose homeostasis and insulin action by ceramide acyl-chain length: A beneficial role for very long-chain sphingolipid species
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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.
Original language | English |
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Journal | Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids |
Volume | 1861 |
Issue number | 11 |
Pages (from-to) | 1828-1839 |
Number of pages | 12 |
ISSN | 1388-1981 |
DOIs | |
Publication status | Published - 1 Nov 2016 |
Bibliographical note
Funding Information:
We thank the Biological Testing Facility at the Garvan Institute and the UNSW Biological Resources Centre (Sydney, Australia) for assistance with animal care. This work was supported by funding from the National Health and Medical Research Council of Australia ( NHMRC - 535921 ), the Diabetes Australia Research Trust , the University of Wollongong and the Australian Research Council (ARC - LE0989078 ). MKM and GJC are supported by NHMRC Research Fellowships ( APP1071143 and APP1107290 ) and TWM and NT are supported by ARC Future Fellowships ( FT110100249 and FT120100371 ).
Publisher Copyright:
© 2016 Elsevier B.V.
- Ceramide species, Endoplasmic reticulum stress, Insulin sensitivity and resistance, Lipid metabolism, Lipidomics, Obesity
Research areas
ID: 322908791