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

Biochim Biophys Acta. 2016 Nov;1861(11):1828-1839. doi: 10.1016/j.bbalip.2016.08.016. Epub 2016 Aug 31.


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.

Keywords: Ceramide species; Endoplasmic reticulum stress; Insulin sensitivity and resistance; Lipid metabolism; Lipidomics; Obesity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acylation
  • Animals
  • Ceramides / metabolism*
  • Diet, High-Fat
  • Diglycerides / metabolism
  • Endoplasmic Reticulum Stress
  • Feeding Behavior
  • Glucose / metabolism*
  • Hepatocytes / enzymology
  • Homeostasis*
  • Insulin / metabolism*
  • Liver / enzymology
  • Liver / metabolism
  • Male
  • Mice
  • Oxidoreductases / metabolism
  • Signal Transduction
  • Species Specificity
  • Sphingolipids / metabolism*
  • Sphingomyelins / metabolism


  • Ceramides
  • Diglycerides
  • Insulin
  • Sphingolipids
  • Sphingomyelins
  • Oxidoreductases
  • dihydroceramide desaturase
  • Glucose