title: 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.
authors: Department of Pharmacology, School of Medical Sciences, UNSW Australia, Sydney, NSW, Australia.
authors: Magdalene K
authors: MK
authors: Montgomery
authors: School of Medicine, University of Wollongong, Wollongong, NSW, Australia; Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, Australia.
authors: Simon H J
authors: SH
authors: Brown
authors: Prince of Wales Clinical School, UNSW Australia, Sydney, NSW, Australia.
authors: Xin Y
authors: XY
authors: Lim
authors: Department of Pharmacology, School of Medical Sciences, UNSW Australia, Sydney, NSW, Australia.
authors: Corrine E
authors: CE
authors: Fiveash
authors: Department of Pharmacology, School of Medical Sciences, UNSW Australia, Sydney, NSW, Australia.
authors: Brenna
authors: B
authors: Osborne
authors: Department of Pharmacology, School of Medical Sciences, UNSW Australia, Sydney, NSW, Australia.
authors: Nicholas L
authors: NL
authors: Bentley
authors: Department of Pharmacology, School of Medical Sciences, UNSW Australia, Sydney, NSW, Australia.
authors: Jeremy P
authors: JP
authors: Braude
authors: School of Medicine, University of Wollongong, Wollongong, NSW, Australia; Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, Australia.
authors: Todd W
authors: TW
authors: Mitchell
authors: School of Mathematics and Statistics, UNSW Australia, Sydney, NSW, Australia.
authors: Adelle C F
authors: AC
authors: Coster
authors: Prince of Wales Clinical School, UNSW Australia, Sydney, NSW, Australia.
authors: Anthony S
authors: AS
authors: Don
authors: Diabetes & Metabolism Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; St Vincent's Clinical School, UNSW Australia, Sydney, NSW, Australia.
authors: Gregory J
authors: GJ
authors: Cooney
authors: Diabetes & Metabolism Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; St Vincent's Clinical School, UNSW Australia, Sydney, NSW, Australia.
authors: Carsten
authors: C
authors: Schmitz-Peiffer
authors: Department of Pharmacology, School of Medical Sciences, UNSW Australia, Sydney, NSW, Australia. Electronic address: n.turner@unsw.edu.au.
authors: Nigel
authors: N
authors: Turner
mesh_terms: D000215:Acylation; D000818:Animals; D002518:Ceramides / Q000378:metabolism*; D059305:Diet, High-Fat; D004075:Diglycerides / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D005247:Feeding Behavior; D005947:Glucose / Q000378:metabolism*; D022781:Hepatocytes / Q000201:enzymology; D006706:Homeostasis; D007328:Insulin / Q000378:metabolism*; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D010088:Oxidoreductases / Q000378:metabolism; D015398:Signal Transduction; D013045:Species Specificity; D013107:Sphingolipids / Q000378:metabolism*; D013109:Sphingomyelins / Q000378:metabolism
chemical_list: D002518:Ceramides; D004075:Diglycerides; D007328:Insulin; D013107:Sphingolipids; D013109:Sphingomyelins; D010088:Oxidoreductases; C108138:dihydroceramide desaturase; D005947:Glucose
keywords: Ceramide species; Endoplasmic reticulum stress; Insulin sensitivity and resistance; Lipid metabolism; Lipidomics; Obesity