Fatty acid‐induced defects in insulin signalling, in myotubes derived from children, are related to ceramide production from palmitate rather than the accumulation of intramyocellular lipid

Sabin, Matthew A.; Stewart, Claire E.H.; Crowne, Elizabeth C.; Turner, Stephen J.; Hunt, Linda P.; Welsh, Gavin I.; Grohmann, Malcolm J.; Holly, Jeff M.P.; Shield, Julian P.H.

doi:10.1002/jcp.20922

Cited by 71Sphingolipid Metabolism and SignalingMetabolism, Diabetes, and CancerLipid metabolism and biosynthesis

Fatty acid‐induced defects in insulin signalling, in myotubes derived from children, are related to ceramide production from palmitate rather than the accumulation of intramyocellular lipid

Sabin, Matthew A., Stewart, Claire E.H., Crowne, Elizabeth C., Turner, Stephen J., Hunt, Linda P., Welsh, Gavin I., Grohmann, Malcolm J., Holly, Jeff M.P. +1 more·2007·Journal of Cellular Physiology

DOI 10.1002/jcp.20922

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Abstract

The elevation of free fatty acids (FFAs), observed in childhood obesity results in intramyocellular lipid (IMCL) accumulation with consequent insulin resistance. Using in vitro differentiated myotubes from normal weight pre‐pubertal children (n = 8), we examined the effects of saturated (palmitate) and unsaturated (oleate) FFAs on insulin‐stimulated AKT phosphorylation (pAKT) and IMCL accumulation. Palmitate decreased pAKT (Mean [SEM] % change pAKT with palmitate 750 µM vs. control; pThr308 site −50.5% [28.7] and pSer473 site −38.7% [11.7]; P < 0.001) with no effect on IMCL formation. Equimolar bromopalmitate did not effect pAKT and blocking ceramide production abolished the palmitate‐induced reduction in signalling, suggesting that ceramide synthesis is critical for palmitate's actions. Oleate did not effect pAKT (1,000 µM oleate; pSer473 site −3.4% [11.4]; P = NS) but increased IMCL accumulation (+32.3% [7.1%]; P < 0.001). Co‐administration of oleate diminished the reduction in pAKT seen with palmitate (+36.4% [23.6] vs. −13.3% [13.6]; P = 0.28), with similar IMCL levels to oleate alone. Co‐administration also caused a significant reduction in 14 C‐ceramide synthesis from 14 C‐palmitate (101.6 [21.6] vs. 371.5 [122.4] DPM/mg protein; P < 0.001). In summary, palmitate appears to cause insulin resistance in children's myotubes via its metabolism to ceramide, and this process appears unrelated to IMCL formation and is ameliorated by oleate. J. Cell. Physiol. 211: 244–252, 2007. © 2007 Wiley‐Liss, Inc.

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Lipid overload impairs oxidative capacity and increases intracellular accumulation of FA-derived metabolites, such as long-chain acyl-CoA, diacylglycerol, ceramide, and triacylglycerol, in skeletal muscle.
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From Mitochondrial Fission Contributes to Mitochondrial Dysfunction and Insulin Resistance in Skeletal Muscle (2012) · cites this paper as [37]
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From Mitochondrial Fission Contributes to Mitochondrial Dysfunction and Insulin Resistance in Skeletal Muscle (2012) · cites this paper as [37]

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Authors: Sabin, M. A., Stewart, C. E. H., Crowne, E. C., Turner, S. J., Hunt, L. P., Welsh, G. I., Grohmann, M. J., Holly, J. M. P., & Shield, J. P. H.
Affiliations: Bristol Royal Hospital for Children (GB)
Manchester Metropolitan University (GB)
ORCID: Sabin, Matthew A.
Stewart, Claire E.H.
Crowne, Elizabeth C.
Hunt, Linda P.
Welsh, Gavin I.
Holly, Jeff M.P.
Venue: Journal of Cellular Physiology
Publisher: Wiley
Published: 2007-01-11
Volume: 211
Issue: 1
Pages: 244-252
ISSN: 0021-9541 (ISSN-L)
1097-4652
DOI: 10.1002/jcp.20922
OpenAlex: W2095018867
Cited by: 71
References: 44
Citations by year: 2025: 1 · 2021: 2 · 2020: 2 · 2019: 2 · 2018: 2 · 2017: 1 · 2016: 2 · 2015: 2 · 2014: 8 · 2013: 9 · 2012: 6
FWCI: 3.57
Type: journal article
Language: en
Open access: closed
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: Journal of Cellular Physiology (publishedVersion)
PubMed (publishedVersion)
Explore Bristol Research (publishedVersion)
e-space (Manchester Metropolitan University) (submittedVersion)
Bristol Research (University of Bristol) (submittedVersion)
Funders: Diabetes UK
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
Keywords: insulin resistance, free fatty acids, palmitate, oleate, ceramide synthesis, intramyocellular lipid, Akt phosphorylation, skeletal muscle myotubes, childhood obesity, saturated vs unsaturated fatty acids
MeSH terms: Cell Differentiation, Cells, Cultured, Ceramides, Child, Child, Preschool, Dose-Response Relationship, Drug, Female, Humans, Infant, Insulin, Male, Oxazines, Palmitates, Phosphoproteins, Phosphoserine, Time Factors, Signal Transduction, Muscle Fibers, Skeletal, Oleic Acid, Lipid Metabolism, Proto-Oncogene Proteins c-akt

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Fatty acid‐induced defects in insulin signalling, in myotubes derived from children, are related to ceramide production from palmitate rather than the accumulation of intramyocellular lipid

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