Abstract | AIMS/HYPOTHESIS: An accumulation of ceramides has been implicated in the generation of insulin resistance in skeletal muscle upon an oversupply of fatty acid. Different ceramide species are generated through the actions of ceramide synthases (CerSs), which incorporate specific acyl side chains. We tested whether particular CerS isoforms promoted insulin resistance through the generation of more inhibitory ceramide species, thus representing potential targets for intervention. METHODS: CerS isoforms CerS1, CerS2, CerS4, CerS5 and CerS6 were overexpressed in L6 myotubes using adenovirus, and cells were treated with palmitate and stimulated with insulin. Alternatively, CerS isoforms were knocked down using siRNAs. Sphingolipids were examined by mass spectrometry and tracer incorporation. Phosphorylation of IRS1 and Akt was measured by immunoblotting, while glucose disposal was assessed by measuring GLUT4 translocation and the incorporation of [(14)C] glucose into glycogen. RESULTS:
Palmitate treatment increased the levels of several ceramides but reduced the levels of sphingomyelins, while insulin had no effect. The fatty acid also inhibited insulin-stimulated Akt phosphorylation and glycogen synthesis. Overexpression of CerS isoforms increased specific ceramides. Unexpectedly, the overexpression of CerS1 and CerS6 promoted insulin action, while no isoform had inhibitory effects. CerS6 knockdown had effects reciprocal to those of CerS6 overexpression. CONCLUSIONS/INTERPRETATION:
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Authors | Georgia Frangioudakis, Barbara Diakanastasis, Bing-Qing M Liao, Jennifer T Saville, Nolan J Hoffman, Todd W Mitchell, Carsten Schmitz-Peiffer |
Journal | Diabetologia
(Diabetologia)
Vol. 56
Issue 12
Pg. 2697-701
(Dec 2013)
ISSN: 1432-0428 [Electronic] Germany |
PMID | 23989724
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Ceramides
- Insulin
- Membrane Proteins
- Palmitates
- Protein Isoforms
- Sphingolipids
- Glycogen
- Oxidoreductases
- dihydroceramide desaturase
- Glucose
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Topics |
- Ceramides
(biosynthesis, metabolism)
- Glucose
(metabolism)
- Glycogen
(metabolism)
- Humans
- Insulin
(metabolism)
- Insulin Resistance
- Mass Spectrometry
- Membrane Proteins
(biosynthesis)
- Muscle Fibers, Skeletal
- Muscle, Skeletal
(cytology, metabolism)
- Oxidoreductases
(metabolism)
- Palmitates
(metabolism, pharmacology)
- Phosphorylation
- Protein Isoforms
(metabolism)
- Sphingolipids
(metabolism)
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