Intracellular ceramide synthesis and protein kinase Cζ activation play an essential role in palmitate-induced insulin resistance in rat L6 skeletal muscle cells

POWELL, Darren J.; TURBAN, Sophie; GRAY, Alexander; HAJDUCH, Eric; HUNDAL, Harinder S.

doi:10.1042/bj20040139

Cited by 267Sphingolipid Metabolism and SignalingMetabolism, Diabetes, and CancerDiet, Metabolism, and Disease

Intracellular ceramide synthesis and protein kinase Cζ activation play an essential role in palmitate-induced insulin resistance in rat L6 skeletal muscle cells

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POWELL, Darren J., TURBAN, Sophie, GRAY, Alexander, HAJDUCH, Eric, HUNDAL, Harinder S.·2004·Biochemical Journal

DOI 10.1042/bj20040139PMC PMC1133819

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Abstract

Non-esterified fatty acids (NEFAs) have been implicated in the pathogenesis of skeletal muscle insulin resistance that may develop, in part, as a consequence of a direct inhibitory effect on early insulin signalling events. Here we report work investigating the mechanism by which palmitate (a saturated free fatty acid) inhibits insulin action in rat L6 myotubes. Palmitate suppressed the insulin-induced plasma membrane recruitment and phosphorylation of protein kinase B (PKB) and this was associated with a loss in insulin-stimulated glucose transport. The inhibition in PKB was not due to a loss in insulin receptor substrate (IRS)1 tyrosine phosphorylation, IRS-1/p85 (phosphoinositide 3-kinase) association or suppression in phosphatidyl 3,4,5 triphosphate synthesis, but was attributable to an elevated intracellular synthesis of ceramide (6-fold) from palmitate and a concomitant activation of protein kinase PKCζ (5-fold). Inhibitors of serine palmitoyl transferase suppressed the intracellular synthesis of ceramide from palmitate, prevented PKCζ activation, and antagonized the inhibition in PKB recruitment/phosphorylation and the loss in insulin-stimulated glucose transport elicited by the NEFA. Inhibiting the palmitate-induced activation of PKCζ with Ro 31.8220, also prevented the loss in the insulin-dependent phosphorylation of PKB caused by palmitate. These findings indicate that intracellular ceramide synthesis and PKCζ activation are important aspects of the mechanism by which palmitate desensitizes L6 muscle cells to insulin.

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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.
“Lipid overload impairs oxidative capacity and increases the intracellular accumulation of FA-derived metabolites, such as long-chain acyl-CoA, diacylglycerol, ceramide, and triacylglycerol, in skeletal muscle (1, 30, 35, 37).”
From Mitochondrial Fission Contributes to Mitochondrial Dysfunction and Insulin Resistance in Skeletal Muscle (2012) · cites this paper as [35]
Increases in lipid derivatives, particularly ceramides, can lead to the activation of PKC isoforms which phosphorylate serine residues on insulin receptor substrate-1 and attenuate PKB activation.
“Increases in these lipid derivatives, particularly ceramides, can lead to the activation of PKC isoforms which lead to the phosphorylation of serine residues on insulin receptor substrate-1(IRS) and attenuating PKB activation [119,120].”
From Omega-3 Fatty Acids and Skeletal Muscle Health (2015) · cites this paper as [119]
The actions of proinflammatory stimuli impair control of numerous signalling pathways regulating skeletal muscle insulin signalling, glucose uptake, mitochondrial fuel oxidation and respiration, impacting negatively upon skeletal muscle energy homeostasis.
“The actions of these stimuli serve to not only further induce tissue expression and secretion of IL-6 and TNFα (via the NFκB pathway, [3, 4]), but impair control of numerous signalling pathways regulating skeletal muscle insulin signalling, glucose uptake, mitochondrial fuel oxidation and respiration that impact negatively upon skeletal muscle energy homeostasis [2, 5–7].”
From Proinflammatory NFkB signalling promotes mitochondrial dysfunction in skeletal muscle in response to cellular fuel overloading (2019) · cites this paper as [6]

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Authors: POWELL, D. J., TURBAN, S., GRAY, A., HAJDUCH, E., & HUNDAL, H. S.
Affiliations: University of Dundee (GB)
Division of Molecular Physiology, Faculty of Life Sciences, MSI/WTB Complex, University of Dundee, Dundee, DD1 5EH, Scotland
Corresponding author: TURBAN, Sophie
ORCID: POWELL, Darren J.
GRAY, Alexander
HUNDAL, Harinder S.
Venue: Biochemical Journal
Publisher: Portland Press Ltd.
Published: 2004-08-24
Volume: 382
Issue: 2
Pages: 619-629
ISSN: 0264-6021 (ISSN-L)
1470-8728
DOI: 10.1042/bj20040139
PMC: PMC1133819
OpenAlex: W1967737207
Cited by: 267
References: 48
Citations by year: 2026: 4 · 2025: 5 · 2024: 7 · 2023: 2 · 2022: 12 · 2021: 6 · 2020: 9 · 2019: 11 · 2018: 9 · 2017: 14 · 2016: 15 · 2015: 19 · 2014: 12 · 2013: 24 · 2012: 11
FWCI: 3.91
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Biochemical Journal (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Discovery Research Portal (University of Dundee) (submittedVersion)
Funders: Diabetes Research and Wellness Foundation
Fondation pour la Recherche Médicale
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
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
Keywords: palmitate, insulin resistance, ceramide synthesis, protein kinase C zeta, skeletal muscle, L6 myotubes, free fatty acids, Akt, insulin signaling, glucose transport, serine palmitoyltransferase, Ro 31-8220, IRS-1, phosphatidylinositol 3,4,5-trisphosphate
MeSH terms: Protein Kinase C zeta, Animals, Cell Line, Ceramides, Enzyme Activation, Insulin Resistance, Palmitates, Protein Kinase C, Adipocytes, Muscle, Skeletal, Muscle Fibers, Skeletal, 3T3-L1 Cells, Intracellular Space, Mice, Rats

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Intracellular ceramide synthesis and protein kinase Cζ activation play an essential role in palmitate-induced insulin resistance in rat L6 skeletal muscle cells

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