Dataset Information

Palmitate-induced skeletal muscle insulin resistance does not require NF-?B activation.

ABSTRACT: Palmitate activates the NF-?B pathway, and induces accumulation of lipid metabolites and insulin resistance in skeletal muscle cells. Little information is available whether and how these processes are causally related. Therefore, the objectives were to investigate whether intra-cellular lipid metabolites are involved in FA-induced NF-?B activation and/or insulin resistance in skeletal muscle and to investigate whether FA-induced insulin resistance and NF-?B activation are causally related. Inhibiting DGAT or CPT-1 by using, respectively, amidepsine or etomoxir increased DAG accumulation and sensitized myotubes to palmitate-induced insulin resistance. While co-incubation of palmitate with etomoxir increased NF-?B transactivation, co-incubation with amidepsine did not, indicating that DAG accumulation is associated with insulin resistance but not with NF-?B activation. Furthermore, pharmacological or genetic inhibition of the NF-?B pathway could not prevent palmitate-induced insulin resistance. In conclusion, we have demonstrated that activation of the NF-?B pathway is not required for palmitate-induced insulin resistance in skeletal muscle cells.

SUBMITTER: Hommelberg PP

PROVIDER: S-EPMC3056136 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Palmitate-induced skeletal muscle insulin resistance does not require NF-κB activation.

Hommelberg Pascal P H PP Plat Jogchum J Sparks Lauren M LM Schols Annemie M W J AM van Essen Anon L M AL Kelders Marco C J M MC van Beurden Denis D Mensink Ronald P RP Langen Ramon C J RC

Cellular and molecular life sciences : CMLS 20100905 7

Palmitate activates the NF-κB pathway, and induces accumulation of lipid metabolites and insulin resistance in skeletal muscle cells. Little information is available whether and how these processes are causally related. Therefore, the objectives were to investigate whether intra-cellular lipid metabolites are involved in FA-induced NF-κB activation and/or insulin resistance in skeletal muscle and to investigate whether FA-induced insulin resistance and NF-κB activation are causally related. Inhi ...[more]

PMID: 20820848

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Project description:Aims/hypothesisEnergy-dense nutrition generally induces insulin resistance, but dietary composition may differently affect glucose metabolism. This study investigated initial effects of monounsaturated vs saturated lipid meals on basal and insulin-stimulated myocellular glucose metabolism and insulin signalling.MethodsIn a randomised crossover study, 16 lean metabolically healthy volunteers received single meals containing safflower oil (SAF), palm oil (PAL) or vehicle (VCL). Whole-body glucose metabolism was assessed from glucose disposal (Rd) before and during hyperinsulinaemic-euglycaemic clamps with D-[6,6-2H2]glucose. In serial skeletal muscle biopsies, subcellular lipid metabolites and insulin signalling were measured before and after meals.ResultsSAF and PAL raised plasma oleate, but only PAL significantly increased plasma palmitate concentrations. SAF and PAL increased myocellular diacylglycerol and activated protein kinase C (PKC) isoform θ (p < 0.05) but only PAL activated PKCɛ. Moreover, PAL led to increased myocellular ceramides along with stimulated PKCζ translocation (p < 0.05 vs SAF). During clamp, SAF and PAL both decreased insulin-stimulated Rd (p < 0.05 vs VCL), but non-oxidative glucose disposal was lower after PAL compared with SAF (p < 0.05). Muscle serine1101-phosphorylation of IRS-1 was increased upon SAF and PAL consumption (p < 0.05), whereas PAL decreased serine473-phosphorylation of Akt more than SAF (p < 0.05).Conclusions/interpretationLipid-induced myocellular insulin resistance is likely more pronounced with palmitate than with oleate and is associated with PKC isoforms activation and inhibitory insulin signalling.Trial registrationClinicalTrials.gov .NCT01736202.FundingGerman Federal Ministry of Health, Ministry of Culture and Science of the State North Rhine-Westphalia, German Federal Ministry of Education and Research, European Regional Development Fund, German Research Foundation, German Center for Diabetes Research.

Project description:Short-term muscle disuse is characterized by skeletal muscle insulin resistance, although this response is divergent across subjects. The mechanisms regulating inactivity-induced insulin resistance between populations that are more or less susceptible to disuse-induced insulin resistance are not known. RNA sequencing was conducted on vastus lateralis muscle biopsies from subjects before and after bed rest (n = 26) to describe the transcriptome of inactivity-induced insulin resistance. Subjects were separated into Low (n = 14) or High (n = 12) Susceptibility Groups based on the magnitude of change in insulin sensitivity after 5 days of bed rest. Both groups became insulin-resistant after bed rest, and there were no differences between groups in nonmetabolic characteristics (body mass, body mass index, fat mass, and lean mass). The High Susceptibility Group had more genes altered >1.5-fold (426 high versus 391 low) and more than twofold (73 high versus 55 low). Twenty-four genes were altered more than twofold in the High Susceptibility Group that did not change in the Low Susceptibility Group. 95 gene changes correlated with the changes in insulin sensitivity; 6 of these genes changed more than twofold in the High Susceptibility Group. Participants in the High Susceptibility Group were uniquely characterized with muscle gene responses described by a decrease in pathways responsible for lipid uptake and oxidation, decreased capacity for triglyceride export (APOB), increased lipogenesis (i.e., PFKFB3, FASN), and increased amino acid export (SLC43A1). These transcriptomic data provide a comprehensive examination of pathways and genes that may be useful biomarkers, or novel targets to offset muscle disuse-induced insulin resistance. NEW & NOTEWORTHY Short-term muscle disuse results in skeletal muscle insulin resistance through mechanisms that are not fully understood. Following a 5-day bed rest intervention, subjects were divided into High and Low Susceptibility Groups to inactivity-induced insulin resistance. This was followed by a genome-wide transcriptional analysis on muscle biopsy samples to gain insight on divergent insulin sensitivity responses. Our primary finding was that the skeletal muscle of subjects who experienced the most inactivity-induced insulin resistance (high susceptibility) was characterized by a decreased preference for lipid oxidation, increased lipogenesis, and increased amino acid export.

Dataset Information

Palmitate-induced skeletal muscle insulin resistance does not require NF-?B activation.

Publications

Palmitate-induced skeletal muscle insulin resistance does not require NF-κB activation.

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