Abstract
It was hypothesized that choline supplementation in insulin resistant (IR) CTP:phosphoethanolamine cytidylyltransferase deficient (Pcyt2+/-) mice would ameliorate muscle function by remodeling glucose and fatty acid (FA) metabolism. Pcyt2+/- mice either received no treatment or were allowed access to 2 mg/mL choline in drinking water for 4 weeks. Skeletal muscle was harvested from choline treated and untreated mice. Lipid analysis and metabolic gene expression and signaling pathways were compared between untreated Pcyt2+/- mice, treated Pcyt2+/- mice, and Pcyt2+/+ mice. The major positive effect of choline supplementation on IR muscle was the reduction of glucose utilization for FA and triglyceride (TAG) synthesis and increased muscle glucose storage as glycogen. Choline reduced the expression of genes for FA and TAG formation (Scd1, Fas, Srebp1c, Dgat1/2), upregulated the genes for FA oxidation (Cpt1, Pparα, Pgc1α), and had minor effects on phospholipid and lipolysis genes. Pcyt2+/- muscle had reduced insulin signaling (IRS1), autophagy (LC3), and choline transport (CTL1) proteins that were restored by choline treatment. Additionally, choline activated AMPK and Akt while inhibiting mTORC1 phosphorylation. These data established that choline supplementation could restore muscle glucose metabolism by reducing lipogenesis and improving mitochondrial and intracellular signaling for protein and energy metabolism in insulin resistant Pcyt2 deficient mice.
Keywords:
Pcyt2; choline; insulin resistance; muscle squelettique; résistance à l’insuline; skeletal muscle; triglycerides; triglycérides.
MeSH terms
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Adaptation, Physiological / drug effects*
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Adaptation, Physiological / genetics
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Administration, Oral
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Animals
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Carnitine O-Palmitoyltransferase / genetics
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Carnitine O-Palmitoyltransferase / metabolism
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Choline / pharmacology*
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Diacylglycerol O-Acyltransferase / genetics
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Diacylglycerol O-Acyltransferase / metabolism
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Fatty Acids / metabolism
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Gene Expression Regulation
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Glucose / metabolism
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Insulin Receptor Substrate Proteins / genetics
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Insulin Receptor Substrate Proteins / metabolism
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Insulin Resistance*
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Lipogenesis / drug effects*
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Lipogenesis / genetics
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Mice
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Mice, Knockout
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / metabolism
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Muscle, Skeletal
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Organic Cation Transport Proteins / genetics
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Organic Cation Transport Proteins / metabolism
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PPAR alpha / genetics
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PPAR alpha / metabolism
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / genetics
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism
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RNA Nucleotidyltransferases / deficiency
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RNA Nucleotidyltransferases / genetics*
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Signal Transduction
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Stearoyl-CoA Desaturase / genetics
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Stearoyl-CoA Desaturase / metabolism
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Sterol Regulatory Element Binding Protein 1 / genetics
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Sterol Regulatory Element Binding Protein 1 / metabolism
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Triglycerides / metabolism
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fas Receptor / genetics
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fas Receptor / metabolism
Substances
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CTL1 protein, mouse
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Fas protein, mouse
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Fatty Acids
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Insulin Receptor Substrate Proteins
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Irs1 protein, mouse
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Map1lc3b protein, mouse
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Microtubule-Associated Proteins
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Organic Cation Transport Proteins
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PPAR alpha
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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Ppargc1a protein, mouse
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Srebf1 protein, mouse
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Sterol Regulatory Element Binding Protein 1
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Triglycerides
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fas Receptor
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Scd1 protein, mouse
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Stearoyl-CoA Desaturase
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DGAT2 protein, mouse
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Dgat1 protein, mouse
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Diacylglycerol O-Acyltransferase
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CPT1B protein, mouse
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Carnitine O-Palmitoyltransferase
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RNA Nucleotidyltransferases
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Ethanolamine-phosphate cytidylyltransferase
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Glucose
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Choline