title: DHA at nutritional doses restores insulin sensitivity in skeletal muscle by preventing lipotoxicity and inflammation.
abstract: Skeletal muscle plays a major role in the control of whole body glucose disposal in response to insulin stimulus. Excessive supply of fatty acids to this tissue triggers cellular and molecular disturbances leading to lipotoxicity, inflammation, mitochondrial dysfunctions, impaired insulin response and decreased glucose uptake. This study was conducted to analyze the preventive effect of docosahexaenoic acid (DHA), a long-chain polyunsaturated n-3 fatty acid, against insulin resistance, lipotoxicity and inflammation in skeletal muscle at doses compatible with nutritional supplementation. DHA (30 μM) prevented insulin resistance in C2C12 myotubes exposed to palmitate (500 μM) by decreasing protein kinase C (PKC)-θ activation and restoring cellular acylcarnitine profile, insulin-dependent AKT phosphorylation and glucose uptake. Furthermore, DHA protected C2C12 myotubes from palmitate- or lipopolysaccharide-induced increase in Ptgs2, interleukin 6 and tumor necrosis factor-α mRNA level, probably through the inhibition of p38 MAP kinase and c-Jun amino-terminal kinase. In LDLR -/- mice fed a high-cholesterol-high-sucrose diet, supplementation with DHA reaching up to 2% of daily energy intake enhanced the insulin-dependent AKT phosphorylation and reduced the PKC-θ activation in skeletal muscle. Therefore, DHA used at physiological doses participates in the regulation of muscle lipid and glucose metabolisms by preventing lipotoxicity and inflammation.
authors.affiliation: UMR 1019, Unité de Nutrition Humaine, INRA, Centre de Recherche en Nutrition Humaine (CRNH) Auvergne, Clermont Université, Université d'Auvergne, F-63000 Clermont-Ferrand, France. Electronic address: frederic.capel@clermont.inra.fr.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Capel
authors.affiliation: Service Maladies Héréditaires du Métabolisme, Centre de Biologie et Pathologie Est, CHU de Lyon, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Acquaviva
authors.affiliation: UMR 1019, Unité de Nutrition Humaine, INRA, Centre de Recherche en Nutrition Humaine (CRNH) Auvergne, Clermont Université, Université d'Auvergne, F-63000 Clermont-Ferrand, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Pitois
authors.affiliation: UMR 1019, Unité de Nutrition Humaine, INRA, Centre de Recherche en Nutrition Humaine (CRNH) Auvergne, Clermont Université, Université d'Auvergne, F-63000 Clermont-Ferrand, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Laillet
authors.affiliation: UMR 1019, Unité de Nutrition Humaine, INRA, Centre de Recherche en Nutrition Humaine (CRNH) Auvergne, Clermont Université, Université d'Auvergne, F-63000 Clermont-Ferrand, France.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Rigaudière
authors.affiliation: UMR 1019, Unité de Nutrition Humaine, INRA, Centre de Recherche en Nutrition Humaine (CRNH) Auvergne, Clermont Université, Université d'Auvergne, F-63000 Clermont-Ferrand, France.
authors.forename: Chrystèle
authors.initials: C
authors.lastname: Jouve
authors.affiliation: INRA, UMR 1019, Plateforme d'Exploration du Métabolisme, UNH, F-63000 Clermont-Ferrand, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Pouyet
authors.affiliation: UMR 1019, Unité de Nutrition Humaine, INRA, Centre de Recherche en Nutrition Humaine (CRNH) Auvergne, Clermont Université, Université d'Auvergne, F-63000 Clermont-Ferrand, France.
authors.forename: Cècile
authors.initials: C
authors.lastname: Gladine
authors.affiliation: UMR 1019, Unité de Nutrition Humaine, INRA, Centre de Recherche en Nutrition Humaine (CRNH) Auvergne, Clermont Université, Université d'Auvergne, F-63000 Clermont-Ferrand, France.
authors.forename: Blandine
authors.initials: B
authors.lastname: Comte
authors.affiliation: Service Maladies Héréditaires du Métabolisme, Centre de Biologie et Pathologie Est, CHU de Lyon, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Vianey Saban
authors.affiliation: UMR 1019, Unité de Nutrition Humaine, INRA, Centre de Recherche en Nutrition Humaine (CRNH) Auvergne, Clermont Université, Université d'Auvergne, F-63000 Clermont-Ferrand, France.
authors.forename: Bèatrice
authors.initials: B
authors.lastname: Morio
mesh_terms: D065567:Absorption, Physiological; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D066273:Diet, Western / Q000009:adverse effects; D019587:Dietary Supplements; D004281:Docosahexaenoic Acids / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D005395:Fish Oils / Q000008:administration & dosage / Q000627:therapeutic use*; D005947:Glucose / Q000378:metabolism; D006614:Hindlimb; D007333:Insulin Resistance; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D050356:Lipid Metabolism; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D009220:Myositis / Q000097:blood / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D000074121:Protein Kinase C-theta; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000819:agonists / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D014413:Tuna
chemical_list: D005395:Fish Oils; D007527:Isoenzymes; D011973:Receptors, LDL; D004281:Docosahexaenoic Acids; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta; D005947:Glucose
keywords: Inflammation; Insulin; Lipotoxicity; Muscle; Omega 3