title: Defects in TLR3 expression and RNase L activation lead to decreased MnSOD expression and insulin resistance in muscle cells of obese people.
abstract: Obesity is associated with chronic low-grade inflammation and oxidative stress that blunt insulin response in its target tissues, leading to insulin resistance (IR). IR is a characteristic feature of type 2 diabetes. Skeletal muscle is responsible for 75% of total insulin-dependent glucose uptake; consequently, skeletal muscle IR is considered to be the primary defect of systemic IR development. Interestingly, some obese people stay insulin-sensitive and metabolically healthy. With the aim of understanding this difference and identifying the mechanisms responsible for insulin sensitivity maintenance/IR development during obesity, we explored the role of the latent endoribonuclease (RNase L) in skeletal muscle cells. RNase L is a regulator of innate immunity, of double-stranded RNA sensors and of toll-like receptor (TLR) 4 signaling. It is regulated during inflammation by interferons and its activity is dependent on its binding to 2-5A, an oligoadenylate synthesized by oligoadenylate synthetases (OAS). Increased expression of RNase L or downregulation of its inhibitor (RLI) improved insulin response in mouse myogenic C2C12 cells and in primary human myotubes from normal-weight subjects treated with palmitate, a saturated free fatty acid (FFA) known to induce inflammation and oxidative stress via TLR4 activation. While RNase L and RLI levels remained unchanged, OAS level was decreased in primary myotubes from insulin-resistant obese subjects (OB-IR) compared with myotubes from insulin-sensitive obese subjects (OB-IS). TLR3 and mitochondrial manganese superoxide dismutase (MnSOD) were also underexpressed in OB-IR myotubes. Activation of RNase L by 2-5A transfection allowed to restore insulin response, OAS, MnSOD and TLR3 expression in OB-IR myotubes. Due to low expression of OAS, OB-IR myotubes present a defect in RNase L activation and TLR3 regulation. Consequently, MnSOD level is low and insulin sensitivity is reduced. These results support that RNase L activity limits FFA/obesity-induced impairment of insulin response in muscle cells via TLR3 and MnSOD expression.
authors.affiliation: U1046, Institut National de la Santé et de la Recherche Médicale (INSERM) - Université Montpellier 1 (UM1) - Université Montpellier 2 (UM2), Montpellier, France.
authors.forename: O
authors.initials: O
authors.lastname: Fabre
authors.affiliation: 1] U1046, Institut National de la Santé et de la Recherche Médicale (INSERM) - Université Montpellier 1 (UM1) - Université Montpellier 2 (UM2), Montpellier, France [2] Département de Pharmacie Clinique, Centre Hospitalier Régional Universitaire (CHRU) Montpellier, Montpellier, France.
authors.forename: C
authors.initials: C
authors.lastname: Breuker
authors.affiliation: 1] U1046, Institut National de la Santé et de la Recherche Médicale (INSERM) - Université Montpellier 1 (UM1) - Université Montpellier 2 (UM2), Montpellier, France [2] Département de Physiologie Clinique, CHRU Montpellier, Montpellier, France.
authors.forename: C
authors.initials: C
authors.lastname: Amouzou
authors.affiliation: U1046, Institut National de la Santé et de la Recherche Médicale (INSERM) - Université Montpellier 1 (UM1) - Université Montpellier 2 (UM2), Montpellier, France.
authors.forename: T
authors.initials: T
authors.lastname: Salehzada
authors.affiliation: Centre National de la Recherche Scientifique (CNRS), Institut de Génétique Humaine (IGH)-UPR 1142, Montpellier, France.
authors.forename: M
authors.initials: M
authors.lastname: Kitzmann
authors.affiliation: 1] U1046, Institut National de la Santé et de la Recherche Médicale (INSERM) - Université Montpellier 1 (UM1) - Université Montpellier 2 (UM2), Montpellier, France [2] Département de Physiologie Clinique, CHRU Montpellier, Montpellier, France.
authors.forename: J
authors.initials: J
authors.lastname: Mercier
authors.affiliation: U1046, Institut National de la Santé et de la Recherche Médicale (INSERM) - Université Montpellier 1 (UM1) - Université Montpellier 2 (UM2), Montpellier, France.
authors.forename: C
authors.initials: C
authors.lastname: Bisbal
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000235:genetics / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016022:Case-Control Studies; D015536:Down-Regulation; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D005260:Female; D006367:HeLa Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008875:Middle Aged; D032448:Myoblasts, Skeletal / Q000201:enzymology*; D009765:Obesity / Q000201:enzymology* / Q000235:genetics; D019308:Palmitic Acid / Q000378:metabolism; D052097:Quadriceps Muscle / Q000201:enzymology*; D034622:RNA Interference; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D000099156:Superoxide Dismutase 2
chemical_list: D015088:2',5'-Oligoadenylate Synthetase; D018528:ATP-Binding Cassette Transporters; D004722:Endoribonucleases; D007328:Insulin; D019308:Palmitic Acid; D013482:Superoxide Dismutase; D051196:Toll-Like Receptor 3; D000099156:Superoxide Dismutase 2; C501917:ABCE1 protein, human; C501918:Abce1 protein, mouse; C495344:TLR3 protein, human; C031956:2-5A-dependent ribonuclease