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lüll Defects in TLR3 expression and RNase L activation lead to decreased MnSOD expression and insulin resistance in muscle cells of obese people Fabre O; Breuker C; Amouzou C; Salehzada T; Kitzmann M; Mercier J; Bisbal CCell Death Dis 2014[Mar]; 5 (3): e1136Obesity 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.|*Insulin Resistance[MESH]|2',5'-Oligoadenylate Synthetase/genetics/metabolism[MESH]|ATP-Binding Cassette Transporters/genetics/metabolism[MESH]|Animals[MESH]|Case-Control Studies[MESH]|Down-Regulation[MESH]|Endoribonucleases/genetics/*metabolism[MESH]|Enzyme Activation[MESH]|Female[MESH]|HeLa Cells[MESH]|Humans[MESH]|Insulin/*metabolism[MESH]|Male[MESH]|Mice[MESH]|Middle Aged[MESH]|Myoblasts, Skeletal/*enzymology[MESH]|Obesity/*enzymology/genetics[MESH]|Palmitic Acid/metabolism[MESH]|Quadriceps Muscle/*enzymology[MESH]|RNA Interference[MESH]|Signal Transduction[MESH]|Superoxide Dismutase/genetics/*metabolism[MESH]|Toll-Like Receptor 3/genetics/*metabolism[MESH]|Transfection[MESH] |