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: O Fabre, C Breuker, C Amouzou, T Salehzada, M Kitzmann, J Mercier, C Bisbal
• Journal: Cell death & disease (Cell Death Dis) Vol. 5 Pg. e1136 (Mar 20 2014) ISSN: 2041-4889 [Electronic] England
• PMID: 24651439 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ABCE1 protein, human
• ATP-Binding Cassette Transporters
• Abce1 protein, mouse
• Insulin
• TLR3 protein, human
• Toll-Like Receptor 3
• Palmitic Acid
• Superoxide Dismutase
• superoxide dismutase 2
• 2',5'-Oligoadenylate Synthetase
• Endoribonucleases
• 2-5A-dependent ribonuclease

Topics

• 2',5'-Oligoadenylate Synthetase (genetics, metabolism)
• ATP-Binding Cassette Transporters (genetics, metabolism)
• Animals
• Case-Control Studies
• Down-Regulation
• Endoribonucleases (genetics, metabolism)
• Enzyme Activation
• Female
• HeLa Cells
• Humans
• Insulin (metabolism)
• Insulin Resistance
• Male
• Mice
• Middle Aged
• Myoblasts, Skeletal (enzymology)
• Obesity (enzymology, genetics)
• Palmitic Acid (metabolism)
• Quadriceps Muscle (enzymology)
• RNA Interference
• Signal Transduction
• Superoxide Dismutase (genetics, metabolism)
• Toll-Like Receptor 3 (genetics, metabolism)
• Transfection