Inhibitory cross-talk between the AMPK and ERK pathways mediates endoplasmic reticulum stress-induced insulin resistance in skeletal muscle

Title
Inhibitory cross-talk between the AMPK and ERK pathways mediates endoplasmic reticulum stress-induced insulin resistance in skeletal muscle
Author(s)
장현욱황승락정용태이선김용득[김용득]유예장영채[장영채]이인규[이인규]
Keywords
ACTIVATED PROTEIN-KINASE; TRANSLATIONAL CONTROL; SIGNALING PATHWAYS; HEPATIC STEATOSIS; GLUCOSE-TRANSPORT; ARRIVE GUIDELINES; ADIPOSE-TISSUE; OBESITY; SENSITIVITY; LIVER
Issue Date
201305
Publisher
WILEY-BLACKWELL
Citation
BRITISH JOURNAL OF PHARMACOLOGY, v.169, no.1, pp.69 - 81
Abstract
Background and Purpose Endoplasmic reticulum (ER) stress has been implicated in the pathogeneses of insulin resistance and type 2 diabetes, and extracellular signal-regulated kinase (ERK) antagonist is an insulin sensitizer that can restore muscle insulin responsiveness in both tunicamycin-treated muscle cells and type 2 diabetic mice. The present study was undertaken to determine whether the chemical or genetic inhibition ER stress pathway targeting by ERK results in metabolic benefits in muscle cells. Experimental Approach ER stress was induced in L6 myotubes using tunicamycin (5g center dot mL1) or thapsigargin (300nM) and cells were transfected with siRNA ERK or AMPK2. Changes in ER stress and in the ERK and AMPK signalling pathways were explored by Western blotting. The phosphorylation levels of insulin receptor substrate 1 were analysed by immunoprecipitation and using glucose uptake assay. Key Results ER stress dampened insulin-stimulated signals and glucose uptake, whereas treatment with the specific ERK inhibitor U0126 (25M) rescued impaired insulin signalling via AMPK activation. In db/db mice, U0126 administration decreased markers of insulin resistance and increased the phosphorylations of Akt and AMPK in muscle tissues. Conclusions and Implications Inhibition of ERK signalling pathways by a chemical inhibitor and knockdown of ERK improved AMPK and Akt signallings and reversed ER stress-induced insulin resistance in L6 myotubes. These findings suggest that ERK signalling plays an important role in the regulation of insulin signals in muscle cells under ER stress.
URI
http://hdl.handle.net/YU.REPOSITORY/25943http://dx.doi.org/10.1111/bph.12124
ISSN
0007-1188
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약학대학 > 약학부 > Articles
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