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KMID : 0857020100250010042
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Kosin Medical Journal
2010 Volume.25 No. 1 p.42 ~ p.50
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Carbon Monoxide Prevents Ob-Rb Transfected Neuronal Cells from ER Stress-Induced Leption Resistance
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Kim Seong-Ju
Kim Taek-Sang
Rhew Hyun-Yul
Chung Hun-Taeg
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Abstract
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Background: It is well known that leptin is an important circulating signal for the inhibition of food intake and the
gain of body weight. Accumulating data suggest that leptin resistance has been considered to be one of the main causes
of obesity. However, the detailed mechanism of leptin resistance is not known yet. Recently, endoplasmic reticulum
(ER) stress-induced unfolded protein response (UPR) is reported to be responsible for the leptin resistance.
Materials & methods: Carbon monoxide (CO), a reaction product of the cytoprotective heme oxygenase (HO)-1, is
anti-apoptotic in a variety of models of cellular injury. Exogenous CO activated Nrf2 through the phosphorylation of
protein kinase R-like endoplasmic reticulum kinase (PERK), resulting in HO-1 expression. CO-induced activation of
PERK was followed by the phosphorylation of eukaryotic translation initiation factor 2a and the expression of
activating transcription factor 4. However, CO fails to induce X-box binding protein-1 expression and activating
transcription factor 6 cleavage. CO prevented X-box binding protein-1 expression and activating transcription factor 6
cleavage induced by ER-stress inducer such as thasigargin (TG), tunicamycin (TM) and homocysteine.
Results: In the present study, we hypothesized that exogenous CO might block the leptin resistance which is induced
by UPR during ER stress. Thasigargin or tunicamycin was used to induce ER stress. The activation status of leptin
signals were measured by western blotting analysis using a phospho-signal transducer and activation of transcription3
(STAT3) antibody. In this study, ER stress markedly inhibited leptin-induced STAT3 phosphorylation.
Conculusion: These results suggest that ER stress induces leptin resistance and exogenous CO-induced phosphorylation
of PERK branch reversed ER stress-induced leptin resistance. Moreover, CO releasing molecule (CORM) blocks the
inhibition of leptin-induced STAT3 phosphorylation. Together, the pathological mechanism of leptin resistance could
be ameliorated by the use of exogenous CO..
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KEYWORD
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Endoplasmic reticulum (ER), Unfolded protein response(UPR), Carbonmonoxide(CO), Leptin resistance, phospho-signal transducer and activation of transcription3 (STAT3)
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