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TM-25659-induced activation of FGF21 level decreases insulin resistance and inflammation in skeletal muscle via GCN2 pathways

Title
TM-25659-induced activation of FGF21 level decreases insulin resistance and inflammation in skeletal muscle via GCN2 pathways
Authors
Jung J.G.Yi S.-A.Choi S.-E.Kang Y.Kim T.H.Jeon J.Y.Bae M.A.Ahn J.H.Jeong H.Hwang E.S.Lee K.-W.
Ewha Authors
황은숙
SCOPUS Author ID
황은숙scopus
Issue Date
2015
Journal Title
Molecules and Cells
ISSN
1016-8478JCR Link
Citation
vol. 38, no. 12, pp. 1037 - 1043
Keywords
FGF21GCN2InflammationInsulin resistanceTM-25659
Publisher
Korean Society for Molecular and Cellular Biology
Indexed
SCI; SCIE; SCOPUS; KCI WOS scopus
Abstract
The TAZ activator 2-butyl-5-methyl-6-(pyridine-3-yl)-3- [2'-(1H-tetrazole-5-yl)-biphenyl-4-ylmethyl]-3H-imidazo[4,5- b]pyridine] (TM-25659) inhibits adipocyte differentiation by interacting with peroxisome proliferator-activated receptor gamma. 1 TM-25659 was previously shown to decrease weight gain in a high fat (HF) diet-induced obesity (DIO) mouse model. However, the fundamental mechanisms underlying the effects of TM-25659 remain unknown. Therefore, we investigated the effects of TM-25659 on skeletal muscle functions in C2 myotubes and C57BL/6J mice. We studied the molecular mechanisms underlying the contribution of TM-25659 to palmitate (PA)-induced insulin resistance in C2 myotubes. TM-25659 improved PAinduced insulin resistance and inflammation in C2 myotubes. In addition, TM-25659 increased FGF21 mRNA expression, protein levels, and FGF21 secretion in C2 myotubes via activation of GCN2 pathways (GCN2-phosphoeIF2α- ATF4 and FGF21). This beneficial effect of TM-25659 was diminished by FGF21 siRNA. C57BL/6J mice were fed a HF diet for 30 weeks. The HF-diet group was randomly divided into two groups for the next 14 days: the HF-diet and HF-diet + TM-25659 groups. The HF diet + TM-25659- treated mice showed improvements in their fasting blood glucose levels, insulin sensitivity, insulin-stimulated Akt phosphorylation, and inflammation, but neither body weight nor food intake was affected. The HF diet + TM- 25659-treated mice also exhibited increased expression of both FGF21 mRNA and protein. These data indicate that TM-25659 may be beneficial for treating insulin resistance by inducing FGF21 in models of PA-induced insulin resistance and HF diet-induced insulin resistance. © The Korean Society for Molecular and Cellular Biology. All rights reserved.
DOI
10.14348/molcells.2015.0100
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약학대학 > 약학과 > Journal papers
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