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

Jong Gab Jung, Sang A. Yi, Sung E. Choi, Yup Kang, Tae Ho Kim, Ja Young Jeon, Myung Ae Bae, Jin Hee Ahn, Hana Jeong, Eun Sook Hwang, Kwan Woo Lee

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

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.

Original languageEnglish
Pages (from-to)1037-1043
Number of pages7
JournalMolecules and Cells
Volume38
Issue number12
DOIs
StatePublished - 4 Nov 2015

Keywords

  • FGF21
  • GCN2
  • Inflammation
  • Insulin resistance
  • TM-25659

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