title: TM-25659-Induced Activation of FGF21 Level Decreases Insulin Resistance and Inflammation in Skeletal Muscle via GCN2 Pathways.
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. 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 PA-induced 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.
authors.affiliation: Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon 443-749, Korea.
authors.forename: Jong Gab
authors.initials: JG
authors.lastname: Jung
authors.affiliation: Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon 443-749, Korea.
authors.forename: Sang-A
authors.initials: SA
authors.lastname: Yi
authors.affiliation: Department of Physiology, Ajou University School of Medicine, Suwon 443-749, Korea.
authors.forename: Sung-E
authors.initials: SE
authors.lastname: Choi
authors.affiliation: Department of Physiology, Ajou University School of Medicine, Suwon 443-749, Korea.
authors.forename: Yup
authors.initials: Y
authors.lastname: Kang
authors.affiliation: Division of Endocrine and Metabolism, Department of Internal Medicine, Seoul Medical Center, Seoul 138-160, Korea.
authors.forename: Tae Ho
authors.initials: TH
authors.lastname: Kim
authors.affiliation: Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon 443-749, Korea.
authors.forename: Ja Young
authors.initials: JY
authors.lastname: Jeon
authors.affiliation: Korea Research Institute of Chemical Technology, University of Science & Technology, Daejeon 305-600, Korea.
authors.forename: Myung Ae
authors.initials: MA
authors.lastname: Bae
authors.affiliation: Korea Research Institute of Chemical Technology, University of Science & Technology, Daejeon 305-600, Korea.
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Ahn
authors.affiliation: College of Pharmacy, Graduate School of Pharmaceutical Sciences, and Global Top5 Research Program, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Hana
authors.initials: H
authors.lastname: Jeong
authors.affiliation: College of Pharmacy, Graduate School of Pharmaceutical Sciences, and Global Top5 Research Program, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Eun Sook
authors.initials: ES
authors.lastname: Hwang
authors.affiliation: Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon 443-749, Korea.
authors.forename: Kwan-Woo
authors.initials: KW
authors.lastname: Lee
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002478:Cells, Cultured; D059305:Diet, High-Fat / Q000009:adverse effects; D005346:Fibroblast Growth Factors / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000276:immunology; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000187:drug effects; D010168:Palmitates / Q000009:adverse effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: C572937:2-butyl-5-methyl-6-(pyridine-3-yl)-3-(2'-(1H-tetrazole-5-yl)-biphenyl-4-ylmethyl)-3H-imidazo(4,5-b)pyridine; D000893:Anti-Inflammatory Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D010168:Palmitates; D013777:Tetrazoles; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; C070634:Eif2ak4 protein, mouse; D017346:Protein Serine-Threonine Kinases
keywords: FGF21; GCN2; TM-25659; inflammation; insulin resistance