Jung Jong Gab, Yi Sang-A, Choi Sung-E, Kang Yup, Kim Tae Ho, Jeon Ja Young, Bae Myung Ae, Ahn Jin Hee, Jeong Hana, Hwang Eun Sook, Lee Kwan-Woo
Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon 443-749, Korea.
Department of Physiology, Ajou University School of Medicine, Suwon 443-749, Korea.
Mol Cells. 2015 Dec;38(12):1037-43. doi: 10.14348/molcells.2015.0100. Epub 2015 Nov 4.
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.
TAZ激活剂2-丁基-5-甲基-6-(吡啶-3-基)-3-[2'-(1H-四唑-5-基)-联苯-4-基甲基]-3H-咪唑并[4,5-b]吡啶](TM-25659)通过与过氧化物酶体增殖物激活受体γ相互作用来抑制脂肪细胞分化。先前研究表明TM-25659可减轻高脂(HF)饮食诱导的肥胖(DIO)小鼠模型的体重增加。然而，TM-25659作用的基本机制仍不清楚。因此，我们研究了TM-25659对C2肌管和C57BL/6J小鼠骨骼肌功能的影响。我们研究了TM-25659在C2肌管中对棕榈酸(PA)诱导的胰岛素抵抗作用的分子机制。TM-25659改善了PA诱导的C2肌管中的胰岛素抵抗和炎症。此外，TM-25659通过激活GCN2途径(GCN2-磷酸化eIF2α-ATF4和FGF21)增加了C2肌管中FGF21 mRNA表达、蛋白水平和FGF21分泌。FGF21 siRNA减弱了TM-25659的这种有益作用。C57BL/6J小鼠喂食HF饮食30周。在接下来的14天里，HF饮食组被随机分为两组：HF饮食组和HF饮食+TM-25659组。经TM-25659处理的HF饮食小鼠的空腹血糖水平、胰岛素敏感性、胰岛素刺激的Akt磷酸化和炎症均有改善，但体重和食物摄入量均未受影响。经TM-25659处理的HF饮食小鼠还表现出FGF21 mRNA和蛋白表达增加。这些数据表明，在PA诱导的胰岛素抵抗和HF饮食诱导的胰岛素抵抗模型中，TM-25659可能通过诱导FGF21对治疗胰岛素抵抗有益。
