Azoramide, a novel regulator, favors adipogenesis against osteogenesis through inhibiting the GLP-1 receptor-PKA-β-catenin pathway.
Azoramide, a novel regulator, favors adipogenesis against osteogenesis through inhibiting the GLP-1 receptor-PKA-β-catenin pathway.
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Azoramide 是一种新型调节剂，通过抑制 GLP-1 受体 -PKA-β-连环蛋白途径促进脂肪生成而不是骨生成
DOI：
10.1186/s13287-018-0771-y
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发表时间：
2018-03-09
影响因子：
7.5
通讯作者：
Lu Z
中科院分区：
文献类型：
--
作者：
Ruan B;Zhu Z;Yan Z;Yang W;Zhai D;Wang L;Ye Z;Lu H;Xiang A;Liang J;Jiang Y;Xu C;Wang Z;Wei M;Lei X;Cao X;Lu Z
间充质干细胞（MSC）的相互命运决定骨或脂肪细胞是由Wnt相关的信号和胰高血糖素样肽-1受体（GLP-1 R）。偶氮酰胺是一种ER应激缓解剂，据报道具有抗糖尿病作用。在这项研究中，我们研究了偶氮酰胺在调节骨髓间充质干细胞成脂或成骨分化的谱系决定中的作用。在这项研究中，骨形态发生蛋白（BMP）2诱导的顶骨骨膜骨形成试验，C3 H10 T1/2和小鼠骨髓MSC衍生的骨形成和脂肪生成试验，骨组织和脂滴的特异性染色的显微计算机断层扫描和组织学分析，以评估的作用，偶氮唑胺MSC分化的谱系确定。收集细胞进行Western blot和实时荧光定量PCR检测，并采用免疫荧光染色方法探讨偶氮酰胺对MSC分化的调控机制。基于体内和体外的MSC衍生的骨形成测定，偶氮酰胺处理显示出有利于脂肪生成而非骨生成的细胞命运决定能力。进一步的机制表征公开了GLP-1 R激动剂肽毒蜥外泌肽-4（Ex-4）和GLP-1 R小干扰（si）RNA均消除了偶氮唑胺的双重作用。此外，cAMP-蛋白激酶A（PKA）介导的细胞核β-catenin活性负责azoramide对骨形成的负作用，有利于脂肪生成。这些数据提供了第一个证据表明，偶氮酰胺可能作为拮抗剂对GLP-1 R的MSC谱系确定。本文的在线版本（10.1186/s13287-018-0771-y）包含补充材料，可供授权用户使用。
The reciprocal fate decision of mesenchymal stem cells (MSCs) to either bone or adipocytes is determined by Wnt-related signaling and the glucagon-like peptide-1 receptor (GLP-1R). Azoramide, an ER stress alleviator, was reported to have an antidiabetic effect. In this study, we investigated the function of azoramide in regulating the lineage determination of MSCs for either adipogenic or osteogenic differentiation. In this study, microcomputed tomography and histological analysis on bone morphogenetic protein (BMP)2-induced parietal periosteum bone formation assays, C3H10T1/2 and mouse bone marrow MSC-derived bone formation and adipogenesis assays, and specific staining for bone tissue and lipid droplets were used to evaluate the role of azoramide on the lineage determination of MSC differentiation. Cells were harvested for Western blot and quantitative real-time polymerase chain reaction (PCR), and immunofluorescence staining was used to explore the potential mechanism of azoramide for regulating MSC differentiation. Based on MSC-derived bone formation assays both in vivo and in vitro, azoramide treatment displayed a cell fate determining ability in favor of adipogenesis over osteogenesis. Further mechanistic characterizations disclosed that both the GLP-1R agonist peptide exendin-4 (Ex-4) and GLP-1R small interfering (si)RNA abrogated azoramide dual effects. Moreover, cAMP-protein kinase A (PKA)-mediated nuclear β-catenin activity was responsible for the negative function of azoramide on bone formation in favor of adipogenesis. These data provide the first evidence to show that azoramide may serve as an antagonist against GLP-1R in MSC lineage determination. The online version of this article (10.1186/s13287-018-0771-y) contains supplementary material, which is available to authorized users.
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影响因子：
12.4
作者：
Chen Q;Shou P;Zheng C;Jiang M;Cao G;Yang Q;Cao J;Xie N;Velletri T;Zhang X;Xu C;Zhang L;Yang H;Hou J;Wang Y;Shi Y
通讯作者：
Shi Y
影响因子：
1.9
作者：
Colaianni, Graziana;Brunetti, Giacomina;Grano, Maria
通讯作者：
Grano, Maria
旧大陆果蝠两种共同分布物种的遗传结构对比
影响因子：
3.7
作者：
Chen J;Rossiter SJ;Flanders JR;Sun Y;Hua P;Miller-Butterworth C;Liu X;Rajan KE;Zhang S
通讯作者：
Zhang S
GLP-1受体的激活通过β-Catenin促进骨髓基质细胞成骨分化
影响因子：
5.9
作者：
Meng J;Ma X;Wang N;Jia M;Bi L;Wang Y;Li M;Zhang H;Xue X;Hou Z;Zhou Y;Yu Z;He G;Luo X
通讯作者：
Luo X
影响因子：
56.9
作者：
Mundy, G;Garrett, R;Gutierrez, G
通讯作者：
Gutierrez, G