Mechanisms of cross talk between insulin and adiponectin signaling pathways

胰岛素和脂联素信号通路之间的串扰机制

• 批准号: 8465221
• 负责人: Lily Q Dong
• 金额: $ 30.55万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8465221
• 关键词: 2,4-thiazolidinedione; Adipocytes; Affect; Amino Acid Sequence; Anti-Inflammatory Agents; Anti-inflammatory; Binding; Cells; Data; Development; Diet; Dimerization; Fatty acid glycerol esters; Genes; Insulin; Insulin Receptor; Insulin Resistance; Insulin Signaling Pathway; Knockout Mice; Maps; Mediating; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; PTB Domain; Peptide Sequence Determination; Pharmaceutical Preparations; Phosphorylation; Play; Property; Protein Isoforms; Proteins; RNA Interference; Receptor Signaling; Research; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Testing; Thiazolidinediones; adiponectin; base; diabetic; in vivo; insulin sensitivity; insulin sensitizing drugs; insulin signaling; novel; novel therapeutics; obesity treatment; overexpression; peptide hormone; platelet protein P47; receptor

Project Description Adiponectin, a peptide hormone mainly produced by adipocytes, is now widely recognized as an insulin sensitizer that possesses anti-diabetic, anti-inflammatory and cardioprotective properties. However, the molecular mechanisms by which adiponectin sensitizes insulin signaling and action remain largely unknown. We have recently identified a pleckstrin homology (PH) and phosphotyrosine binding (PTB) domain- containing protein, APPL1 that interacts directly with the adiponectin receptors AdipoR1 and AdipoR2. Suppression of APPL1 by RNAi not only inhibits adiponectin signaling but also insulin-stimulated Akt phosphorylation, suggesting that APPL1 may play an essential role in the crosstalk between the adiponectin and insulin signaling pathways (Mao et al, 2006, Nat. Cell Biol, 8, 516-523). Consistent with this view, our preliminary data have shown that APPL1 interacts directly with the insulin receptor and more interestingly, this interaction is enhanced by adiponectin stimulation. In addition, we have found that APPL1 undergoes adiponectin-stimulated phosphorylation at Ser430; this suggests a potential mechanism by which adiponectin regulates the interaction between APPL1 and the insulin receptor. Furthermore, we have found that APPL2, an APPL1 isoform which shares 54% identity in protein sequence with APPL1, dimerizes with APPL1 and inhibits adiponectin signaling when overexpressed in cells. Based on these novel findings, we hypothesize that the interaction between APPL ispforms and signaling molecules in the adiponectin and insulin signaling pathways may play a key role in the crosstalk between these two important signaling pathways. To test this hypothesis, we will: 1) Characterize the interaction between APPL1 and signaling molecules in the insulin receptor (IR) signaling pathway and the roles of the interaction in insulin signaling; 2) Elucidate the roles of APPL2 in regulating adiponectin and insulin signaling and function; and 3) Determine whether APPL1 plays a role in insulin signaling and the insulin sensitizing effect of adiponectin in vivo.

项目描述 脂联素是一种主要由脂肪细胞产生的肽类激素，目前被广泛应用 被认为是一种胰岛素增敏剂，具有抗糖尿病、抗炎和 心脏保护特性。然而，脂联素的分子机制 使胰岛素信号变得敏感，其作用仍然很大程度上未知。我们最近有 鉴定了普莱克斯特林同源性（PH）和磷酸酪氨酸结合（PTB）结构域- 含有与脂联素受体 AdipoR1 直接相互作用的蛋白质 APPL1 和AdipoR2。 RNAi 抑制 APPL1 不仅会抑制脂联素信号传导， 胰岛素刺激的 Akt 磷酸化，表明 APPL1 可能发挥重要作用 在脂联素和胰岛素信号通路之间的串扰中发挥重要作用 (Mao 等人, 2006, Nat. Cell Biol, 8, 516-523)。与这一观点相一致，我们初步 数据显示 APPL1 直接与胰岛素受体等相互作用 有趣的是，脂联素刺激增强了这种相互作用。此外，我们还有 发现 APPL1 在 Ser430 处经历脂联素刺激的磷酸化；这 提出脂联素调节之间相互作用的潜在机制 APPL1 和胰岛素受体。此外，我们发现APPL2，APPL1 与 APPL1 的蛋白质序列有 54% 同一性的同种型，与 当细胞中过度表达时，APPL1 会抑制脂联素信号传导。基于这些 新的发现，我们假设 APPL ispforms 和信号传导之间的相互作用 脂联素和胰岛素信号通路中的分子可能在 这两个重要信号通路之间的串扰。为了检验这个假设，我们 将： 1) 表征 APPL1 和信号分子之间的相互作用 胰岛素受体（IR）信号通路及其在胰岛素中相互作用的作用 信号发送； 2) 阐明APPL2在调节脂联素和胰岛素信号传导中的作用 和功能； 3) 确定 APPL1 是否在胰岛素信号传导中发挥作用以及 体内脂联素的胰岛素增敏作用。

项目成果

Adiponectin regulates bone marrow mesenchymal stem cell niche through a unique signal transduction pathway: an approach for treating bone disease in diabetes.

脂联素通过独特的信号转导途径调节骨髓间充质干细胞生态位：一种治疗糖尿病骨病的方法。

• 发表时间: 2015-01
• 作者: Yu, Liming;Tu, Qisheng;Han, Qianqian;Zhang, Lan;Sui, Lei;Zheng, Leilei;Meng, Shu;Tang, Yin;Xuan, Dongying;Zhang, Jin;Murray, Dana;Shen, Qingping;Cheng, Jessica;Kim, Sung;Dong, Lily Q;Valverde, Paloma;Cao, Xinming;Chen, Jake
• 通讯作者: Chen, Jake

Lack of adiponectin leads to increased lymphocyte activation and increased disease severity in a mouse model of multiple sclerosis.

在多发性硬化症小鼠模型中，脂联素的缺乏会导致淋巴细胞活化增加和疾病严重程度增加。

• 发表时间: 2013-08
• 影响因子: 5.4
• 作者: Piccio, Laura;Cantoni, Claudia;Henderson, Jacob G;Hawiger, Daniel;Ramsbottom, Michael;Mikesell, Robert;Ryu, Jiyoon;Hsieh, Chyi;Cremasco, Viviana;Haynes, Wesley;Dong, Lily Q;Chan, Lawrence;Galimberti, Daniela;Cross, Anne H
• 通讯作者: Cross, Anne H

Deficiency of APPL1 in mice impairs glucose-stimulated insulin secretion through inhibition of pancreatic beta cell mitochondrial function.

小鼠中 APPL1 的缺乏会通过抑制胰腺 β 细胞线粒体功能来损害葡萄糖刺激的胰岛素分泌。

• 发表时间: 2013-09
• 影响因子: 8.2
• 作者: Wang, Chen;Li, Xiaowen;Mu, Kaida;Li, Ling;Wang, Shihong;Zhu, Yunxia;Zhang, Mingliang;Ryu, Jiyoon;Xie, Zhifang;Shi, Dongyun;Zhang, Weiping J;Dong, Lily Q;Jia, Weiping
• 通讯作者: Jia, Weiping