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.

项目说明 脂联素是一种主要由脂肪细胞产生的多肽激素，目前被广泛应用 公认为胰岛素增敏剂，具有抗糖尿病、抗炎和 心脏保护功能。然而，脂联素的分子机制 增敏胰岛素的信号和作用在很大程度上仍不清楚。我们最近做了 鉴定了一个Pleckstrin同源(PH)和磷酸酪氨酸结合(PTB)结构域- 含有APPL1的蛋白质，直接与脂联素受体AdipoR1相互作用 和AdipoR2。RNAi抑制APPL1不仅抑制脂联素信号转导，而且 也有胰岛素刺激的Akt磷酸化，提示APPL1可能在 脂联素和胰岛素信号通路之间的相互作用 (毛等人，2006，NAT。细胞生物，8,516-523)。与这一观点一致，我们初步的 数据显示，APPL1直接与胰岛素受体相互作用，甚至更多 有趣的是，这种相互作用通过脂联素刺激而增强。此外，我们还有 发现APPL1在Ser430处经历脂联素刺激的磷酸化；这 提示了一种潜在的机制，即脂联素调节 APPL1和胰岛素受体。此外，我们还发现APPL2，一种APPL1 异构体与APPL1在蛋白质序列上有54%的同源性，与 APPL1，并在细胞中过表达时抑制脂联素信号。基于这些 新的发现，我们假设APPL之间的相互作用是形式和信号 脂联素和胰岛素信号通路中的分子可能在 这两条重要的信号通路之间的串扰。为了检验这一假设，我们 将：1)描述APPL1和信号分子之间的相互作用 胰岛素受体(IR)信号通路及其相互作用在胰岛素中的作用 2)阐明APPL2在调节脂联素和胰岛素信号转导中的作用 和功能；以及3)确定APPL1是否在胰岛素信号转导中发挥作用 脂联素在体内的胰岛素增敏作用。

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来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。

• DOI: 10.1002/stem.1844
• 发表时间: 2015-01
• 期刊: Stem cells (Dayton, Ohio)
• 作者: Yu L;Tu Q;Han Q;Zhang L;Sui L;Zheng L;Meng S;Tang Y;Xuan D;Zhang J;Murray D;Shen Q;Cheng J;Kim SH;Dong LQ;Valverde P;Cao X;Chen J
• 通讯作者: Chen J

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

• DOI: 10.1002/eji.201242836
• 发表时间: 2013-08
• 期刊: European journal of immunology
• 影响因子: 5.4
• 作者: Piccio L;Cantoni C;Henderson JG;Hawiger D;Ramsbottom M;Mikesell R;Ryu J;Hsieh CS;Cremasco V;Haynes W;Dong LQ;Chan L;Galimberti D;Cross AH
• 通讯作者: Cross AH

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

• DOI: 10.1007/s00125-013-2971-4
• 发表时间: 2013-09
• 期刊: Diabetologia
• 影响因子: 8.2
• 作者: Wang C;Li X;Mu K;Li L;Wang S;Zhu Y;Zhang M;Ryu J;Xie Z;Shi D;Zhang WJ;Dong LQ;Jia W
• 通讯作者: Jia W