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: 8204236
• 负责人: Lily Q Dong
• 金额: $ 1.21万
• 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 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8204236
• 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; Health; 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

DESCRIPTION (provided by applicant): 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 isoforms 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. PUBLIC HEALTH RELEVANCE: We believe that results from the proposed study will provide critical information on the molecular mechanism underlying the insulin sensitizing effect of adiponectin, which should have significant implications in the development of new therapeutic drugs for the treatment of obesity, insulin resistance, and type 2 diabetes.

描述（申请人提供）：脂联素是一种主要由脂肪细胞产生的肽激素，目前被广泛认为是一种具有抗糖尿病、抗炎和心脏保护特性的胰岛素增敏剂。然而，脂联素使胰岛素信号传导和作用敏感的分子机制仍然很大程度上未知。我们最近鉴定了一种含有普莱克斯特林同源性 (PH) 和磷酸酪氨酸结合 (PTB) 结构域的蛋白 APPL1，它直接与脂联素受体 AdipoR1 和 AdipoR2 相互作用。 RNAi 对 APPL1 的抑制不仅抑制脂联素信号传导，而且抑制胰岛素刺激的 Akt 磷酸化，表明 APPL1 可能在脂联素和胰岛素信号传导途径之间的串扰中发挥重要作用 (Mao et al, 2006, Nat. Cell Biol, 8, 516-523）。与这一观点一致，我们的初步数据表明 APPL1 直接与胰岛素受体相互作用，更有趣的是，这种相互作用通过脂联素刺激而增强。此外，我们发现APPL1在Ser430处经历脂联素刺激的磷酸化；这表明脂联素调节 APPL1 和胰岛素受体之间相互作用的潜在机制。此外，我们发现APPL2（APPL1的同种型）与APPL1在蛋白质序列上具有54%的同一性，当在细胞中过度表达时，APPL2与APPL1形成二聚体并抑制脂联素信号传导。基于这些新发现，我们假设 APPL 异构体与脂联素和胰岛素信号通路中信号分子之间的相互作用可能在这两个重要信号通路之间的串扰中发挥关键作用。为了检验这一假设，我们将： 1) 表征 APPL1 与胰岛素受体 (IR) 信号通路中信号分子之间的相互作用以及相互作用在胰岛素信号传导中的作用； 2）阐明APPL2在调节脂联素和胰岛素信号传导和功能中的作用； 3)确定APPL1是否在胰岛素信号传导和体内脂联素的胰岛素增敏作用中发挥作用。公共健康相关性：我们相信，拟议研究的结果将为脂联素胰岛素增敏作用的分子机制提供关键信息，这对开发治疗肥胖、胰岛素抵抗和糖尿病的新治疗药物具有重要意义。 2型糖尿病。