Mechanisms of cross talk between insulin and adiponectin signaling pathways

产品描述（由申请人提供）：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，脂联素使胰岛素信号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列克底物蛋白同源性（PH）和磷酸酪氨酸结合（PTB）结构域的蛋白，APPL 1，其直接与脂联素受体AdipoR 1和AdipoR 2相互作用。RNAi对APPL 1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APPL 1可能在脂联素和胰岛素信号传导途径之间的串扰中起重要作用（Mao等人，2006，Nat. Cell Biol，8，516-523）。与这一观点一致，我们的初步数据表明，APPL 1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增强。此外，我们发现APPL 1在Ser 430处经历脂联素刺激的磷酸化;这表明脂联素调节APPL 1与胰岛素受体之间相互作用的潜在机制。此外，我们已经发现APPL 2，一种APPL 1同种型，与APPL 1在蛋白质序列上具有54%的同一性，当在细胞中过表达时，与APPL 1二聚化并抑制脂联素信号传导。基于这些新的发现，我们推测，APPL异构体和信号分子之间的相互作用，在脂联素和胰岛素信号通路可能发挥关键作用，这两个重要的信号通路之间的串扰。为了验证这一假设，我们将：1）表征APPL 1与胰岛素受体（IR）信号通路中的信号分子之间的相互作用以及这种相互作用在胰岛素信号传导中的作用; 2）阐明APPL 2在调节脂联素和胰岛素信号传导和功能中的作用;以及3）确定APPL 1是否在体内胰岛素信号传导中起作用以及脂联素的胰岛素增敏作用。公共卫生相关性：我们相信，从拟议的研究结果将提供关键信息的分子机制脂联素的胰岛素增敏作用，这应该有显着的意义，在开发新的治疗药物，用于治疗肥胖，胰岛素抵抗和2型糖尿病。

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.