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.
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.
|Cai, Huan; Dong, Lily Q; Liu, Feng (2016) Recent Advances in Adipose mTOR Signaling and Function: Therapeutic Prospects. Trends Pharmacol Sci 37:303-317|
|Yu, Liming; Tu, Qisheng; Han, Qianqian et al. (2015) Adiponectin regulates bone marrow mesenchymal stem cell niche through a unique signal transduction pathway: an approach for treating bone disease in diabetes. Stem Cells 33:240-52|
|Liu, Meilian; Chen, Hongzhi; Wei, Li et al. (2015) Endoplasmic reticulum (ER) localization is critical for DsbA-L protein to suppress ER stress and adiponectin down-regulation in adipocytes. J Biol Chem 290:10143-8|
|Zhang, Lan; Meng, Shu; Tu, Qisheng et al. (2014) Adiponectin ameliorates experimental periodontitis in diet-induced obesity mice. PLoS One 9:e97824|
|Ryu, Jiyoon; Galan, Amanda K; Xin, Xiaoban et al. (2014) APPL1 potentiates insulin sensitivity by facilitating the binding of IRS1/2 to the insulin receptor. Cell Rep 7:1227-38|
|Wang, Chen; Li, Xiaowen; Mu, Kaida et al. (2013) Deficiency of APPL1 in mice impairs glucose-stimulated insulin secretion through inhibition of pancreatic beta cell mitochondrial function. Diabetologia 56:1999-2009|
|Piccio, Laura; Cantoni, Claudia; Henderson, Jacob G et al. (2013) Lack of adiponectin leads to increased lymphocyte activation and increased disease severity in a mouse model of multiple sclerosis. Eur J Immunol 43:2089-100|
|Liu, Meilian; Zhou, Lijun; Wei, Li et al. (2012) Phosphorylation of adaptor protein containing pleckstrin homology domain, phosphotyrosine binding domain, and leucine zipper motif 1 (APPL1) at Ser430 mediates endoplasmic reticulum (ER) stress-induced insulin resistance in hepatocytes. J Biol Chem 287:26087-93|
|Tu, Qisheng; Zhang, Jin; Dong, Lily Q et al. (2011) Adiponectin inhibits osteoclastogenesis and bone resorption via APPL1-mediated suppression of Akt1. J Biol Chem 286:12542-53|
|Holmes, R M; Yi, Z; De Filippis, E et al. (2011) Increased abundance of the adaptor protein containing pleckstrin homology domain, phosphotyrosine binding domain and leucine zipper motif (APPL1) in patients with obesity and type 2 diabetes: evidence for altered adiponectin signalling. Diabetologia 54:2122-31|
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