DOI QR코드

DOI QR Code

IRS-2 Partially Compensates for the Insulin Signal Defects in IRS-1-/- Mice Mediated by miR-33

  • Tang, Chen-Yi (Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University) ;
  • Man, Xiao-Fei (Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University) ;
  • Guo, Yue (Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University) ;
  • Tang, Hao-Neng (Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University) ;
  • Tang, Jun (Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University) ;
  • Zhou, Ci-La (Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University) ;
  • Tan, Shu-Wen (Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University) ;
  • Wang, Min (Department of Endocrinology, Xiangya Hospital, Central South University) ;
  • Zhou, Hou-De (Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University)
  • Received : 2016.09.19
  • Accepted : 2017.01.04
  • Published : 2017.02.28

Abstract

Insulin signaling is coordinated by insulin receptor substrates (IRSs). Many insulin responses, especially for blood glucose metabolism, are mediated primarily through Irs-1 and Irs-2. Irs-1 knockout mice show growth retardation and insulin signaling defects, which can be compensated by other IRSs in vivo; however, the underlying mechanism is not clear. Here, we presented an Irs-1 truncated mutated mouse ($Irs-1^{-/-}$) with growth retardation and subcutaneous adipocyte atrophy. $Irs-1^{-/-}$ mice exhibited mild insulin resistance, as demonstrated by the insulin tolerance test. Phosphatidylinositol 3-kinase (PI3K) activity and phosphorylated Protein Kinase B (PKB/AKT) expression were elevated in liver, skeletal muscle, and subcutaneous adipocytes in Irs-1 deficiency. In addition, the expression of IRS-2 and its phosphorylated version were clearly elevated in liver and skeletal muscle. With miRNA microarray analysis, we found miR-33 was down-regulated in bone marrow stromal cells (BMSCs) of $Irs-1^{-/-}$ mice, while its target gene Irs-2 was up-regulated in vitro studies. In addition, miR-33 was down-regulated in the presence of Irs-1 and which was up-regulated in fasting status. What's more, miR-33 restored its expression in re-feeding status. Meanwhile, miR-33 levels decreased and Irs-2 levels increased in liver, skeletal muscle, and subcutaneous adipocytes of $Irs-1^{-/-}$ mice. In primary cultured liver cells transfected with an miR-33 inhibitor, the expression of IRS-2, PI3K, and phosphorylated-AKT (p-AKT) increased while the opposite results were observed in the presence of an miR-33 mimic. Therefore, decreased miR-33 levels can up-regulate IRS-2 expression, which appears to compensate for the defects of the insulin signaling pathway in Irs-1 deficient mice.

Keywords

insulin signaling pathway;IRS-1;IRS-2;miR-33

Acknowledgement

Supported by : National Natural Scientific Foundation of China, Hunan Provincial Natural Science Foundation of Chin

References

  1. Araki, E., Lipes, M.A., Patti, M.E., Bruning, J.C., Haag, B. 3rd., Johnson, R.S., and Kahn, C.R.(1994). Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene. Nature 372, 186-190. https://doi.org/10.1038/372186a0
  2. Bae, C.R., Hasegawa, K., Akieda-Asai, S., Kawasaki, Y., Senba, K., Cha, Y.S., and Date, Y. (2014). Possible involvement of food texture in insulin resistance and energy metabolism in male rats. J. Endocrinol. 222, 61-72. https://doi.org/10.1530/JOE-13-0553
  3. Benito, M. (2011). Tissue specificity on insulin action and resistance: past to recent mechanisms. Acta Physiol. 201, 297-312. https://doi.org/10.1111/j.1748-1716.2010.02201.x
  4. Berindan-Neagoe, I., Monroig Pdel, C., Pasculli, B., and Calin, G.A. (2014) MicroRNAome genome: a treasure for cancer diagnosis and therapy. CA Cancer J. Clin. 64, 311-336. https://doi.org/10.3322/caac.21244
  5. Blaak, E.E. (2005). Metabolic fluxes in skeletal muscle in relation to obesity and insulin resistance. Best Pract. Res. Clin. Endocrinol. Metab. 19, 391-403. https://doi.org/10.1016/j.beem.2005.04.001
  6. Bruning, J.C., Winnay, J., Cheatham, B., and Kahn, C.R. (1997). Differential signaling by insulin receptor substrate 1 (IRS-1) and IRS-2 in IRS-1-deficient cells. Mol. Cell Biol. 17, 1513-1521. https://doi.org/10.1128/MCB.17.3.1513
  7. Bu, Y.H., He, Y.L., Zhou, H.D., Liu, W., Peng, D., Tang, A.G., Tang, L.L., Xie, H., Huang, Q.X., Luo, X.H., et al. (2010). Insulin receptor substrate 1 regulates the cellular differentiation and the matrix metallopeptidase expression of preosteoblastic cells. J. Endocrinol. 206, 271-277. https://doi.org/10.1677/JOE-10-0064
  8. Cheng, C.J., Bahal, R., Babar, I.A., Pincus, Z., Barrera, F., Liu, C., Svoronos, A., Braddock, D.T., Glazer, P.M., Engelman, D.M., et al. (2015). MicroRNA silencing for cancer therapy targeted to the tumour microenvironment. Nature 518, 107-110. https://doi.org/10.1038/nature13905
  9. Davalos, A., Goedeke, L., Smibert, P., Ramirez, C.M., Warrier, N.P., Andreo, U., Cirera-Salinas, D., Rayner, K., Suresh, U., Pastor-Pareja, J.C., et al. (2011). miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling. Proc. Natl. Acad. Sci. USA 108, 9232-9237. https://doi.org/10.1073/pnas.1102281108
  10. Fang, J.K., Zhou, Y.P., and Li, M.L. (2014). [Research progress on effects of traditional Chinese medicines on proliferation, apoptosis and differentiation of bone marrow mesenchymal stem cells]. Zhongguo Zhong Yao Za Zhi. 39, 2834-2837.
  11. Fernandez-Hernando, C., Ramirez, C.M., Goedeke, L., and Suarez, Y. (2013). MicroRNAs in metabolic disease. Arterioscler Thromb. Vasc. Biol. 33, 178-185. https://doi.org/10.1161/ATVBAHA.112.300144
  12. Giudice, A., D'Arena, G., Crispo, A., Tecce, M.F., Nocerino, F., Grimaldi, M., Rotondo, E., D'Ursi, A.M., Scrima, M., Galdiero, M., et al. (2016). Role of viral miRNAs and epigenetic modifications in epsteinbarr virus-associated gastric carcinogenesis. Oxid. Med. Cell Longev. 2016, 6021934.
  13. Gonzalez-Rodriguez, A., Clampit, J.E., Escribano, O., Benito, M., Rondinone, C.M., and Valverde, A.M. (2007). Developmental switch from prolonged insulin action to increased insulin sensitivity in protein tyrosine phosphatase 1B-deficient hepatocytes. Endocrinology 148, 594-608.30. https://doi.org/10.1210/en.2006-0644
  14. Guay, C., and Regazzi, R. (2015). MicroRNAs and the functional beta cell mass: for better or worse. Diabetes Metab. 41, 369-377.20. https://doi.org/10.1016/j.diabet.2015.03.006
  15. Guo, S. (2013). Molecular basis of insulin resistance: The role of IRS and Foxo1 in the control of diabetes mellitus and its complications. Drug Discov. Today Dis. Mech. 10, e27-e33. https://doi.org/10.1016/j.ddmec.2013.06.003
  16. Guo, S. (2014). Insulin signaling, resistance, and the metabolic syndrome: insights from mouse models into disease mechanisms. J. Endocrinol. 220, T1-T23. https://doi.org/10.1530/JOE-13-0327
  17. Guo, Y., Tang, C.Y., Man, X.F., Tang, H.N., Tang, J., Wang, F., Zhou, C.L., Tan, S.W., Feng, Y.Z., and Zhou, H.D. (2016). Insulin receptor substrate-1 time-dependently regulates bone formation by controlling collagen Ialpha2 expression via miR-342. FASEB J. 30, 4214-4226. https://doi.org/10.1096/fj.201600445RR
  18. Kaburagi, Y., Satoh, S., Tamemoto, H., Yamamoto-Honda, R., Tobe, K., Veki, K., Yamauchi, T., Kono-Sugita, E., Sekihara, H., Aizawa, S., et al. (1997). Role of insulin receptor substrate-1 and pp60 in the regulation of insulin-induced glucose transport and GLUT4 translocation in primary adipocytes. J. Biol. Chem. 272, 25839-25844. https://doi.org/10.1074/jbc.272.41.25839
  19. Kadowaki, T. (2000). Insights into insulin resistance and type 2 diabetes from knockout mouse models. J. Clin. Invest. 106, 459-465. https://doi.org/10.1172/JCI10830
  20. Kido, Y., Burks, D.J., Withers, D., Bruning, J.C., Kahn, C.R., White, M.F., and Accili, D. (2000). Tissue-specific insulin resistance in mice with mutations in the insulin receptor, IRS-1, and IRS-2. J. Clin. Invest. 105, 199-205. https://doi.org/10.1172/JCI7917
  21. Kong, Y.W., Ferland-McCollough, D., Jackson, T.J., and Bushell, M. (2012). microRNAs in cancer management. Lancet Oncol. 13, e249-258. https://doi.org/10.1016/S1470-2045(12)70073-6
  22. Kubota, N., Terauchi, Y., Tobe, K., Yano, W., Suzuki, R., Ueki, K., Takamoto, I., Satoh, H., Maki, T., Kubota, T., et al. (2004). Insulin receptor substrate 2 plays a crucial role in beta cells and the hypothalamus. J. Clin. Invest. 114, 917-927. https://doi.org/10.1172/JCI21484
  23. Leibiger, I.B., Leibiger, B., and Berggren, P.O. (2008). Insulin signaling in the pancreatic beta-cell. Annu. Rev. Nutr. 28, 233-251. https://doi.org/10.1146/annurev.nutr.28.061807.155530
  24. Li, X., and Song, G. (2012). [Roles of matrix metalloproteinase in migration and differentiation of bone marrow-derived mesenchymal stem cells]. Sheng Wu Yi Xue Gong Cheng Xue Za Zhi. 29, 387-391.
  25. Li, Y., Wang, J., Gu, T., and Yamahara, J. (2014). Oleanolic acid supplement attenuates liquid fructose-induced adipose tissue insulin resistance through the insulin receptor substrate- 1/phosphatidylinositol 3-kinase/Akt signaling pathway in rats. Toxicol. Appl. Pharmacol. 277, 155-163. https://doi.org/10.1016/j.taap.2014.03.016
  26. Lu, J., Zeng, Y., Hou, W., Zhang, S., Li, L., Luo, X., Xi, W., Chen, Z., and Xiang, M. (2012). The soybean peptide aglycin regulates glucose homeostasis in type 2 diabetic mice via IR/IRS1 pathway. J. Nutr. Biochem. 23, 1449-1457. https://doi.org/10.1016/j.jnutbio.2011.09.007
  27. Man, X.F., Tan, S.W., Tang, H.N., Guo, Y., Tang, C.Y., Tang, J., Zhou, C.L., and Zhou, H.D. (2016). MiR-503 inhibits adipogenesis by targeting bone morphogenetic protein receptor 1a. Am. J. Transl. Res. 8, 2727-2737.
  28. Mao, Y., Mohan, R., Zhang, S., and Tang, X. (2013). MicroRNAs as pharmacological targets in diabetes. Pharmacol. Res. 75, 37-47. https://doi.org/10.1016/j.phrs.2013.06.005
  29. Newsholme, E.A., and Dimitriadis, G. (2001). Integration of biochemical and physiologic effects of insulin on glucose metabolism. Exp. Clin. Endocrinol. Diabetes 109, S122-134. https://doi.org/10.1055/s-2001-18575
  30. Papaetis, G.S., Papakyriakou, P., and Panagiotou, T.N. (2015). Central obesity, type 2 diabetes and insulin: exploring a pathway full of thorns. Arch. Med. Sci. 11, 463-482.
  31. Patti, M.E., Sun, X.J., Bruening, J.C., Araki, E., Lipes, M.A., White, M.F., and Kahn, C.R. (1995). 4PS/insulin receptor substrate (IRS)-2 is the alternative substrate of the insulin receptor in IRS-1-deficient mice. J. Biol. Chem. 270, 24670-24673. https://doi.org/10.1074/jbc.270.42.24670
  32. Rebustini, I.T., Vlahos, M., Packer, T., Kukuruzinska, M.A., and Maas, R.L. (2016). An integrated miRNA functional screening and target validation method for organ morphogenesis. Sci. Rep. 6, 23215. https://doi.org/10.1038/srep23215
  33. Richardson, K., Nettleton, J.A., Rotllan, N., Tanaka, T., Smith, C.E., Lai, C.Q., Parnell, L.D., Lee, Y.C., Lahti, J., Lemaitre, R.N., et al. (2013). Gain-of-function lipoprotein lipase variant rs13702 modulates lipid traits through disruption of a microRNA-410 seed site. Am. J. Hum. Genet. 92, 5-14. https://doi.org/10.1016/j.ajhg.2012.10.020
  34. Rondinone, C.M., Wang, L.M., Lonnroth, P., Wesslau, C., Pierce, J.H., and Smith, U. (1997). Insulin receptor substrate (IRS) 1 is reduced and IRS-2 is the main docking protein for phosphatidylinositol 3-kinase in adipocytes from subjects with non-insulin-dependent diabetes mellitus. Proc. Natl. Acad. Sci. USA 94, 4171-4175. https://doi.org/10.1073/pnas.94.8.4171
  35. Rui, L. (2014). Energy metabolism in the liver. Compr. Physiol. 4, 177-197.
  36. Sawka-Verhelle, D., Tartare-Deckert, S., White, M.F., and Van Obberghen, E. (1996). Insulin receptor substrate-2 binds to the insulin receptor through its phosphotyrosine-binding domain and through a newly identified domain comprising amino acids 591-786. J. Biol. Chem. 271, 5980-5983. https://doi.org/10.1074/jbc.271.11.5980
  37. Sesti, G., Federici, M., Hribal., M.L., Lauro, D., Sbraccia, P., and Lauro, R. (2001). Defects of the insulin receptor substrate (IRS) system in human metabolic disorders. FASEB J. 15, 2099-2111. https://doi.org/10.1096/fj.01-0009rev
  38. Simmons, J.G., Ling, Y., Wilkins, H., Fuller, C.R., D'Ercole, A.J., Fagin, J., and Lund, P.K. (2007). Cell-specific effects of insulin receptor substrate-1 deficiency on normal and IGF-I-mediated colon growth. Am. J. Physiol. Gastrointest Liver Physiol. 293, G995-1003. https://doi.org/10.1152/ajpgi.00537.2006
  39. Sun, X.J., Wang, L.M., Zhang, Y., Yenush, L., Myers, M.G., Jr., Glasheen, E., Lane, W.S., Pierce, J.H., and White, M.F. (1995). Role of IRS-2 in insulin and cytokine signaling. Nature 377, 173-177. https://doi.org/10.1038/377173a0
  40. Valverde, A.M., Lorenzo, M., Pons, S., White, M.F., and Benito, M. (1998). Insulin receptor substrate (IRS) proteins IRS-1 and IRS-2 differential signaling in the insulin/insulin-like growth factor-I pathways in fetal brown adipocytes. Mol. Endocrinol. 12, 688-697. https://doi.org/10.1210/mend.12.5.0106
  41. White, M.F. (2003). Insulin signaling in health and disease. Science 302, 1710-1711. https://doi.org/10.1126/science.1092952
  42. Withers, D.J.., Gutierrez, J.S., Towery, H., Burks, D.J., Ren, J.M., Previs, S., Zhang, Y., Bernal, D., Pons, S., Shulman, G.I., et al. (1998). Disruption of IRS-2 causes type 2 diabetes in mice. Nature 391, 900-904. https://doi.org/10.1038/36116
  43. Zhang, J., and Liu, F. (2014). Tissue-specific insulin signaling in the regulation of metabolism and aging. IUBMB Life 66, 485-495. https://doi.org/10.1002/iub.1293
  44. Zhou, L., Chen, H., Xu, P., Cong, L.N., Sciacchitano, S., Li, Y., Graham, D., Jacobs, A.R., Taylor, S.I., and Quon, M.J. (1999). Action of insulin receptor substrate-3 (IRS-3) and IRS-4 to stimulate translocation of GLUT4 in rat adipose cells. Mol. Endocrinol. 13, 505-514. https://doi.org/10.1210/mend.13.3.0242

Cited by

  1. The Role of Insulin-Like Growth Factor 1 in the Progression of Age-Related Hearing Loss vol.9, pp.1663-4365, 2017, https://doi.org/10.3389/fnagi.2017.00411
  2. T cells by elevating IRS-1 pathway pp.00099104, 2017, https://doi.org/10.1111/cei.13067
  3. MicroRNAs as Regulators of Insulin Signaling: Research Updates and Potential Therapeutic Perspectives in Type 2 Diabetes vol.19, pp.12, 2018, https://doi.org/10.3390/ijms19123705