DOI QR코드

DOI QR Code

Dietary Exposure to Transgenic Rice Expressing the Spider Silk Protein Fibroin Reduces Blood Glucose Levels in Diabetic Mice: The Potential Role of Insulin Receptor Substrate-1 Phosphorylation in Adipocytes

  • Park, Ji-Eun (Dept. of Anatomy and Cell Biology, College of Medicine, Dong-A University) ;
  • Jeong, Yeon Jae (Dept. of Anatomy and Cell Biology, College of Medicine, Dong-A University) ;
  • Park, Joon Beom (Dept. of Anatomy and Cell Biology, College of Medicine, Dong-A University) ;
  • Kim, Hye Young (Dept. of Anatomy and Cell Biology, College of Medicine, Dong-A University) ;
  • Yoo, Young Hyun (Dept. of Anatomy and Cell Biology, College of Medicine, Dong-A University) ;
  • Lee, Kwang Sik (College of Life Sciences and Natural Resources, Dong-A University) ;
  • Yang, Won Tae (College of Life Sciences and Natural Resources, Dong-A University) ;
  • Kim, Doh Hoon (College of Life Sciences and Natural Resources, Dong-A University) ;
  • Kim, Jong-Min (Dept. of Anatomy and Cell Biology, College of Medicine, Dong-A University)
  • Received : 2019.07.10
  • Accepted : 2019.08.13
  • Published : 2019.09.30

Abstract

Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance (IR). T2DM is correlated with obesity and most T2DM medications have been developed for enhancing insulin sensitivity. Silk protein fibroin (SPF) from spiders has been suggested as an attractive biomaterial for medical purposes. We generated transgenic rice (TR) expressing SPF and fed it to diabetic $BKS.Cg-m+/+Lepr^{db}$ mice to monitor the changes in blood glucose levels and adipose tissue proteins associated with energy metabolism and insulin signaling. In the present study, the adipocyte size in abdominal fat in TR-SPF-fed mice was remarkably smaller than that of the control. Whereas the adenosine monophosphate-activated protein kinase (AMPK)-activated protein kinase and insulin receptor substrate 1 (IRS1) protein levels were increased in abdominal adipose tissues after TR-SPF feeding, levels of six-transmembrane protein of prostate 2 (STAMP2) proteins decreased. Phosphorylation of AMPK at threonine 172 and IRS1 at serine 307 and tyrosine 632 were both increased in adipose tissues from TR-SPF-fed mice. Increased expression and phosphorylation of IRS1 at both serine 307 and tyrosine 632 in adipose tissues indicated that adipocytes obtained from abdominal fat in TR-SPF-fed mice were more susceptible to insulin signaling than that of the control. STAMP2 protein levels decreased in adipose tissues from TR-SPF-fed mice, indicating that STAMP2 proteins were reducing adipocytes that were undergoing lipolysis. Taken together, this study showed that TR-SPF was effective in reducing blood glucose levels in diabetic mice and that concurrent lipolysis in abdominal adipocytes was associated with alterations of AMPK, IRS1, and STAMP2. Increased IRS1 expression and its phosphorylation by TR-SFP were considered to be particularly important in the induction of lipolysis in adipocytes, as well as in reducing blood glucose levels in this animal model.

Keywords

References

  1. Altman GH, Diaz F, Jakuba C, Calabro T, Horan RL, Chen J, Lu H, Richmond J, Kaplan DL (2003). Silk-based biomaterials. Biomaterials 24:401-416. https://doi.org/10.1016/S0142-9612(02)00353-8
  2. Boles A, Kandimalla R, Reddy PH (2017) Dynamics of diabetes and obesity: Epidemiological perspective. Biochim Biophys Acta Mol Basis Dis 1863:1026-1036. https://doi.org/10.1016/j.bbadis.2017.01.016
  3. Czech MP (2017) Insulin action and resistance in obesity and type 2 diabetes. Nat Med 23:804-814. https://doi.org/10.1038/nm.4350
  4. Danielsson A, Ost A, Nystrom FH, Stralfors P (2005) Attenuation of insulin-stimulated insulin receptor substrate-1 serine 307 phosphorylation in insulin resistance of type 2 diabetes. J Biol Chem 280:34389-34392. https://doi.org/10.1074/jbc.C500230200
  5. Do SG, Park JH, Nam H, Kim JB, Lee JY, Oh YS, Suh JG (2012) Silk fibroin hydrolysate exerts an anti-diabetic effect by increasing pancreatic $\beta$ cell mass in C57BL/KsJdb/db mice. J Vet Sci 13:339-344. https://doi.org/10.4142/jvs.2012.13.4.339
  6. Gauthier MS, Miyoshi H, Souza SC, Cacicedo JM, Saha AK, Greenberg AS, Ruderman NB (2008) AMP-activated protein kinase is activated as a consequence of lipolysis in the adipocyte: potential mechanism and physiological relevance. J Biol Chem 283:16514-16524. https://doi.org/10.1074/jbc.M708177200
  7. Gotoh K, Izumi H, Kanamoto T, Tamada Y, Nakashima H (2000) Sulfated fibroin, a novel sulfated peptide derived from silk, inhibits human immunodeficiency virus replication in vitro. Biosci Biotechnol Biochem 64:1664-1670. https://doi.org/10.1271/bbb.64.1664
  8. Hyun CK, Kim IY, Frost SC (2004) Soluble fibroin enhances insulin sensitivity and glucose metabolism in 3T3-L1 adipocytes. J Nutr 134:3257-3263. https://doi.org/10.1093/jn/134.12.3257
  9. Igarashi K, Yoshioka K, Mizutani K, Miyakoshi M, Murakami T, Akizawa T (2006) Blood pressure-depressing activity of a peptide derived from silkworm fibroin in spontaneously hypertensive rats. Biosci Biotechnol Biochem 70:517-520. https://doi.org/10.1271/bbb.70.517
  10. Jung EY, Lee HS, Lee HJ, Kim JM, Lee KW, Suh HJ (2010) Feeding silk protein hydrolysates to C57BL/KsJdb/db mice improves blood glucose and lipid profiles. Nutr Res 30:783-790. https://doi.org/10.1016/j.nutres.2010.10.006
  11. Kim HY, Park SY, Lee MH, Rho JH, Oh YJ, Jung HU, Yoo SH, Jeong NY, Lee HJ, Suh S, Seo SY, Cheong J, Jeong JS, Yoo YH (2015) Hepatic STAMP2 alleviates high fat diet-induced hepatic steatosis and insulin resistance. J Hepatol 63:477-485. https://doi.org/10.1016/j.jhep.2015.01.025
  12. Kluge JA, Rabotyagova O, Leisk GG, Kaplan DL (2008) Spider silks and their applications. Trends Biotechnol 26:244-251. https://doi.org/10.1016/j.tibtech.2008.02.006
  13. Lee KS, Kim BY, Kim DH, Jin BR (2012) Molecular cloning and characterization of the partial major ampullate silk protein gene from the spider Araneus ventricosus. J Asia Pac Entomol 15:641-646. https://doi.org/10.1016/j.aspen.2012.08.004
  14. Lee KS, Kim BY, Kim DH, Jin BR (2014) Spider silk fibroin enhances insulin secretion and reduces blood glucose levels in diabetic mice. J Asia-Pacific Entomol 17:907-909. https://doi.org/10.1016/j.aspen.2014.10.005
  15. Lee KS, Kim BY, Kim DH, Jin BR (2016) Recombinant spider silk fibroin protein produces a non-cytotoxic and non-inflammatory response. J Asia-Pacific Entomol 19:1015-1018. https://doi.org/10.1016/j.aspen.2016.09.004
  16. Mohanty A, Sarma NP, Tyagi AK (1999) Agrobacteriummediated high frequency transformation of an elite indica rice variety Pusa Basmati 1 and transmission of the transgenes to R2 progeny. Plant Sci 147:127-137. https://doi.org/10.1016/S0168-9452(99)00103-X
  17. Morigny P, Houssier M, Mouisel E, Langin D (2016) Adipocyte lipolysis and insulin resistance. Biochimie 125:259-266. https://doi.org/10.1016/j.biochi.2015.10.024
  18. Musi N, Goodyear LJ (2006) Insulin resistance and improvements in signal transduction. Endocrine 29:73-80. https://doi.org/10.1385/ENDO:29:1:73
  19. Park KJ, Jin HH, Hyun CK (2002) Antigenotoxicity of peptides produced from silk fibroin. Process Biochem 38:411-418. https://doi.org/10.1016/S0032-9592(02)00136-X
  20. Rena G, Hardie DG, Pearson ER (2017) The mechanisms of action of metformin. Diabetologia 60:1577-1585. https://doi.org/10.1007/s00125-017-4342-z
  21. Sanchez-Rangel E, Inzucchi SE (2017) Metformin: clinical use in type 2 diabetes. Diabetologia 2017 60:1586-1593.
  22. Sikkeland J, Saatcioglu F (2013) Differential expression and function of stamp family proteins in adipocyte differentiation. PLOS ONE 8:e68249. https://doi.org/10.1371/journal.pone.0068249
  23. Thomas CC, Philipson LH (2015) Update on diabetes classification. Med Clin North Am 99:1-16. https://doi.org/10.1016/j.mcna.2014.08.015
  24. Toki S (1997) Rapid and efficient Agrobacterium-mediated transformation in rice. Plant Mol Bio Rep 15:16-21. https://doi.org/10.1007/BF02772109
  25. Wellen KE, Fucho R, Gregor MF, Furuhashi M, Morgan C, Lindstad T, Vaillancourt E, Gorgun CZ, Saatcioglu F, Hotamisligil GS (2007) Coordinated regulation of nutrient and inflammatory responses by STAMP2 is essential for metabolic homeostasis. Cell 129:537-548. https://doi.org/10.1016/j.cell.2007.02.049