Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Sulfuretin Prevents Obesity and Metabolic Diseases in Diet Induced Obese Mice

  • Kim, Suji (Department of Food Science and Biotechnology, Sungkyunkwan University) ;
  • Song, No-Joon (Department of Food Science and Biotechnology, Sungkyunkwan University) ;
  • Chang, Seo-Hyuk (Department of Food Science and Biotechnology, Sungkyunkwan University) ;
  • Bahn, Gahee (School of Pharmacy, Sungkyunkwan University) ;
  • Choi, Yuri (School of Pharmacy, Sungkyunkwan University) ;
  • Rhee, Dong- Kwon (School of Pharmacy, Sungkyunkwan University) ;
  • Yun, Ui Jeong (Department of Food Science and Biotechnology, Sungkyunkwan University) ;
  • Choi, Jinhee (Department of Food Science and Biotechnology, Sungkyunkwan University) ;
  • Lee, Jeon (Department of Food Science and Biotechnology, Sungkyunkwan University) ;
  • Yoo, Jae Hyuk (Department of Medicine, Program in Molecular Medicine, University of Utah) ;
  • Shin, Donghan (Department of Medicine, Program in Molecular Medicine, University of Utah) ;
  • Park, Ki-Moon (Department of Food Science and Biotechnology, Sungkyunkwan University) ;
  • Kang, Hee (Department of Oriental Medical Science, Graduate School of East-West Medicine, Kyunghee University) ;
  • Lee, Sukchan (Department of Integrative Biotechnology, Sungkyunkwan University) ;
  • Ku, Jin-Mo (Biomaterials Research and Development Team, Bio-Center, Gyeonggido Business Science Accelerator) ;
  • Cho, Yoon Shin (Department of Biomedical Science, Hallym University) ;
  • Park, Kye Won (Department of Food Science and Biotechnology, Sungkyunkwan University)
  • Received : 2018.05.20
  • Accepted : 2018.06.26
  • Published : 2019.01.01
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Abstract

The global obesity epidemic and associated metabolic diseases require alternative biological targets for new therapeutic strategies. In this study, we show that a phytochemical sulfuretin suppressed adipocyte differentiation of preadipocytes and administration of sulfuretin to high fat diet-fed obese mice prevented obesity and increased insulin sensitivity. These effects were associated with a suppressed expression of inflammatory markers, induced expression of adiponectin, and increased levels of phosphorylated ERK and AKT. To elucidate the molecular mechanism of sulfuretin in adipocytes, we performed microarray analysis and identified activating transcription factor 3 (Atf3) as a sulfuretin-responsive gene. Sulfuretin elevated Atf3 mRNA and protein levels in white adipose tissue and adipocytes. Consistently, deficiency of Atf3 promoted lipid accumulation and the expression of adipocyte markers. Sulfuretin's but not resveratrol's anti-adipogenic effects were diminished in Atf3 deficient cells, indicating that Atf3 is an essential factor in the effects of sulfuretin. These results highlight the usefulness of sulfuretin as a new anti-obesity intervention for the prevention of obesity and its associated metabolic diseases.

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References

  1. Auh, Q. S., Park, K. R., Yun, H. M., Lim, H. C., Kim, G. H., Lee, D. S., Kim, Y. C., Oh, H. and Kim, E. C. (2016) Sulfuretin promotes osteoblastic differentiation in primary cultured osteoblasts and in vivo bone healing. Oncotarget 7, 78320-78330. https://doi.org/10.18632/oncotarget.12460
  2. Ding, S. and Schultz, P. G. (2004) A role for chemistry in stem cell biology. Nat. Biotechnol. 22, 833-840. https://doi.org/10.1038/nbt987
  3. Favre, D., Le Gouill, E., Fahmi, D., Verdumo, C., Chinetti-Gbaguidi, G., Staels, B., Caiazzo, R., Pattou, F., Le, K. A., Tappy, L., Regazzi, R., Giusti, V., Vollenweider, P., Waeber, G. and Abderrahmani, A. (2011) Impaired expression of the inducible cAMP early repressor accounts for sustained adipose CREB activity in obesity. Diabetes 60, 3169-3174. https://doi.org/10.2337/db10-1743
  4. Graham, D. J., Ouellet-Hellstrom, R., MaCurdy, T. E., Ali, F., Sholley, C., Worrall, C. and Kelman, J. A. (2010) Risk of acute myocardial infarction, stroke, heart failure, and death in elderly Medicare patients treated with rosiglitazone or pioglitazone. JAMA 304, 411-418. https://doi.org/10.1001/jama.2010.920
  5. Hai, T., Wolford, C. C. and Chang, Y. S. (2010) ATF3, a hub of the cellular adaptive-response network, in the pathogenesis of diseases: is modulation of inflammation a unifying component? Gene. Expr. 15, 1-11. https://doi.org/10.3727/105221610X12819686555015
  6. Halaas, J. L., Gajiwala, K. S., Maffei, M., Cohen, S. L., Chait, B. T., Rabinowitz, D., Lallone, R. L., Burley, S. K. and Friedman, J. M. (1995) Weight-reducing effects of the plasma protein encoded by the obese gene. Science 269, 543-546. https://doi.org/10.1126/science.7624777
  7. Hartman, M. G., Lu, D., Kim, M. L., Kociba, G. J., Shukri, T., Buteau, J., Wang, X., Frankel, W. L., Guttridge, D., Prentki, M., Grey, S. T., Ron, D. and Hai, T. (2004) Role for activating transcription factor 3 in stress-induced beta-cell apoptosis. Mol. Cell. Biol. 24, 5721-5732. https://doi.org/10.1128/MCB.24.13.5721-5732.2004
  8. Hasani-Ranjbar, S., Nayebi, N., Larijani, B. and Abdollahi, M. (2009) A systematic review of the efficacy and safety of herbal medicines used in the treatment of obesity. World J. Gastroenterol. 15, 3073-3085. https://doi.org/10.3748/wjg.15.3073
  9. Hong, J. W. and Park, K. W. (2010) Further understanding of fat biology: lessons from a fat fly. Exp. Mol. Med. 42, 12-20. https://doi.org/10.3858/emm.2010.42.1.007
  10. Jang, M. K., Kim, C. H., Seong, J. K. and Jung, M. H. (2012) ATF3 inhibits adipocyte differentiation of 3T3-L1 cells. Biochem. Biophys. Res. Commun. 421, 38-43. https://doi.org/10.1016/j.bbrc.2012.03.104
  11. Kim, J. H., Shin, Y. C. and Ko, S. G. (2014a) Integrating traditional medicine into modern inflammatory diseases care: multitargeting by Rhus verniciflua Stokes. Mediators Inflamm. 2014, 154561. https://doi.org/10.1155/2014/154561
  12. Kim, M. J., Jang, W. S., Lee, I. K., Kim, J. K., Seong, K. S., Seo, C. R., Song, N. J., Bang, M. H., Lee, Y. M., Kim, H. R., Park, K. M. and Park, K. W. (2014b) Reciprocal regulation of adipocyte and osteoblast differentiation of mesenchymal stem cells by Eupatorium japonicum prevents bone loss and adiposity increase in osteoporotic rats. J. Med. Food 17, 772-781. https://doi.org/10.1089/jmf.2013.3056
  13. Lazar, M. A. (2005) PPAR gamma, 10 years later. Biochimie 87, 9-13. https://doi.org/10.1016/j.biochi.2004.10.021
  14. Lee, Y. R., Hwang, J. K., Koh, H. W., Jang, K. Y., Lee, J. H., Park, J. W. and Park, B. H. (2012) Sulfuretin, a major flavonoid isolated from Rhus verniciflua, ameliorates experimental arthritis in mice. Life Sci. 90, 799-807. https://doi.org/10.1016/j.lfs.2012.04.015
  15. Lehmann, J. M., Moore, L. B., Smith-Oliver, T. A., Wilkison, W. O., Willson, T. M. and Kliewer, S. A. (1995) An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J. Biol. Chem. 270, 12953-12956. https://doi.org/10.1074/jbc.270.22.12953
  16. Nguyen, C. T., Kim, E. H., Luong, T. T., Pyo, S. and Rhee, D. K. (2016) ATF3 confers resistance to pneumococcal infection through positive regulation of cytokine production. J. Infect. Dis. 210, 1745-1754. https://doi.org/10.1093/infdis/jiu352
  17. Nissen, S. E. and Wolski, K. (2007) Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N. Engl. J. Med. 356, 2457-2471. https://doi.org/10.1056/NEJMoa072761
  18. Nolan, J. J., Ludvik, B., Beerdsen, P., Joyce, M. and Olefsky, J. (1994) Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. N. Engl. J. Med. 331, 1188-1193. https://doi.org/10.1056/NEJM199411033311803
  19. Orhan, N., Icoz, U. G., Altun, L. and Aslan, M. (2016) Anti-hyperglycaemic and antioxidant effects of Bidens tripartita and quantitative analysis on its active principles. Iran. J. Basic Med. Sci. 19, 1114-1124.
  20. Qi, L., Saberi, M., Zmuda, E., Wang, Y., Altarejos, J., Zhang, X., Dentin, R., Hedrick, S., Bandyopadhyay, G., Hai, T., Olefsky, J. and Montminy, M. (2009) Adipocyte CREB promotes insulin resistance in obesity. Cell Metab. 9, 277-286. https://doi.org/10.1016/j.cmet.2009.01.006
  21. Roh, K., Kim, S., Kang, H., Ku, J. M., Park, K. W. and Lee, S. (2017) Sulfuretin has therapeutic activity against acquired lymphedema by reducing adipogenesis. Pharmacol. Res. 121, 230-239. https://doi.org/10.1016/j.phrs.2017.05.003
  22. Rosen, E. D. and MacDougald, O. A. (2006) Adipocyte differentiation from the inside out. Nat. Rev. Mol. Cell Biol. 7, 885-896. https://doi.org/10.1038/nrm2066
  23. Rynes, J., Donohoe, C. D., Frommolt, P., Brodesser, S., Jindra, M. and Uhlirova, M. (2012) Activating transcription factor 3 regulates immune and metabolic homeostasis. Mol. Cell. Biol. 32, 3949-3962. https://doi.org/10.1128/MCB.00429-12
  24. Shan, Y., Akram, A., Amatullah, H., Zhou, D. Y., Gali, P.L., Maron-Gutierrez, T., Gonzalez-Lopez, A., Zhou, L., Rocco, P. R., Hwang, D., Albaiceta, G. M., Haitsma, J. J. and dos Santos, C. C. (2015) ATF3 protects pulmonary resident cells from acute and ventilatorinduced lung injury by preventing Nrf2 degradation. Antioxid. Redox. Signal. 22, 651-668. https://doi.org/10.1089/ars.2014.5987
  25. Song, M. Y., Jeong, G. S., Kwon, K. B., Ka, S. O., Jang, H. Y., Park, J. W., Kim, Y. C. and Park, B. H. (2010a) Sulfuretin protects against cytokine-induced beta-cell damage and prevents streptozotocin-induced diabetes. Exp. Mol. Med. 42, 628-638. https://doi.org/10.3858/emm.2010.42.9.062
  26. Song, M. Y., Jeong, G. S., Lee, H. S., Kwon, K. S., Lee, S. M., Park, J. W., Kim, Y. C. and Park, B. H. (2010b) Sulfuretin attenuates allergic airway inflammation in mice. Biochem. Biophys. Res. Commun. 400, 83-88. https://doi.org/10.1016/j.bbrc.2010.08.014
  27. Song, N. J., Kwon, S. M., Kim, S., Yoon, H. J., Seo, C. R., Jang, B., Chang, S. H., Ku, J. M., Lee, J. S., Park, K. M., Hong, J. W., Kim, G. H. and Park, K. W. (2015) Sulfuretin induces osteoblast differentiation through activation of TGF-beta signaling. Mol. Cell Biochem. 410, 55-63. https://doi.org/10.1007/s11010-015-2537-5
  28. Suganami, T., Yuan, X., Shimoda, Y., Uchio-Yamada, K., Nakagawa, N., Shirakawa, I., Usami, T., Tsukahara, T., Nakayama, K., Miyamoto, Y., Yasuda, K., Matsuda, J., Kamei, Y., Kitajima, S. and Ogawa, Y. (2009) Activating transcription factor 3 constitutes a negative feedback mechanism that attenuates saturated Fatty acid/toll-like receptor 4 signaling and macrophage activation in obese adipose tissue. Circ. Res. 105, 25-32. https://doi.org/10.1161/CIRCRESAHA.109.196261
  29. Tontonoz, P. and Spiegelman, B. M. (2008) Fat and beyond: the diverse biology of PPARgamma. Annu. Rev. Biochem. 77, 289-312. https://doi.org/10.1146/annurev.biochem.77.061307.091829
  30. Waki, H. and Tontonoz, P. (2007) Endocrine functions of adipose tissue. Annu. Rev. Pathol. 2, 31-56. https://doi.org/10.1146/annurev.pathol.2.010506.091859
  31. Wang, S., Moustaid-Moussa, N., Chen, L., Mo, H., Shastri, A., Su, R., Bapat, P., Kwun, I., and Shen, C. L. (2014) Novel insights of dietary polyphenols and obesity. J. Nutr. Biochem. 25, 1-18. https://doi.org/10.1016/j.jnutbio.2013.09.001
  32. Willson, T. M., Lambert, M. H. and Kliewer, S. A. (2001) Peroxisome proliferator-activated receptor gamma and metabolic disease. Annu. Rev. Biochem. 70, 341-367. https://doi.org/10.1146/annurev.biochem.70.1.341
  33. Wu, Z., Xie, Y., Bucher, N. L. and Farmer, S. R. (1995) Conditional ectopic expression of C/EBP beta in NIH-3T3 cells induces PPAR gamma and stimulates adipogenesis. Genes. Dev. 9, 2350-2363. https://doi.org/10.1101/gad.9.19.2350
  34. Yang, D. K. and Kang, H.-S. (2018) Anti-diabetic effect of cotreatment with quercetin and resveratrol in streptozotocin-induced diabetic rats. Biomol. Ther. (Seoul) 26, 130-138. https://doi.org/10.4062/biomolther.2017.254
  35. Yin, X., Dewille, J. W., and Hai, T. (2008) A potential dichotomous role of ATF3, an adaptive-response gene, in cancer development. Oncogene 27, 2118-2127. https://doi.org/10.1038/sj.onc.1210861
  36. Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L. and Friedman, J. M. (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425-432. https://doi.org/10.1038/372425a0
  37. Zmuda, E. J., Qi, L., Zhu, M. X., Mirmira, R. G., Montminy, M. R. and Hai, T. (2010) The roles of ATF3, an adaptive-response gene, in high-fat-diet-induced diabetes and pancreatic beta-cell dysfunction. Mol. Endocrinol. 24, 1423-1433. https://doi.org/10.1210/me.2009-0463

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