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Widdrol Blocks 3T3-L1 Preadipocytes Growth and Differentiation Due to Inhibition of Mitotic Clonal Expansion

  • Yun, Hee-Jung (Department of Biomaterial Control (BK21 Program), Dong-Eui University Graduate School) ;
  • Kim, Jeong-Hwan (Department of Biomaterial Control (BK21 Program), Dong-Eui University Graduate School) ;
  • Jeong, Hyun-Young (Department of Life Science and Biotechnology, College of Natural Science, Dong-Eui University) ;
  • Ji, Hyang-Hwa (Department of Biomaterial Control (BK21 Program), Dong-Eui University Graduate School) ;
  • Nam, Soo-Wan (Department of Biomaterial Control (BK21 Program), Dong-Eui University Graduate School) ;
  • Lee, Eun-Woo (Department of Biomaterial Control (BK21 Program), Dong-Eui University Graduate School) ;
  • Kim, Byung-Woo (Department of Biomaterial Control (BK21 Program), Dong-Eui University Graduate School) ;
  • Kwon, Hyun-Ju (Department of Biomaterial Control (BK21 Program), Dong-Eui University Graduate School)
  • Received : 2011.10.12
  • Accepted : 2012.02.15
  • Published : 2012.06.28

Abstract

Adipocyte differentiation is strongly associated with obesity, which causes metabolic disorders. In this study, we investigated the inhibitory effects of widdrol on 3T3-L1 preadipocyte growth and differentiation. Widdrol decreased lipid droplet accumulation and down-regulated adipogenic transcription factors such as C/$EBP{\alpha}$, C/$EBP{\beta}$, and $PPAR{\gamma}$. Widdrol blocked preadipocyte proliferation and differentiation through the inhibition of mitotic clonal expansion, which was accompanied by the failure of degradation of p21, a cyclin-dependent kinase inhibitor. Cell-cycle analysis clearly indicated that widdrol actively induces cell-cycle arrest at the G1-S phage transition, causing cells to remain in the preadipocyte state. Moreover, widdrol increased p21 expression and inhibited Rb phosphorylation in preadipocyte incubated in a hormone medium. Therefore, these findings clearly suggest that widdrol blocks preadipocyte growth and differentiation through the inhibition of mitotic clonal expansion by p21-and Rb-dependent G1 arrest and can be developed as a potent anti-adipogenic agent for reducing obesity.

Keywords

References

  1. Bray, G. A. and L. A. Tartaglia. 2000. Medicinal strategies in the treatment of obesity. Nature 404: 672-677.
  2. Caro, J. F., L. G. Dohm, W. J. Pories, and M. K. Sinha. 1989. Cellular alterations in liver, skeletal muscle, and adipose tissue responsible for insulin resistance in obesity and type II diabetes. Diab. Metab. Rev. 5: 665-689. https://doi.org/10.1002/dmr.5610050804
  3. Cornelius, P., O. A. MacDougald, and M. D. Lane. 1994. Regulation of adipocyte development. Annu. Rev. Nutr. 14: 99-129. https://doi.org/10.1146/annurev.nu.14.070194.000531
  4. Couillard, C., P. Mauriege, P. Imbeault, D. Prud'homme, A. Nadeau, A. Tremblay, et al. 2000. Hyperleptinemia is more closely associated with adipose cell hypertrophy than with adipose tissue hyperplasia. Int. J. Obes. Relat. Metab. Disord. 24: 782-788. https://doi.org/10.1038/sj.ijo.0801227
  5. DeGregori, J. 2004. The Rb network. J. Cell Sci. 117: 3411-3413. https://doi.org/10.1242/jcs.01189
  6. Farmer, S. R. 2006. Transcriptional control of adipocyte formation. Cell Metab. 4: 263-273. https://doi.org/10.1016/j.cmet.2006.07.001
  7. Formiguera, X. and A. Canton. 2004. Obesity: Epidemiology and clinical aspects. Best Pract. Res. Clin. Gastroenterol. 18: 1125-1146.
  8. Furuyashiki, T., H. Nagayasu, Y. Aoki, H. Bessho, T. Hashimoto, K. Kanazawa, and H. Ashida. 2004. Tea catechin suppresses adipocyte differentiation accompanied by down-regulation of PPARgamma2 and C/EBPalpha in 3T3-L1 cells. Biosci. Biotechnol. Biochem. 68: 2353-2359. https://doi.org/10.1271/bbb.68.2353
  9. Gregoire, F. M., C. M. Smas, and H. S. Sul. 1998. Understanding adipocyte differentiation. Physiol. Rev. 78: 783-809.
  10. Harbour, J. W. and D. C. Dean. 2000. Rb function in cell-cycle regulation and apoptosis. Nat. Cell Biol. 2: E65-E67. https://doi.org/10.1038/35008695
  11. Hemati, N., S. E. Ross, R. L. Erickson, G. E. Groblewski, and O. A. MacDougald. 1997. Signaling pathways through which insulin regulates CCAAT/enhancer binding protein alpha (C/EBPalpha) phosphorylation and gene expression in 3T3-L1 adipocytes. Correlation with GLUT4 gene expression. J. Biol. Chem. 272: 25913-25919. https://doi.org/10.1074/jbc.272.41.25913
  12. Hung, P. F., B. T. Wu, H. C. Chen, Y. H. Chen, C. L. Chen, M. H. Wu, et al. 2005. Antimitogenic effect of green tea (-)-epigallocatechin gallate on 3T3-L1 preadipocytes depends on the ERK and CDK2 pathways. Am. J. Physiol. Cell Physiol. 288: C1094-C1108. https://doi.org/10.1152/ajpcell.00569.2004
  13. Jones, K. H. and J. A. Senft. 1985. An improved method to determine cell viability by simultaneous staining with fluorescein diacetate - propidium iodine. J. Histochem. Cytochem. 33: 77-79. https://doi.org/10.1177/33.1.2578146
  14. Kwon, H. J., Y. K. Hong, C. Park, Y. H. Choi, H. J. Yun, E. W. Lee, and B. W. Kim. 2010. Widdrol induces cell cycle arrest, associated with MCM down-regulation, in human colon adenocarcinoma cells. Cancer Lett. 290: 96-103. https://doi.org/10.1016/j.canlet.2009.09.003
  15. Lee, C. K., J. M. Fang, and Y. S. Cheng. 1995. Norditerpenes from Juniperus chinensis. Phytochemistry 39: 391-394. https://doi.org/10.1016/0031-9422(94)00868-T
  16. Lee, W. J., E. H. Koh, J. C. Won, M. S. Kim, J. Y. Park, and K. U. Lee. 2005. Obesity: The role of hypothalamic AMP-activated protein kinase in body weight regulation. Int. J. Biochem. Cell Biol. 37: 2254-2259. https://doi.org/10.1016/j.biocel.2005.06.019
  17. Mayer, M. A., C. Hocht, A. Puyo, and C. A. Taira. 2009. Recent advances in obesity pharmacotherapy. Curr. Clin. Pharmacol. 4: 53-61. https://doi.org/10.2174/157488409787236128
  18. Morrison, R. F. and S. R. Farmer. 1999. Role of PPARgamma in regulating a cascade expression of cyclin-dependent kinase inhibitors, p18 (INK4c) and p21 (Waf1/Cip1), during adipogenesis. J. Biol. Chem. 274: 17088-17097. https://doi.org/10.1074/jbc.274.24.17088
  19. Nakayama, T., S. Suzuki, H. Kudo, S. Sassa, M. Nomura, and S. Sakamoto. 2007. Effects of three Chinese herbal medicines on plasma and liver lipids in mice fed a high-fat diet. J. Ethnopharmacol. 109: 236-240. https://doi.org/10.1016/j.jep.2006.07.041
  20. Otto, T. C. and M. D. Lane. 2005. Adipose development: From stem cell to adipocyte. Crit. Rev. Biochem. Mol. Biol. 40: 229-242. https://doi.org/10.1080/10409230591008189
  21. Park, M. Y., K. S. Lee, and M. K. Sung. 2005. Effects of dietary mulberry, Korea red ginseng, and banaba on glucose homeostasis in relation to PPAR-${\alpha}$, PPAR-${\gamma}$ and LPL mRNA expressions. Life Sci. 77: 3344-3354. https://doi.org/10.1016/j.lfs.2005.05.043
  22. Roncari, D. A., D. C. Lau, and S. Kindler. 1981. Exaggerated replication in culture of adipocyte precursors from massively obese persons. Metabolism 30: 425-427. https://doi.org/10.1016/0026-0495(81)90174-8
  23. Rosen, E. D. and B. M. Spiegelman. 2000. Molecular regulation of adipogenesis. Annu. Rev. Cell Dev. Biol. 16: 145-171. https://doi.org/10.1146/annurev.cellbio.16.1.145
  24. Sherr, C. J. and J. M. Roberts. 1999. CDK inhibitors: Positive and negative regulators of G1-phase progression. Genes Dev. 13: 1501-1512. https://doi.org/10.1101/gad.13.12.1501
  25. Tafuri, S. R. 1996. Troglitazone enhances differentiation, basal glucose uptake, and Glut1 protein levels in 3T3-L1 adipocytes. Endocrinology 137: 4706-4712. https://doi.org/10.1210/en.137.11.4706
  26. Tang, Q. Q., T. C. Otto, and M. D. Lane. 2003. Mitotic clonal expansion: A synchronous process required for adipogenesis. Proc. Natl. Acad. Sci. USA 100: 44-49. https://doi.org/10.1073/pnas.0137044100
  27. Tong, Q. and G. S. Hotamisligil. 2001. Molecular mechanisms of adipocyte differentiation. Rev. Endocr. Metab. Disord. 2: 349-355. https://doi.org/10.1023/A:1011863414321
  28. Visscher, T. L. and J. C. Seidell. 2001. The public health impact of obesity. Annu. Rev. Public Health 22: 355-375. https://doi.org/10.1146/annurev.publhealth.22.1.355
  29. Wang, Y. W. and P. J. Jones. 2004. Conjugated linoleic acid and obesity control: Efficacy and mechanisms. Int. J. Obes. Relat. Metab. Disord. 28: 941-955. https://doi.org/10.1038/sj.ijo.0802641
  30. Yarelis, O. N., S. S. Iraida, G. C. Isidro, and H. G. Rosario. 2006. The antifungal activity of widdrol and its biotransformation by Colletotrichum gloeosporioides (penz.) Penz & Sacc. and Botrytis cinerea Pers.; Fr. J. Agric. Food Chem. 54: 7517-7521. https://doi.org/10.1021/jf061436m
  31. Yarelis, O. N., S. S. Iraida, G. C. Isidro, and H. G. Rosario. 2007. Sesquiterpenes from the wood of Juniperus lucayana. Phytochemistry 68: 2409-2414. https://doi.org/10.1016/j.phytochem.2007.05.030
  32. Yun, J. W. 2010. Possible anti-obesity therapeutics from nature - A review. Phytochemistry 71: 1625-1641. https://doi.org/10.1016/j.phytochem.2010.07.011

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