Journal of Nutrition and Health

The Korean Nutrition Society (한국영양학회)
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Effects of (6)-gingerol, ginger component on adipocyte development and differentiation in 3T3-L1

생강 성분인 (6)-Gingerol이 3T3-L1에서 지방세포 증식과 분화 과정에 미치는 영향

  • Received : 2015.07.14
  • Accepted : 2015.08.13
  • Published : 2015.08.31
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Abstract

Purpose: The objective of this study was to investigate the effects of (6)-gingerol, ginger components proliferation and adipocyte differentiation from early to lately steps. Methods: 3T3-L1 preadipocytes were cultured. Differentiation of confluent cells was induced with dexamethasone, isobutylxanthin and insulin for 2 day and cells were cultured by medium with insulin in presence of various concentrations 0, 25, 50, $100({\mu}mol/L)$ of (6)-gingerol for 4 day. Cell viability was measured using the EZ Cytox assay kit. In addition, we examined the expression of mRNA levels associated with each adipocyte differentiation step by real time reverse transcription polymerase chain reaction. Results: (6)-Gingerol inhibited adipocyte proliferation in a dose and time dependent manner. Expression of $C/EBP{\beta}$, associated with early differentiation step remained unchaged. However, intermmediate, late differentiation step and adipocytokines were effectively changed in dose-dependently manner in cell groups treated with (6)-gingerol. Conclusion: This study has shown that treatment with (6)-gingerol inhibited adipocyte proliferation as well as each adipocyte differentiation step. In particular, the (6)-gingerol more effectively inhibited adipocyte differentiation from intermmediate differentiation step.

본 연구에서는 한국 음식의 양념류, 향신료로 많이 사용해온 생강의 여러 성분 중 (6)-gingerol을 3T3-L1 preadipocyte에 처리하였을 때 지방세포의 증식과 분화되는 과정에 미치는 영향에 대해 관찰해보고자 하였다. 실험 결과 (6)-gingerol의 첨가량이 증가할수록 세포의 증식이 유의적으로 억제되었다. 지방 분화과정 중에서의 (6)-gingerol은 분화초기에는 효과가 나타나지 않았지만, 지방세포로의 변화가 가속화되는 중기 과정에 관여하는 $PPAR{\gamma}$, $C/EBP{\alpha}$는 (6)-gingerol의 처리로 두 유전자의 발현이 억제되는 것을 확인할 수 있었고, 후기 관련 유전자인 FABP4, AP2의 발현도 (6)-gingerol의 처리군에서 발현이 유의적으로 감소되었다. 또한, 지방세포에서만 분비되는 adipocytokine 중 leptin 발현에는 (6)-gingerol의 처리가 유의적으로 억제되었으나, adiponectin의 경우에는 유의적인 효과는 나타나지 않았다.

Keywords

References

  1. Hirsch J, Batchelor B. Adipose tissue cellularity in human obesity. Clin Endocrinol Metab 1976; 5(2): 299-311. https://doi.org/10.1016/S0300-595X(76)80023-0
  2. Harmon AW, Harp JB. Differential effects of flavonoids on 3T3-L1 adipogenesis and lipolysis. Am J Physiol Cell Physiol 2001; 280(4): C807-C813. https://doi.org/10.1152/ajpcell.2001.280.4.C807
  3. Ross SR, Graves RA, Greenstein A, Platt KA, Shyu HL, Mellovitz B, Spiegelman BM. A fat-specific enhancer is the primary determinant of gene expression for adipocyte P2 in vivo. Proc Natl Acad Sci U S A 1990; 87(24): 9590-9594. https://doi.org/10.1073/pnas.87.24.9590
  4. Tontonoz P, Hu E, Graves RA, Budavari AI, Spiegelman BM. mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer. Genes Dev 1994; 8(10): 1224-1234. https://doi.org/10.1101/gad.8.10.1224
  5. Darlington GJ, Ross SE, MacDougald OA. The role of C/EBP genes in adipocyte differentiation. J Biol Chem 1998; 273(46): 30057-30060. https://doi.org/10.1074/jbc.273.46.30057
  6. Yoshitoshi Y, Naito C, Oda T. The cause and treatment of obesity. Naika 1964; 13: 287-298.
  7. Noh SK. Functional action of flavonoids for treatment of obesity. Food Ind Nutr 2002; 7(2): 27-29.
  8. Lee SY. Recent advance in drug therapy of obesity. Proceedings of the Korean Society of Applied Pharmacology Spring Symposium 2001; 2001 Apr 13; Kyung Hee University. Seoul: Korean Society of Applied Pharmacology; 2001. p. 3-30.
  9. Beaulieu JF, Quaroni A. Clonal analysis of sucrase-isomaltase expression in the human colon adenocarcinoma Caco-2 cells. Biochem J 1991; 280(Pt 3): 599-608. https://doi.org/10.1042/bj2800599
  10. Mathew AG, Krishnamurthy N, Nambudiri ES, Lewis YS. Oil of ginger. Flavour Ind 1973; 4(5): 226-232.
  11. Kang JH, Ahn BW, Lee DH, Byun HS, Kim SB, Park YH. Inhibitory effects of ginger and garlic extracts on the DNA damage. Korean J Food Sci Technol 1988; 20(3): 287-292.
  12. Katiyar SK, Agarwal R, Mukhtar H. Inhibition of tumor promotion in SENCAR mouse skin by ethanol extract of Zingiber officinale rhizome. Cancer Res 1996; 56: 1023-1030.
  13. Shin JH, Lee SJ, Sung NJ. Effects of Zingiber mioga, Zingiber mioga root and Zingiber officinale on the lipid concentration in hyperlipidemic rats. J Korean Soc Food Sci Nutr 2002; 31(4): 679-684. https://doi.org/10.3746/jkfn.2002.31.4.679
  14. Kang NE, Ha AW, Kim JY, Kim WK. Resveratrol inhibits the protein expression of transcription factors related adipocyte differentiation and the activity of matrix metalloproteinase in mouse fibroblast 3T3-L1 preadipocytes. Nutr Res Pract 2012; 6(6): 499-504. https://doi.org/10.4162/nrp.2012.6.6.499
  15. Kwon SY, Kang KJ. The effect of conjugated linoleic acid isomers on the cell proliferation, apotosis and expressions of uncoupling protein (UCP) genes during differentiation of 3T3-L1 preadipocytes. Korean J Nutr 2004; 37(7): 533-539.
  16. Kim MJ, Yoo YC, Kim HJ, Shin SK, Sohn EJ, Min AY, Sung NY, Kim MR. Aged black garlic exerts anti-inflammatory effects by decreasing no and proinflammatory cytokine production with less cytoxicity in LPS-stimulated raw 264.7 macrophages and LPSinduced septicemia mice. J Med Food 2014; 17(10): 1057-1063. https://doi.org/10.1089/jmf.2013.3043
  17. Kim WK, Kim JH, Jeong da H, Chun YH, Kim SH, Cho KJ, Chang MJ. Radish (Raphanus sativus L. leaf) ethanol extract inhibits protein and mRNA expression of ErbB(2) and ErbB(3) in MDA-MB-231 human breast cancer cells. Nutr Res Pract 2011; 5(4): 288-293. https://doi.org/10.4162/nrp.2011.5.4.288
  18. Chu SK, Seo EY, Kim WK, Kang NE. Effect of cyanidin on cell motility and invasion in MDA-MB-231 human breast cancer cells. Korean J Nutr 2008; 41(8): 711-717.
  19. Rosen ED, Walkey CJ, Puigserver P, Spiegelman BM. Transcriptional regulation of adipogenesis. Genes Dev 2000; 14(11): 1293-1307.
  20. Sivakumar V, Sivakumar S. Effect of an indigenous herbal compound preparation 'Trikatu' on the lipid profiles of atherogenic diet and standard diet fed Rattus norvegicus. Phytother Res 2004; 18(12): 976-981. https://doi.org/10.1002/ptr.1586
  21. Goyal RK, Kadnur SV. Beneficial effects of Zingiber officinale on goldthioglucose induced obesity. Fitoterapia 2006; 77(3): 160-163. https://doi.org/10.1016/j.fitote.2006.01.005
  22. Lekstrom-Himes J, Xanthopoulos KG. Biological role of the CCAAT/enhancer-binding protein family of transcription factors. J Biol Chem 1998; 273(44): 28545-28548. https://doi.org/10.1074/jbc.273.44.28545
  23. Hendricks-Taylor LR, Bachinski LL, Siciliano MJ, Fertitta A, Trask B, de Jong PJ, Ledbetter DH, Darlington GJ. The CCAAT/enhancer binding protein(C/EBP ${\alpha}$) gene (CEBPA) maps to human chromosome 19q13.1 and the related nuclear factor NF-IL6 (C/EBP ${\beta}$)gene (CEBPB) maps to human chromosome 20q13.1. Genomics 1992; 14(1): 12-17. https://doi.org/10.1016/S0888-7543(05)80276-9
  24. Zhang DE, Zhang P, Wang ND, Hetherington CJ, Darlington GJ, Tenen DG. Absence of granulocyte colony-stimulating factor signaling and neutrophil development in CCAAT enhancer binding protein ${\alpha}$-deficient mice. Proc Natl Acad Sci U S A 1997; 94(2): 569-574. https://doi.org/10.1073/pnas.94.2.569
  25. Wu Z, Rosen ED, Brun R, Hauser S, Adelmant G, Troy AE, McKeon C, Darlington GJ, Spiegelman BM. Cross-regulation of C/EBP alpha and PPAR gamma controls the transcriptional pathway of adipogenesis and insulin sensitivity. Mol Cell 1999; 3(2): 151-158. https://doi.org/10.1016/S1097-2765(00)80306-8
  26. Johansen LM, Iwama A, Lodie TA, Sasaki K, Felsher DW, Golub TR, Tenen DG. c-Myc is a critical target for c/$EBP\alpha$ in granulopoiesis. Mol Cell Biol 2001; 21(11): 3789-3806. https://doi.org/10.1128/MCB.21.11.3789-3806.2001
  27. McKnight SL. McBindall--a better name for CCAAT/enhancer binding proteins? Cell 2001; 107(3): 259-261. https://doi.org/10.1016/S0092-8674(01)00543-8
  28. Sugahara K, Iyama KI, Kimura T, Sano K, Darlington GJ, Akiba T, Takiguchi M. Mice lacking CCAAt/enhancer-binding protein-${\alpha}$ show hyperproliferation of alveolar type II cells and increased surfactant protein mRNAs. Cell Tissue Res 2001; 306(1): 57-63. https://doi.org/10.1007/s004410100420
  29. Takai N, Kawamata N, Walsh CS, Gery S, Desmond JC, Whittaker S, Said JW, Popoviciu LM, Jones PA, Miyakawa I, Koeffler HP. Discovery of epigenetically masked tumor suppressor genes in endometrial cancer. Mol Cancer Res 2005; 3(5): 261-269. https://doi.org/10.1158/1541-7786.MCR-04-0110
  30. Tada Y, Brena RM, Hackanson B, Morrison C, Otterson GA, Plass C. Epigenetic modulation of tumor suppressor CCAAT/enhancer binding protein ${\alpha}$ activity in lung cancer. J Natl Cancer Inst 2006; 98(6): 396-406. https://doi.org/10.1093/jnci/djj093
  31. Nerlov C. C/$EBP\alpha$ mutations in acute myeloid leukaemias. Nat Rev Cancer 2004; 4(5): 394-400. https://doi.org/10.1038/nrc1363
  32. Zhu Y, Qi C, Korenberg JR, Chen XN, Noya D, Rao MS, Reddy JK. Structural organization of mouse peroxisome proliferator-activated receptor gamma ($mPPAR\gamma$) gene: alternative promoter use and different splicing yield two $mPPAR\gamma$ isoforms. Proc Natl Acad Sci U S A 1995; 92(17): 7921-7925. https://doi.org/10.1073/pnas.92.17.7921
  33. Vidal-Puig A, Jimenez-Linan M, Lowell BB, Hamann A, Hu E, Spiegelman B, Flier JS, Moller DE. Regulation of PPAR gamma gene expression by nutrition and obesity in rodents. J Clin Invest 1996; 97(11): 2553-2561. https://doi.org/10.1172/JCI118703
  34. Ohnishi R, Matsui-Yuasa I, Deguchi Y, Yaku K, Tabuchi M, Munakata H, Akahoshi Y, Kojima-Yuasa A. 1'-acetoxychavicol acetate inhibits adipogenesis in 3T3-L1 adipocytes and in high fatfed rats. Am J Chin Med 2012; 40(6): 1189-1204. https://doi.org/10.1142/S0192415X12500887
  35. Isa Y, Miyakawa Y, Yanagisawa M, Goto T, Kang MS, Kawada T, Morimitsu Y, Kubota K, Tsuda T. 6-Shogaol and 6-gingerol, the pungent of ginger, inhibit TNF-alpha mediated downregulation of adiponectin expression via different mechanisms in 3T3-L1 adipocytes. Biochem Biophys Res Commun 2008; 373(3): 429-434. https://doi.org/10.1016/j.bbrc.2008.06.046
  36. Vidal-Puig A, Jimenez-Linan M, Lowell BB, Hamann A, Hu E, Spiegelman B, Flier JS, Moller DE. Regulation of PPAR${\gamma}$ gene expression by nutrition and obesity in rodents. J Clin Invest 1996; 97(11): 2553-2561. https://doi.org/10.1172/JCI118703
  37. Vidal-Puig A, Considine RV, Jimenez-Linan M, Werman A, Pories WJ, Caro JF, Flier JS. Peroxisome proliferator-activated receptor gene expression in human tissues. Effects of obesity, weight loss, and regulation by insulin and glucocorticoids. J Clin Invest 1997; 99(10): 2416-2422. https://doi.org/10.1172/JCI119424
  38. Tzeng TF, Chang CJ, Liu IM. 6-gingerol inhibits rosiglitazoneinduced adipogenesis in 3T3-L1 adipocytes. Phytother Res 2014; 28(2): 187-192. https://doi.org/10.1002/ptr.4976
  39. Spiegelman BM, Frank M, Green H. Molecular cloning of mRNA from 3T3 adipocytes. Regulation of mRNA content for glycerophosphate dehydrogenase and other differentiation-dependent proteins during adipocyte development. J Biol Chem 1983; 258(16): 10083-10089.
  40. Hunt CR, Ro JH, Dobson DE, Min HY, Spiegelman BM. Adipocyte P2 gene: developmental expression and homology of 5'-flanking sequences among fat cell-specific genes. Proc Natl Acad Sci U S A 1986; 83(11): 3786-3790. https://doi.org/10.1073/pnas.83.11.3786
  41. Hotamisligil GS, Johnson RS, Distel RJ, Ellis R, Papaioannou VE, Spiegelman BM. Uncoupling of obesity from insulin resistance through a targeted mutation in aP2, the adipocyte fatty acid binding protein. Science 1996; 274(5291): 1377-1379. https://doi.org/10.1126/science.274.5291.1377
  42. Uysal KT, Scheja L, Wiesbrock SM, Bonner-Weir S, Hotamisligil GS. Improved glucose and lipid metabolism in genetically obese mice lacking aP2. Endocrinology 2000; 141(9): 3388-3396. https://doi.org/10.1210/endo.141.9.7637
  43. Tzeng TF, Liu IM. 6-gingerol prevents adipogenesis and the accumulation of cytoplasmic lipid droplets in 3T3-L1 cells. Phytomedicine 2013; 20(6): 481-487. https://doi.org/10.1016/j.phymed.2012.12.006
  44. Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D, Lallone RL, Burley SK, Friedman JM. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 1995; 269(5223): 543-546. https://doi.org/10.1126/science.7624777
  45. Tyagi N, Givvimani S, Qipshidze N, Kundu S, Kapoor S, Vacek JC, Tyagi SC. Hydrogen sulfide mitigates matrix metalloproteinase-9 activity and neurovascular permeability in hyperhomocysteinemic mice. Neurochem Int 2010; 56(2): 301-307. https://doi.org/10.1016/j.neuint.2009.11.002
  46. Saravanan G, Ponmurugan P, Deepa MA, Senthilkumar B. Antiobesity action of gingerol: effect on lipid profile, insulin, leptin, amylase and lipase in male obese rats induced by a high-fat diet. J Sci Food Agric 2014; 94(14): 2972-2977. https://doi.org/10.1002/jsfa.6642
  47. Okamoto M, Irii H, Tahara Y, Ishii H, Hirao A, Udagawa H, Hiramoto M, Yasuda K, Takanishi A, Shibata S, Shimizu I. Synthesis of a new [6]-gingerol analogue and its protective effect with respect to the development of metabolic syndrome in mice fed a high-fat diet. J Med Chem 2011; 54(18): 6295-6304. https://doi.org/10.1021/jm200662c

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