Nutrition Research and Practice

The Korean Nutrition Society (한국영양학회)
권호 표지
DOI QR코드

DOI QR Code

Effects of quercetin on cell differentiation and adipogenesis in 3T3-L1 adipocytes

  • Hong, Seo Young (Department of Food Science and Nutrition, Dankook University) ;
  • Ha, Ae Wha (Department of Food Science and Nutrition, Dankook University) ;
  • Kim, Wookyoung (Department of Food Science and Nutrition, Dankook University)
  • Received : 2020.12.11
  • Accepted : 2021.01.20
  • Published : 2021.08.01
Download PDF
⟨ Previous Next ⟩

Abstract

BACKGROUND/OBJECTIVES: Adipocytes undergo angiogenesis to receive nutrients and oxygen needed for adipocyte' growth and differentiation. No study relating quercetin with angiogenesis in adipocytes exists. Therefore, this study investigated the role of quercetin on adipogenesis in 3T3-L1 cells, acting through matrix metalloproteinases (MMPs). MATERIALS/METHODS: After proliferating preadipocytes into adipocytes, various quercetin concentrations were added to adipocytes, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays were performed to evaluate cell proliferation. Glycerol-3-phosphate dehydrogenase (GPDH) activity was investigated as an indicator of fat accumulation. The mRNA expressions of transcription factors related to adipocyte differentiation, CCAAT/enhancer-binding proteins (C/EBPs), peroxisomal proliferatoractivated receptors (PPAR)-γ, and adipocyte protein 2 (aP2), were investigated. The mRNA expressions of proteins related to angiogenesis, vascular endothelial growth factor (VEGF)-α, vascular endothelial growth factor receptor (VEGFR)-2, MMP-2, and MMP-9, were investigated. Enzyme activities and concentrations of MMP-2 and MMP-9 were also measured. RESULTS: Quercetin treatment suppressed fat accumulation and the expressions of adipocyte differentiation-related genes (C/EBPα, C/EBPβ, PPAR-γ, and aP2) in a concentration-dependent manner in 3T3-L1 cells. Quercetin treatments reduced the mRNA expressions of VEGF-α, VEGFR-2, MMP-2, and MMP-9 in 3T3-L1 cells. The activities and concentrations of MMP-2 and MMP-9 were also decreased significantly as the concentration of quercetin increased. CONCLUSIONS: The results confirm that quercetin inhibits adipose tissue differentiation and fat accumulation in 3T3-L1 cells, which could occur through inhibition of the angiogenesis process related to MMPs.

Keywords

Acknowledgement

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2018R1D1A1B07043918).

References

  1. Lijnen HR. Angiogenesis and obesity. Cardiovasc Res 2008;78:286-93. https://doi.org/10.1093/cvr/cvm007
  2. Cao Y. Angiogenesis modulates adipogenesis and obesity. J Clin Invest 2007;117:2362-8. https://doi.org/10.1172/JCI32239
  3. Ali AT, Hochfeld WE, Myburgh R, Pepper MS. Adipocyte and adipogenesis. Eur J Cell Biol 2013;92:229-36. https://doi.org/10.1016/j.ejcb.2013.06.001
  4. Almalki SG, Llamas Valle Y, Agrawal DK. MMP-2 and MMP-14 silencing inhibits VEGFR2 cleavage and induces the differentiation of porcine adipose-derived mesenchymal stem cells to endothelial cells. Stem Cells Transl Med 2017;6:1385-98. https://doi.org/10.1002/sctm.16-0329
  5. Bagchi M, Kim LA, Boucher J, Walshe TE, Kahn CR, D'Amore PA. Vascular endothelial growth factor is important for brown adipose tissue development and maintenance. FASEB J 2013;27:3257-71. https://doi.org/10.1096/fj.12-221812
  6. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med 2003;9:669-76. https://doi.org/10.1038/nm0603-669
  7. Berg G, Barchuk M, Miksztowicz V. Behavior of metalloproteinases in adipose tissue, liver and arterial wall: an update of extracellular matrix remodeling. Cells 2019;8:158. https://doi.org/10.3390/cells8020158
  8. Carullo G, Cappello AR, Frattaruolo L, Badolato M, Armentano B, Aiello F. Quercetin and derivatives: useful tools in inflammation and pain management. Future Med Chem 2017;9:79-93. https://doi.org/10.4155/fmc-2016-0186
  9. Chen S, Jiang H, Wu X, Fang J. Therapeutic effects of quercetin on inflammation, obesity, and type 2 diabetes. Mediators Inflamm 2016;2016:9340637. https://doi.org/10.1155/2016/9340637
  10. Zhao Y, Chen B, Shen J, Wan L, Zhu Y, Yi T, Xiao Z. The beneficial effects of quercetin, curcumin, and resveratrol in obesity. Oxid Med Cell Longev 2017;2017:1459497. https://doi.org/10.1155/2017/1459497
  11. Ahn J, Lee H, Kim S, Park J, Ha T. The anti-obesity effect of quercetin is mediated by the AMPK and MAPK signaling pathways. Biochem Biophys Res Commun 2008;373:545-9. https://doi.org/10.1016/j.bbrc.2008.06.077
  12. Bae CR, Park YK, Cha YS. Quercetin-rich onion peel extract suppresses adipogenesis by down-regulating adipogenic transcription factors and gene expression in 3T3-L1 adipocytes. J Sci Food Agric 2014;94:2655-60. https://doi.org/10.1002/jsfa.6604
  13. Lu J, Wang Z, Li S, Xin Q, Yuan M, Li H, Song X, Gao H, Pervaiz N, Sun X, et al. Quercetin inhibits the migration and invasion of hcclm3 cells by suppressing the expression of p-Akt1, matrix metalloproteinase (MMP) MMP-2, and MMP-9. Med Sci Monit 2018;24:2583-9. https://doi.org/10.12659/MSM.906172
  14. Ren KW, Li YH, Wu G, Ren JZ, Lu HB, Li ZM, Han XW. Quercetin nanoparticles display antitumor activity via proliferation inhibition and apoptosis induction in liver cancer cells. Int J Oncol 2017;50:1299-311. https://doi.org/10.3892/ijo.2017.3886
  15. Chuang CH, Yeh CL, Yeh SL, Lin ES, Wang LY, Wang YH. Quercetin metabolites inhibit MMP-2 expression in A549 lung cancer cells by PPAR-γ associated mechanisms. J Nutr Biochem 2016;33:45-53. https://doi.org/10.1016/j.jnutbio.2016.03.011
  16. Zhao J, Fang Z, Zha Z, Sun Q, Wang H, Sun M, Qiao B. Quercetin inhibits cell viability, migration and invasion by regulating miR-16/HOXA10 axis in oral cancer. Eur J Pharmacol 2019;847:11-8. https://doi.org/10.1016/j.ejphar.2019.01.006
  17. Kim WK, Kang NE, Kim MH, Ha AW. Peanut sprout ethanol extract inhibits the adipocyte proliferation, differentiation, and matrix metalloproteinases activities in mouse fibroblast 3T3-L1 preadipocytes. Nutr Res Pract 2013;7:160-5. https://doi.org/10.4162/nrp.2013.7.3.160
  18. Kim HL, Ha AW, Kim WK. Effect of saccharin on inflammation in 3T3-L1 adipocytes and the related mechanism. Nutr Res Pract 2020;14:109-16. https://doi.org/10.4162/nrp.2020.14.2.109
  19. Harwood M, Danielewska-Nikiel B, Borzelleca JF, Flamm GW, Williams GM, Lines TC. A critical review of the data related to the safety of quercetin and lack of evidence of in vivo toxicity, including lack of genotoxic/carcinogenic properties. Food Chem Toxicol 2007;45:2179-205. https://doi.org/10.1016/j.fct.2007.05.015
  20. Eseberri I, Miranda J, Lasa A, Churruca I, Portillo MP. Doses of quercetin in the range of serum concentrations exert delipidating effects in 3T3-L1 preadipocytes by acting on different stages of adipogenesis, but not in mature adipocytes. Oxid Med Cell Longev 2015;2015:480943. https://doi.org/10.1155/2015/480943
  21. Lee CW, Seo JY, Lee J, Choi JW, Cho S, Bae JY, Sohng JK, Kim SO, Kim J, Park YI. 3-O-Glucosylation of quercetin enhances inhibitory effects on the adipocyte differentiation and lipogenesis. Biomed Pharmacother 2017;95:589-98. https://doi.org/10.1016/j.biopha.2017.08.002
  22. Yang JY, Della-Fera MA, Rayalam S, Ambati S, Hartzell DL, Park HJ, Baile CA. Enhanced inhibition of adipogenesis and induction of apoptosis in 3T3-L1 adipocytes with combinations of resveratrol and quercetin. Life Sci 2008;82:1032-9. https://doi.org/10.1016/j.lfs.2008.03.003
  23. Lee MS, Kim Y. Effects of isorhamnetin on adipocyte mitochondrial biogenesis and AMPK activation. Molecules 2018;23:1853. https://doi.org/10.3390/molecules23081853
  24. Lefterova MI, Zhang Y, Steger DJ, Schupp M, Schug J, Cristancho A, Feng D, Zhuo D, Stoeckert CJ Jr, Liu XS, Lazar MA. PPARγ and C/EBP factors orchestrate adipocyte biology via adjacent binding on a genomewide scale. Genes Dev 2008;22:2941-52. https://doi.org/10.1101/gad.1709008
  25. Kawamura T, Murakami K, Bujo H, Unoki H, Jiang M, Nakayama T, Saito Y. Matrix metalloproteinase-3 enhances the free fatty acids-induced VEGF expression in adipocytes through toll-like receptor 2. Exp Biol Med (Maywood) 2008;233:1213-21. https://doi.org/10.3181/0801-RM-20
  26. Park BY, Lee H, Woo S, Yoon M, Kim J, Hong Y, Lee HS, Park EK, Hahm JC, Kim JW, et al. Reduction of adipose tissue mass by the angiogenesis inhibitor ALS-L1023 from Melissa officinalis. PLoS One 2015;10:e0141612. https://doi.org/10.1371/journal.pone.0141612
  27. Chavey C, Mari B, Monthouel MN, Bonnafous S, Anglard P, Van Obberghen E, Tartare-Deckert S. Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation. J Biol Chem 2003;278:11888-96. https://doi.org/10.1074/jbc.M209196200
  28. Maquoi E, Munaut C, Colige A, Collen D, Lijnen HR. Modulation of adipose tissue expression of murine matrix metalloproteinases and their tissue inhibitors with obesity. Diabetes 2002;51:1093-101. https://doi.org/10.2337/diabetes.51.4.1093
  29. Pratheeshkumar P, Budhraja A, Son YO, Wang X, Zhang Z, Ding S, Wang L, Hitron A, Lee JC, Xu M, et al. Quercetin inhibits angiogenesis mediated human prostate tumor growth by targeting VEGFR-2 regulated AKT/mTOR/P70S6K signaling pathways. PLoS One 2012;7:e47516. https://doi.org/10.1371/journal.pone.0047516
  30. Bouloumie A, Sengenes C, Portolan G, Galitzky J, Lafontan M. Adipocyte produces matrix metalloproteinases 2 and 9: involvement in adipose differentiation. Diabetes 2001;50:2080-6. https://doi.org/10.2337/diabetes.50.9.2080
  31. Andres S, Pevny S, Ziegenhagen R, Bakhiya N, Schafer B, Hirsch-Ernst KI, Lampen A. Safety aspects of the use of quercetin as a dietary supplement. Mol Nutr Food Res 2018;62:1700447. https://doi.org/10.1002/mnfr.201700447
  32. Conquer JA, Maiani G, Azzini E, Raguzzini A, Holub BJ. Supplementation with quercetin markedly increases plasma quercetin concentration without effect on selected risk factors for heart disease in healthy subjects. J Nutr 1998;128:593-7. https://doi.org/10.1093/jn/128.3.593
  33. Carbonaro M, Grant G. Absorption of quercetin and rutin in rat small intestine. Ann Nutr Metab 2005;49:178-82. https://doi.org/10.1159/000086882
  34. Egert S, Bosy-Westphal A, Seiberl J, Kurbitz C, Settler U, Plachta-Danielzik S, Wagner AE, Frank J, Schrezenmeir J, Rimbach G, et al. Quercetin reduces systolic blood pressure and plasma oxidised low-density lipoprotein concentrations in overweight subjects with a high-cardiovascular disease risk phenotype: a double-blinded, placebo-controlled cross-over study. Br J Nutr 2009;102:1065-74. https://doi.org/10.1017/S0007114509359127
  35. Shi Y, Williamson G. Quercetin lowers plasma uric acid in pre-hyperuricaemic males: a randomised, double-blinded, placebo-controlled, cross-over trial. Br J Nutr 2016;115:800-6. https://doi.org/10.1017/S0007114515005310
  36. Williamson G, Manach C. Bioavailability and bioefficacy of polyphenols in humans. II. Review of 93 intervention studies. Am J Clin Nutr 2005;81:243S-255S. https://doi.org/10.1093/ajcn/81.1.243S