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Resveratrol Ameliorates High-fat-induced Metabolic Complications by Changing the Expression of Inflammasome Markers and Macrophage M1 and M2 Markers in Obese Mice

라스베라트롤 투여가 고지방식이 비만쥐의 지방조직에서의 inflammasome과 대식세포 마커에 미치는 영향

  • Lee, Young-Ran (Center for Sport Science in Jeonbuk) ;
  • Pitriani, Pipit (Department of Sports Science, College of Natural Science, Chungnam National University) ;
  • Park, Hee-Geun (Department of Sports Science, College of Natural Science, Chungnam National University) ;
  • Lee, Wang-Lok (Department of Sports Science, College of Natural Science, Chungnam National University)
  • Received : 2017.09.06
  • Accepted : 2017.11.13
  • Published : 2017.12.30

Abstract

The purpose of this study was to investigate the effects of resveratrol supplementation on inflammasome, inflammation, and macrophage markers in subcutaneous adipose tissue of high-fat-diet-induced obese mice. C57BL/6 mice were randomly assigned to three groups: normal diet control (NC; n=10), high-fat diet control (HC; n=10), or high fat with resveratrol (HRE; n=10) group. The mice were fed a high-fat diet (60% of calories from fat) or normal diet (18% of calories from fat). Resveratrol dissolved in a 0.1ml solution of dimethyl sulfoxide was supplemented orally at 25 mg/kg body weight. After 15 weeks, the body weight was significantly higher in the high-fat diet group than in the normal diet group. The inflammasome markers NLRP3, ASC, and caspase1 were significantly lower in the HRE group than in the HC group. The levels of an inflammation marker, IL-18, were also significantly lower in the HRE group than in the NC and HC groups. The levels of macrophage markers F480 and CD86 were significantly lower in the HRE group than in the HC group. The levels of the M2 macrophage marker CD206 were significantly decreased in the HC and HRE groups. Resveratrol had a positive effect on ameliorating the complications of high fat diet-induced obesity by reducing inflammasome and M1 macrophage gene expressions. However, resveratrol supplementation did not reduce inflammation gene expression.

본 연구 목적은 고지방식이 유도 비만 쥐의 피하지방조직에서 라스베라트롤 투여가 대식세포 침윤관련 염증인자에 미치는 영향을 규명하고자 하였다. 본 연구를 위해 정상식이군, 고지방식이군, 고지방식이+라스베라트롤 투여군으로 분류한 후, 라스베라트롤 투여군은 15주간 25 mg/kg 농도로 Dimethyl Sulfoxide에 용해하여 투여하였으며, 비교군은 Dimethyl Sulfoxide 용액만을 투여하였다. 연구결과 고지방식이군은 정상식이군에 비하여 체중이 유의하게 증가하였고, 라스베라트롤 투여군에서 고지방식이 군보다 NLRP3. ASC, Casepase1 mRNA 발현이 감소하였다. 또한 염증마커로 알려진 IL-18 mRNA 발현이 라스베라트롤 투여군에서 정상식이군과 고지방식이군보다 낮게 나타났다. 대식세포 침윤 마커인 F480, CD86 mRNA 발현에서도 라스베라트롤 투여군에서 고지방식이 군보다 유의한 감소를 보였다. 따라서 라스베라트롤 투여는 고지방식이 유도 비만 상황에서 대식세포 침윤 염증과 inflammasome에 긍정적인 영향을 미치는 것으로 보여진다.

Keywords

References

  1. Ahn, J., Cho, I., Kim, S., Kim, D. and Ha, T. 2008. Dietary resveratrol alters lipid metabolism-rRelated gene expression of mice on an atherogenic diet. J. Hepatol. 49, 1019-1028. https://doi.org/10.1016/j.jhep.2008.08.012
  2. Benetti, E., Fausto, C., Nimesh, S. A. P. and Massimo, C. 2013. The NLRP3 inflammasome as a novel player of the intercellular crosstalk in metabolic disorders. J. Pharmacol. 154, 165-173.
  3. Boutens, L. and Stienstera, R. 2016. Adipose tissue macrop hages : going off track during obesity. Diabetilogy 59, 879-894. https://doi.org/10.1007/s00125-016-3904-9
  4. Castoldi, A., Cristiane N. S., Niels Olsen, S. C. and Pedro, M. M. 2016. The macrophage switch in obesity development. Front. Immunol. 6, 1-11.
  5. Chang, C., Lin, K., Peng, K., Day, Y. and Hung, L. 2016. Resveratrol exerts anti-obesity effects in high-fat diet obese mice and displays differential dosage effects on cytotoxicity, differentiation, and lipolysis in 3T3-L1 cells. Endocr. J. 63, 169-178. https://doi.org/10.1507/endocrj.EJ15-0545
  6. Chang, Y., Ka, S., Hsu, W., Chen, A., Chao, L., Lin, C., Hsieh, C., Chen, M., Chiu, H., Ho, C., Chic, Y., Liu, M. and Hua, K. 2015. Resveratrol inhibits NLRP3 inflammasome activation by preserving mitochondrial integrity and augmenting autophagy. J. Cell. Physiol. 230, 1567-1579. https://doi.org/10.1002/jcp.24903
  7. Chawla, A., Khoa, N. and Sharon, Y. 2012. Macrophage -mediated inflammation in metabolic disease. Nat. Rev. Immunol. 11, 738-749.
  8. Chen, Q., Ermao W., Liping, M. and Pei, Z. 2012. Dietary Resveratrol increases the expression of hepatic 7${\alpha}$-hydroxylase and ameliorates hypercholesterolemia in high-fat fed C57BL/6J mice. Lipids Health Dis. 11, 56. https://doi.org/10.1186/1476-511X-11-56
  9. Fernando, C., Ricardo V. G. and Alejandra, L. 2014. Obesity, adipose tissue, inflammation and update on obesity management. Obes. Rev. 1, 1-8.
  10. Ghanim, H., Sia, C. L., Abuaysheh, S., Korzeniewski, K., Patnaik, P., Marumganti, A., Chaudhuri, A. and Dandona, P. 2010. An antiinflammatory and reactive oxygen species suppressive effects of an extract of polygonum cuspidatum containing resveratrol. J. Clin. Endocrinol. Metab. 95, 1-8. https://doi.org/10.1210/jc.2009-2363
  11. Gonzalez-Castejon, M. and Rodriguez-Casado, A. 2011. Dietary phytochemicals and their potential effects on obesity: a review. Pharmacol. Res. 64, 438-455. https://doi.org/10.1016/j.phrs.2011.07.004
  12. Goossens, G. H., Blaak, E. E., Theunissen, R., Duijvstijn, A. M., Cle'ment, K., Tervaert, J. W. and Thewissen, M. M. 2012. Expression of NLRP3 inflammasome and T cell population markers in adipose tissue are associated with insulin resistance and impaired glucose metabolism in humans. Mol. Immunol. 50, 142-149. https://doi.org/10.1016/j.molimm.2012.01.005
  13. Greenberg, A. S. and Obin, M. S. 2006. Obesity and the role of adipose tissue in iInflammation and metabolism. Am. J. Clin. Nutr. 83, 461S-465S. https://doi.org/10.1093/ajcn/83.2.461S
  14. Haneklaus, Moritz. and O'Neill, L. A. 2015. NLRP3 at the interface of metabolism and inflammation. Immunol. Rev. 265, 53-62. https://doi.org/10.1111/imr.12285
  15. Haneklaus, M., O'Neill, L. A. and Coll, R. C. 2013. Modulatory mechanisms controlling the NLRP3 inflammasome in inflammation: recent developments. Curr. Opin. Immunol. 25, 40-45. https://doi.org/10.1016/j.coi.2012.12.004
  16. Jeong, J., Lee, Y., Park, H. and Lee, W. 2015. The effects of either resveratrol or exercise on macrophage infiltration and switching from M1 to M2 in high fat diet mice. J. Exerc. Nutr. Biochem. 19, 65-72. https://doi.org/10.5717/jenb.2015.15060203
  17. Jeong, J., Lee, Y., Park, H. and Lee, W. 2015. Moderate exercise training is more effective than resveratrol supplementation for ameliorating lipid metabolic complication in skeletal muscle of high fat diet-iduced obese mice. J. Exerc. Nutr. Biochem. 19, 131-137. https://doi.org/10.5717/jenb.2015.15062211
  18. Jun, J., Lee, W., Park, H., Lee, S., Jeong, S. and Lee, Y. 2014. Moderate intensity exercise inhibits macrophage infiltration and attenuates adipocyte inflammation in ovariectomized rats. J. Exerc. Nutr. Biochem. 18, 119-127. https://doi.org/10.5717/jenb.2014.18.1.119
  19. Ku, C. R., Cho, Y. H., Hong, Z. Y., Lee, H., Hohg, S. S. and Lee, E. J. 2016. The effects of high fat diet and resveratrol on mitochondrial activity of brown adipocytes. Endocrinol. Metab. 31, 328-335. https://doi.org/10.3803/EnM.2016.31.2.328
  20. Lagouge, M., Argmann, C., Gerhart-Hines, Z., Meziane, H., Lerin, C., Daussin, F., Messadeg, N., Milne, J., Lambert, P., Elliott, P., Geny, B., Laakso, M., Puigserver, P. and Auwerx, J. 2006. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1${\alpha}$. Cell 127, 1109-1122. https://doi.org/10.1016/j.cell.2006.11.013
  21. Lee, Y., Jeong, S., Park, H., Jung, J. and Lee, W. 2013. The effects of either resveratrol supplementation or aerobic exercise training combined with a low fat diet on the molecules of adipogenesis and adipocyte inflammation in high fat diet-induced obese mice. J. Exerc. Nutr. Biochem. 17, 15-20.
  22. Leiro, J., Álvarez, E., Garcia, D. and Orallo, F. 2002. Resveratrol modulates rat macrophage functions. Int. Immunopharmacol. 2, 767-774. https://doi.org/10.1016/S1567-5769(02)00014-0
  23. Lumeng, C. N., Jennifer L. B. and Alan, R. S. 2007. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J. Clin. Invest. 117, 175-184. https://doi.org/10.1172/JCI29881
  24. Lv, Z. M., Wang, Q., Chen, Y. H., Wang, S. H. and Huang, D. Q. 2015. Resveratrol attenuates inflammation and oxidative stress in epididymal white adipose tissue: implications for its involvement in improving steroidogenesis in diet-induced obese mice. Mol. Reprod. Dev. 82, 321-328. https://doi.org/10.1002/mrd.22478
  25. Makki, K., Froguel, O. and Wolowczuk, L. 2013. Adipose tissue in obesity-related inflammation and insulin resistance: cells, cytokines, and chemokines. ISRN Inflamm. 2013, 1-12.
  26. Manach, C., Scalbert, A., Morand, C., Remesy, C. and Jimenez, L. 2004. Polyphenols: food sources and bioavailability Am. J. Clin. Nutr. 79, 727-747. https://doi.org/10.1093/ajcn/79.5.727
  27. McGettrick, A. F. and O'Neill, L. A. 2013. How metabolism generates signals during innate immunity and inflammation. J. Biol. Chem. 288, 22893-22898. https://doi.org/10.1074/jbc.R113.486464
  28. Medzhitov, R. 2008. Origin and physiological roles of inflammation. Nature 454, 428-435. https://doi.org/10.1038/nature07201
  29. Metchnikoff, I. and Nobel, P. 2015. Macrophage polarization. Biorad 2, 1-8.
  30. Park, H., Lee, Y., Jun, J. and Lee, W. 2014. Exercise training is more effective than resveratrol supplementation on alleviation of inflammation in peritoneal macrophages of high Fat diet mice. J. Exerc. Nutr. Biochem. 18, 79-87. https://doi.org/10.5717/jenb.2014.18.1.79
  31. Poulsen, M. M., Fjeldborg, K., Ornstrup, M. J., Kjaer, T. N., Nohr, M. K. and Pedersen, S. B. 2015. Resveratrol and inflammation: challenges in translating pre-clinical findings to improved patient outcomes. Biochim. Biophys. Acta. 1852, 1124-1136. https://doi.org/10.1016/j.bbadis.2014.12.024
  32. Qiu, Y., Shan, B., Yang, L. and Liu, Y. 2016. Adipose tissue macrophage in immune regulation of metabolism. Sci. China. Life. Sci. 59, 1232-1240. https://doi.org/10.1007/s11427-016-0155-1
  33. Rebecca, L. S. and Laurel, L. L. 2012. Distinct licensing of IL-18 and IL-1 ${\beta}$ secretion in response to NLRP3 inflammasome activation. PLoS. One 7, 1-9.
  34. Schroder, K., Zhou, R. and Tschopp, J. 2010. The NLRP3 inflammasome: a sensor for metabolic danger? Science 327, 296-300. https://doi.org/10.1126/science.1184003
  35. Signorelli, P. and Ghidoni, R. 2005. Resveratrol as an anticancer nutrient: molecular basis, open questions and promises. J. Nutr. Biochem. 16, 449-466. https://doi.org/10.1016/j.jnutbio.2005.01.017
  36. Skeldon, A. M., Faraj, M. and Saleh, M. 2014. Caspases and inflammasomes in metabolic inflammation. Immunol. Cell. Biol. 92, 304-313. https://doi.org/10.1038/icb.2014.5
  37. Stienstra, R., van Diepen, J. A., Tack, C. J., Zaki, M. H., van de Veerdonk, F. L., Perera, D., Neale, G. A., Hooiveld, G. J., Hijmans, A., Vroegrijk, I., van den Berg, S., Romijn, J., Rensen, P. C., Joosten, L. A., Netea, M. G. and Kanneganti, T. D. 2011. Inflammasome is a central player in the induction of obesity and insulin resistance. Proc. Natl. Acad. Sci. USA 108, 15324-15329. https://doi.org/10.1073/pnas.1100255108
  38. Strowig, T., Henao-Mejia, J., Eran, E. and Richard, F. 2012. Inflammasomes in health and disease. Nature 481, 278-286. https://doi.org/10.1038/nature10759
  39. Tschopp, J. and Schroder, K. 2010. NLRP3 inflammasome activation: The convergence of multiple signalling pathways on ROS production? Nat. Rev. Immunol. 10, 210-215. https://doi.org/10.1038/nri2725
  40. Vandanmagsar, B., Youm, Y. H., Ravussin, A., Galgani, J. E., Stadler, K., Mynatt, R. L., Ravussin, E., Stephens, J. M. and Dixit, V. D. 2011. The NALP3/NLRP3 inflammasome instigates obesity-induced autoinflammation and insulin resistance. Nat. Med. 17, 179-188. https://doi.org/10.1038/nm.2279
  41. Vauzour, D., Ana, R. M., Giulia, C., Maria, O. C. and Jeremy, P. E. 2010. Polyphenols and human health: prevention of disease and mechanisms of action. Nutrients 2, 1106-1131. https://doi.org/10.3390/nu2111106
  42. Shu, W., Naima, M. M., Lixia, C., Huanbiao, M., Anuradha, S., Rui, S., Priyanka, B., Kwun, I. S. 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
  43. Weisberg, S. P., McCann, D., Desai, M., Rosenbaum, M., Leibel, R. L. and Ferrante, A. W. 2003. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112, 1796-1808. https://doi.org/10.1172/JCI200319246
  44. Yang, S. J. and Lim, Y. 2014. Resveratrol ameliorates hepatic metaflammation and inhibits NLRP3 inflammasome activation. Metabolism 63, 693-701. https://doi.org/10.1016/j.metabol.2014.02.003