Document Type : Research Paper I Open Access I Released under CC BY-NC 4.0 license
Authors
1 .PhD Student of Sport Biochemistry and Metabolism, Islamic Azad University, Central Tehran Branch
2 Associate Professor of Endocrinology and Metabolism Research Institute, Shahid Beheshti University of Medical Sciences, Tehran
Abstract
The purpose of this study was to determine the effects of resveratrol supplementation and Aerobic training on protein levels of SIRT-1, PGC-1α and UCP-1 liver tissue and abdominal & inguinal subcutaneous adipose tissue in adult male Wistar rats. In this study, 28 male rat (w=260+10gr, 8 weeks) divided into 4 (n=8) groups: control (C), aerobic training (T), complement-training (T-R) and supplements (S) randomly. Training groups exercised for 14 weeks (5 sessions a week, each session 45 minutes on a treadmill. ELISA (sandwich double) was used to measure tissue proteins UCP-1, SIRT1, PGC-1α. ANOVA test used for data analysis and statistical significance (p≤0.05) were considered. SIRT1 and PGC-1α protein was observed changes in liver tissue and subcutaneous / visceral white adipose tissue, respectively (P≤0.05) and (P≤0.001). Increased protein UCP-1 is also measured in tissues-workout supplement after supplement in combination with aerobic activity (P≤0.001). According to our results, are likely to impact more powerful, resveratrol supplementation with aerobic physical activity increases the amount of UCP-1, SIRT1, PGC-1α tissue to separate than from physical activity or resveratrol supplements, And is likely to Improved liver function and change subcutaneous white adipose tissue to beige or intermediate phenotype.
Keywords
1. Shimizu, M., Kubota, M., Tanaka, T. &Moriwaki, H. Nutraceutical Approach forPreventing Obesity Related Colorectal and Liver Carcinogenesis. Int. J. Mol. Sci. (2012) 13, 579–595.
2. Buzzetti E, Pinzani M, Tsochatzis EA. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism 2016; 65: 1038-1048 [PMID: 26823198]
3. Lomonaco R, Ortiz-Lopez C, Orsak B, Webb A, Hardies J, Darland C, Finch J, Gastaldelli A, Harrison S, Tio F, Cusi K. Effect of adipose tissue insulin resistance on metabolic parameters and liver histology in obese patients with nonalcoholic fatty liver disease. Hepatology 2012; 55: 1389-1397 [PMID: 22183689]
4. Misra VL, Khashab M, Chalasani N. Nonalcoholic fatty liver disease and cardiovascular risk. Curr Gastroenterol Rep 2009; 11: 50-55 [PMID: 19166659]
5. Sanyal AJ. NASH: A global health problem. Hepatol Res 2011; 41: 670-674 [PMID: 21711426]
6. Lowell BB, Shulman GI. Mitochondrial dysfunction and type 2 diabetes. Science 2005; 307: 384-387 [PMID: 15662004]
7. Perry RJ, Zhang D, Zhang XM, Boyer JL, Shulman GI. Controlled-release mitochondrial protonophore reverses diabetes and steatohepatitis in rats. Science 2015; 347: 1253-1256 [PMID: 25721504]
8. Golabi P, Locklear CT, Austin P, Afdhal S, Byrns M, Gerber L, Younossi ZM. Effectiveness of exercise in hepatic fat mobilization in non-alcoholic fatty liver disease: Systematic review. World J Gastroenterol 2016; 22: 6318-6327 [PMID: 27468220 DOI: 10.3748/wjg.v22.i27.6318]
9. Gariani K, Menzies KJ, Ryu D, Wegner CJ, Wang X, Ropelle ER, Moullan N, Zhang H, Perino A, Lemos V, Kim B, Park YK, Piersigilli A, Pham TX, Yang Y, Ku CS, Koo SI, Fomitchova A, Cantó C, Schoonjans K, Sauve AA, Lee JY, Auwerx J. Eliciting the mitochondrial unfolded protein response by nicotinamide adenine dinucleotide repletion reverses fatty liver disease in mice. Hepatology 2016; 63: 1190-1204 [PMID: 26404765]
10. Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A. Resveratrol improves health and survival of mice on a highcalorie diet. Nature 2006; 444: 337–42.
11. Matos RS, Baroncini LAV, Précoma LB, Winter G, Lambach PH, Caron EY, Kaiber F & Précoma DB (2012). Resveratrol causes antiatherogenic effects in an animal model of atherosclerosis. Arq Bras Cardiol 98, 136–142.
12. Sin, T.K., Yung, B.Y., Siu, P.M.,. Modulation of SIRT1-Foxo1 signaling axis by resveratrol: Implications in skeletal muscle aging and insulin resistance. Cell. Physiol. Biochem. 2015, 35 (2), 541–552
13. Ling Li,1Ruping Pan,1Rong Li,1Bernd Niemann,2Anne-Cathleen Aurich,1Ying Chen,1and Susanne Rohrbach1,3 Mitochondrial Biogenesis and Peroxisome Proliferator–Activated Receptor-? Coactivator-1? (PGC-1?) Deacetylation by Physical Activity Intact Adipocytokine Signaling Is Required Diabetes 60:157–167, 2011
14. Wu J, Cohen P, Spiegelman B M. Adaptive thermogenesis in adipocytes: is beige the new brown? Genes and Development. 2013;27 (3):234-50.
15. Pacholec, M., Bleasdale, J.E., Chrunyk, B., Cunningham, D., Flynn, D., Garofalo, R.S., Griffith, D., Griffor, M., Loulakis, P., Pabst, B., et al.. SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1. J. Biol. Chem. (2010), 285, 8340- 8351
16. Boström P, Wu J, Jedrychowski MP, KordeA,Ye L, Lo JC, Rasbach KA, Boström EA, Choi JH, Long JZ, Kajimura S, Zingaretti MC, Vind BF, Tu H, Cinti S, Højlund K, Gygi SP, Spie-gelman BM: A PGC-1Α-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 2012; 48 463–468.
17. Ikeda S, Kawamoto H, Kasaoka K, Hitomi Y, Kizaki T, Sankai Y, Ohno H, Haga S, Takemasa T. Muscle type-specific response of PGC-1 alpha and oxidative enzymes during voluntary wheel running in mouse skeletal muscle. Acta Physiol (Oxf) 2006;188:217–223
18. Um JH , Park SJ , Kang H , et al . AMP-activated protein kinase-deficient mice are resistant to the metabolic effect of resveratrol. Diabetes. 2010;59:554-563
19. Polyzos S A, Kountouras J, Shields K, Mantzoros C S. Irisin: A renaissance in
metabolism? Metabolism. 2013; 62(8): 1037-44.
20. Chang JS, Fernand V, Zhang Y, Shin J, Jun HJ, Joshi Y, Gettys TW. NT-PGC-1alpha protein is sufficient to link beta3-adrenergic receptor activation to transcriptional and physiological components of adaptive thermogenesis. J Biol Chem. 2012; 287:9100–9111. [PubMed: 22282499]
21. Sluse FE, Jarmuszkiewicz W, Navet R, Douette P, Mathy G, Sluse-Goffart CM. Mitochondrial UCPs: new insights into regulation and impact. Biochimica et Biophysica Acta (BBA) - Bioenergetics. 2006;1757 (5-6):480-5.
22. Perry RJ, Zhang D, Zhang XM, Boyer JL, Shulman GI. Controlled-release mitochondrial protonophore reverses diabetes and steatohepatitis in rats. Science 2015; 347: 1253-1256 [PMID: 25721504]
23. Alisi A, Manco M, Panera N, Nobili V. Association between type two diabetes and non-alcoholic fatty liver disease in youth. Ann Hepatol 2009; 8 Suppl 1: S44-S50 [PMID: 19381124]
24. Nobili V, Svegliati-Baroni G, Alisi A, Miele L, Valenti L, Vajro P. A 360-degree overview of paediatric NAFLD: recent insights. J Hepatol 2013; 58: 1218-1229 [PMID: 23238106]
25: Petrovic N, Walden TB, Shabalina IG, Timmons JA, Cannon B, Nedergaard J. Chronic Peroxisome Proliferator-activated Receptor γ (PPARγ ) Activation of Epididymally Derived White Adipocyte Cultures Reveals a Population of Thermogenically Competent, UCP-1-containing Adipocytes Molecularly Distinct from Classic Brown Adipocytes. Journal of Biological Chemistry.2010; 285:7153–7164. [PubMed: 20028987]
26. Jun Hyun Jeong, Young Ran Lee, Hee Geun Park, and Wang Lok Lee The effects of either resveratrol or exercise on macrophage infiltration and switching from M1 to M2 in high fat diet mice J Exerc Nutrition Biochem. 2015 Jun; 19 (2): 65–72.
27. Leone TC, Lehman JJ, Finck BN, Schaeffer PJ,Wende AR, Boudina S, Courtois M,Wozniak DF, Sambandam N, Bernal-Mizrachi C, Chen Z, Holloszy JO, Medeiros DM, Schmidt RE, Saffitz JE, Abel ED, Semenkovich CF & Kelly DP. PGC-1α deficiency causes multi-system energy metabolic derangements: muscle dysfunction, abnormal weight control and hepatic steatosis. PLoS Biol (2005) 3, e101.
28. Kristin I. Stanford,1,2Roeland J.W. Middelbeek,1,2,3and Laurie J. Goodyear , Exercise Effects on White Adipose Tissue: Beiging and Metabolic Adaptations Diabetes 2015;64:2361–2368 | DOI: 10.2337/db15-0227
29. Granneman JG, Li P, Zhu Z, Lu Y. Metabolic and cellular plasticity in white adipose tissue I: effects of beta3-adrenergic receptor activation. Am J PhysiolEndocrinolMetab. 2005; 289:E608–616. [PubMed:15941787]
30. Li P, Zhu Z, Lu Y, Granneman JG. Metabolic and cellular plasticity in white adipose tissue II: role of peroxisome proliferator-activated receptor-α. Am J of PhysiolEndocrinolMetab. 2005; 289:E617–E626. [PubMed: 15941786]
31. Chih-Hsueh Lin & Cheng-Chieh Lin & Wei-Jen Ting & Pei-Ying Pai&et al . Resveratrol enhanced FOXO3 phosphorylation via synergeticactivation of SIRT1 and PI3K/Akt signaling to improve the effects of exercise in elderly rat hearts. Age (Dordr). 2014;36 (5):9705
32. Pontus B, Jun W, Mark P J, Anisha K, Li Y, James C, et al. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature. 2012; 463-81.
33. Lin, H., Lin, C., Ting, J., Pai, Y., Kuo, H., Ho, T.J., Kuo, W., Chang, C.H., Huang, C.Y., Lin, T.,. Resveratrol enhanced FOXO3 phosphorylation via synergetic activation of SIRT1 and PI3K/Akt signaling to improve the effects of exercise in elderly rat hearts. Age (Dordr) 2014, 36 (5), 9705
34. Lagouge, M. et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1 alpha. Cell (2006) 127, 1109–1122
35. Fatiha Nassir, Jamal A Ibdah: Sirtuins and nonalcoholic fatty liver disease; World J Gastroenterol 2016 December 14; 22(46): 10084-10092 December 14, 2016|Volume 22|Issue 46
36. Wu T, Liu YH, Fu YC, Liu XM, Zhou XH. Direct evidence of sirtuin downregulation in the liver of non-alcoholic fatty liver disease patients. Ann Clin Lab Sci 2014; 44: 410-418 [PMID: 25361925]
37. Andrade JM, Paraíso AF, de Oliveira MV, Martins AM, Neto JF, Guimarães AL, de Paula AM, Qureshi M, Santos SH. Resveratrol attenuates hepatic steatosis in high-fat fed mice by decreasing lipogenesis and inflammation. Nutrition 2014; 30: 915-919 [PMID: 24985011]
38. Tobita T, Guzman-Lepe J, Takeishi K, Nakao T, Wang Y, Meng F, Deng CX, Collin de l’Hortet A, Soto-Gutierrez A. SIRT1 Disruption in Human Fetal Hepatocytes Leads to Increased Accumulation of Glucose and Lipids. PLoS One 2016; 11: e0149344 [PMID: 26890260]
39. Chachay VS, Macdonald GA, Martin JH, Whitehead JP, O’ Moore-Sullivan TM, Lee P, Franklin M, Klein K, Taylor PJ, Ferguson M, Coombes JS, Thomas GP, Cowin GJ, Kirkpatrick CM, Prins JB, Hickman IJ. Resveratrol does not benefit patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2014; 12: 2092-2103.e1-6 [PMID: 24582567]
40. Smith JJ, Kenney RD, Gagne DJ, Frushour BP, Ladd W, Galonek HL, Israelian K, Song J, Razvadauskaite G, Lynch AV, Carney DP, Johnson RJ, Lavu S, Iffland A, Elliott PJ, Lambert PD, Elliston KO, Jirousek MR, Milne JC, Boss O. Small molecule activators of SIRT1 replicate signaling pathways triggered by calorie restriction in vivo. BMC Syst Biol 2009; 3: 31 [PMID: 19284563 DOI: 10.1186/1752-0509-3-31]
41. Milne JC, Lambert PD, Schenk S, Carney DP, Smith JJ, Gagne DJ, Jin L, Boss O, Perni RB, Vu CB, Bemis JE, Xie R, Disch JS, Ng PY, Nunes JJ, Lynch AV, Yang H, Galonek H, Israelian K, Choy W, Iffland A, Lavu S, Medvedik O, Sinclair DA, Olefsky JM, Jirousek MR, Elliott PJ, Westphal CH. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature 2007; 450: 712-716 [PMID: 18046409]
42. Feige JN, Lagouge M, Canto C, Strehle A, Houten SM, Milne JC, Lambert PD, Mataki C, Elliott PJ, Auwerx J. Specific SIRT1 activation mimics low energy levels and protects against dietinduced metabolic disorders by enhancing fat oxidation. Cell Metab 2008; 8: 347-358 [PMID: 19046567]
43. Baur, J.A., Biochemical effects of SIRT1 activators. Biochim.Biophys.Acta 2010, 1804(8), 1626–1634..
44. Lagouge M , Argmann C , Gerhart-Hines Z, et al. Resveratrol improves mitochondrial function and protects against metabolic disease by acti-vating SIRT1 and PGC-1alpha .Cell .2006 ; 127 : 1109 – 1122 .
45. Rivera, L., Moron, R., Zarzuelo, A. &Galisteo, M. Long-term resveratrol administration reduces metabolic disturbances and lowers blood pressure in obese Zucker rats. Biochem.Pharmacol. 2009.77, 1053–1063.
46. Oberdoerffer, P., Michan, S., McVay, M., Mostoslavsky, R., Vann, J., Park, S.K.,Hartlerode, A., Stegmuller, J., Hafner, A., Loerch, P., Wright, S.M., Mills, K.D.,Bonni, A., Yankner, B.A., Scully, R., Prolla, T.A., Alt, F.W., Sinclair, D.A.,.SIRT1 redistribution on chromatin promotes genomic stability but alters geneexpression during aging. Cell 2008 135 (5), 907–918
47. Nemoto, S., Fergusson, M.M., and Finkel, T.. SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1{alpha}. J. Biol. Chem. 2005,280, 16456-16460.
48. Fortunato RS, Ignacio DL, Padron AS, Pecanha R, Marassi MP,Rosenthal D,Werneck-de-Castro JP & Carvalho DP.The effect of acute exercise session on thyroid hormone economy in rats. J Endocrinol (2008) 198, 347–353
49. Wang MY, Unger RH. Role of PP2C in cardiac lipid accumulation in obese rodents and its prevention by troglitazone. Am J Physiol Endocrinol Metab 2005; 288: E216–21.
50. Viollet B, Foretz M, Guigas B, Horman S, Dentin R, Bertrand L. Activation of AMP-activated protein kinase in the liver: a new strategy for the management of metabolic hepatic disorders. J Physiol 2006; 574: 41–53.
51. Ikeda S, Kawamoto H, Kasaoka K, Hitomi Y, Kizaki T, Sankai Y, Ohno H, Haga S, Takemasa T. Muscle type-specific response of PGC-1 alpha and oxidative enzymes during voluntary wheel running in mouse skeletal muscle. Acta Physiol (Oxf) 2006;188:217–223
)