Chronic aerobic exercise improves insulin sensitivity and modulates Nrf2 and NF‑κB/IκBα pathways in the skeletal muscle of rats fed with a high fat diet

Yu,Qian; Xia,Zhengyun; Liong,Emily  Chiu; Tipoe,George  Lim

doi:10.3892/mmr.2019.10787

Chronic aerobic exercise improves insulin sensitivity and modulates Nrf2 and NF‑κB/IκBα pathways in the skeletal muscle of rats fed with a high fat diet

Authors:
- Qian Yu
- Zhengyun Xia
- Emily Chiu Liong
- George Lim Tipoe
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Affiliations: School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, P.R. China
Published online on: October 31, 2019 https://doi.org/10.3892/mmr.2019.10787
Pages: 4963-4972
Copyright: © Yu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The present study aimed to investigate the molecular mechanisms of the ameliorative effects of chronic aerobic exercise on non‑alcoholic steatohepatitis (NASH) in rat skeletal muscle. Female Sprague‑Dawley rats (n=6‑9 per group) were divided into four groups: i) Rats fed with normal chow; ii) exercise rats fed with normal chow + exercise (run on a rotarod for 30 min per day from 9‑12 weeks); iii) rats fed with a high‑fat diet (HFD); iv) rats fed with an HFD + exercise. All HFD rats were fed with an HFD consisting of 30% fat from fish oil throughout the study for 12 weeks. Exercise decreased the levels of hepatic lipogenic markers carbohydrate‑responsive element‑binding protein, fat‑specific protein 27 and liver X receptor and improved systemic glucose and insulin intolerance in the NASH animal model. The beneficial effects may have been mediated partly via the tripartite motif‑containing family protein 72 (TRIM72)/PI3K/Akt/mTOR pathway, accompanied with an upregulation of glucose transporter 4 in the skeletal muscle. The exercise regimen activated the master regulator of antioxidant enzymes, nuclear factor erythroid 2‑related factor 2, with upregulation of superoxide dismutase [Cu‑Zn] expression and a corresponding decrease in kelch‑like ECH‑associated protein 1 expression, but failed to decrease the levels of the oxidative marker malondialdehyde in the HFD rat skeletal muscle. Chronic exercise decreased the expression of the inflammation marker NF‑κB, followed by a decrease in interleukin‑6 and tumor necrosis factor‑α levels, as verified by a corresponding increase in the level of NF‑κB inhibitor α expression. Exercise may exert its beneficial effects by improving muscle insulin sensitivity via the TRIM72/PI3K/Akt/mTOR pathway, contributing to the improvement of systemic insulin intolerance, and finally leading to decreased hepatic lipogenesis during NASH. The attenuation of insulin resistance by exercise may be partly achieved through a decrease in the level of inflammation and an increased antioxidant response.

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1	Tilg H and Kaser A: Treatment strategies in nonalcoholic fatty liver disease. Nat Clin Pract Gastroenterol Hepatol. 2:148–155. 2005. View Article : Google Scholar : PubMed/NCBI
2	Krenkel O, Hundertmark J, Abdallah AT, Kohlhepp M, Puengel T, Roth T, Branco DPP, Mossanen JC, Luedde T, Trautwein C, et al: Myeloid cells in liver and bone marrow acquire a functionally distinct inflammatory phenotype during obesity-related steatohepatitis. Gut. May 10–2019.(Epub ahead of print). View Article : Google Scholar : PubMed/NCBI
3	Jennison E, Patel J, Scorletti E and Byrne CD: Diagnosis and management of non-alcoholic fatty liver disease. Postgrad Med J. 95:314–322. 2019. View Article : Google Scholar : PubMed/NCBI
4	Duque-Guimarães DE and Ozanne SE: Nutritional programming of insulin resistance: Causes and consequences. Trends Endocrinol Metab. 24:525–535. 2013. View Article : Google Scholar : PubMed/NCBI
5	Flannery C, Dufour S, Rabøl R, Shulman GI and Petersen KF: Skeletal muscle insulin resistance promotes increased hepatic de novo lipogenesis, hyperlipidemia, and hepatic steatosis in the elderly. Diabetes. 61:2711–2717. 2012. View Article : Google Scholar : PubMed/NCBI
6	Jornayvaz FR, Samuel VT and Shulman GI: The role of muscle insulin resistance in the pathogenesis of atherogenic dyslipidemia and nonalcoholic fatty liver disease associated with the metabolic syndrome. Annu Rev Nutr. 30:273–290. 2010. View Article : Google Scholar : PubMed/NCBI
7	Kato K, Takeshita Y, Misu H, Zen Y, Kaneko S and Takamura T: Liver steatosis is associated with insulin resistance in skeletal muscle rather than in the liver in Japanese patients with non-alcoholic fatty liver disease. J Diabetes Investig. 6:158–163. 2015. View Article : Google Scholar : PubMed/NCBI
8	Rabøl R, Petersen KF, Dufour S, Flannery C and Shulman GI: Reversal of muscle insulin resistance with exercise reduces postprandial hepatic de novo lipogenesis in insulin resistant individuals. Proc Natl Acad Sci USA. 108(8): 13705–13709. 2011. View Article : Google Scholar : PubMed/NCBI
9	Wellen KE and Hotamisligil GS: Inflammation, stress, and diabetes. J Clin Invest. 115:1111–1119. 2005. View Article : Google Scholar : PubMed/NCBI
10	de Luca and Olefsky JM: Inflammation and insulin resistance. FEBS Lett. 582:97–105. 2008. View Article : Google Scholar : PubMed/NCBI
11	Stump CS, Henriksen EJ, Wei Y and Sowers JR: The metabolic syndrome: Role of skeletal muscle metabolism. Ann Med. 38:389–402. 2006. View Article : Google Scholar : PubMed/NCBI
12	Henriksen EJ: Exercise training and the antioxidant alpha-lipoic acid in the treatment of insulin resistance and type 2 diabetes. Free Radic Biol Med. 40:3–12. 2006. View Article : Google Scholar : PubMed/NCBI
13	Henriksen EJ, Diamond-Stanic MK and Marchionne EM: Oxidative stress and the etiology of insulin resistance and type 2 diabetes. Free Radic Biol Med. 51:993–999. 2011. View Article : Google Scholar : PubMed/NCBI
14	Johnson NA, Keating SE and George J: Exercise and the liver: Implications for therapy in fatty liver disorders. Semin Liver Dis. 32:65–79. 2012. View Article : Google Scholar : PubMed/NCBI
15	Keating SE, Hackett DA, George J and Johnson NA: Exercise and non-alcoholic fatty liver disease: A systematic review and meta-analysis. J Hepatol. 57:157–166. 2012. View Article : Google Scholar : PubMed/NCBI
16	Kistler KD, Brunt EM, Clark JM, Diehl AM, Sallis JF and Schwimmer JB; NASH CRN Research Group, : Physical activity recommendations, exercise intensity, and histological severity of nonalcoholic fatty liver disease. Am J Gastroenterol. 106:460–468; quiz 469. 2011. View Article : Google Scholar : PubMed/NCBI
17	Lau JK, Zhang X and Yu J: Animal models of non-alcoholic fatty liver disease: Current perspectives and recent advances. J Pathol. 241:36–44. 2017. View Article : Google Scholar : PubMed/NCBI
18	Takahashi Y, Soejima Y and Fukusato T: Animal models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World J Gastroenterol. 18:2300–2308. 2012. View Article : Google Scholar : PubMed/NCBI
19	Tipoe GL, Ho CT, Liong EC, Leung TM, Lau TY, Fung ML and Nanji AA: Voluntary oral feeding of rats not requiring a very high fat diet is a clinically relevant animal model of non-alcoholic fatty liver disease (NAFLD). Histol Histopathol. 24:1161–1169. 2009.PubMed/NCBI
20	Liu Y, Li Q, Wang H, Zhao X, Li N, Zhang H, Chen G and Liu Z: Fish oil alleviates circadian bile composition dysregulation in male mice with NAFLD. J Nutr Biochem. 69:53–62. 2019. View Article : Google Scholar : PubMed/NCBI
21	Yamazaki T, Nakamori A, Sasaki E, Wada S and Ezaki O: Fish oil prevents sucrose-induced fatty liver but exacerbates high-safflower oil-induced fatty liver in ddy mice. Hepatology. 46:1779–1790. 2007. View Article : Google Scholar : PubMed/NCBI
22	Tipoe GL, Leung TM, Liong EC, Lau TY, Fung ML and Nanji AA: Epigallocatechin-3-gallate (EGCG) reduces liver inflammation, oxidative stress and fibrosis in carbon tetrachloride (CCl4)-induced liver injury in mice. Toxicology. 273:45–52. 2010. View Article : Google Scholar : PubMed/NCBI
23	Kleiner DE, Brunt EM, Van Natta, Behling C, Contos MJ, Cummings OW, Ferrell LD, Liu YC, Torbenson MS, Unalp-Arida A, et al: Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 41:1313–1321. 2005. View Article : Google Scholar : PubMed/NCBI
24	Liu Y, Tipoe GL and Fung ML: Melatonin attenuates intermittent hypoxia-induced lipid peroxidation and local inflammation in rat adrenal medulla. Int J Mol Sci. 15:18437–18452. 2014. View Article : Google Scholar : PubMed/NCBI
25	Chen B, Ma Y, Xue X, Wei J, Hu G and Lin Y: Tetramethylpyrazine reduces inflammation in the livers of mice fed a high fat diet. Mol Med Rep. 19:2561–2568. 2019.PubMed/NCBI
26	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
27	Cao CM, Zhang Y, Weisleder N, Ferrante C, Wang X, Lv F, Zhang Y, Song R, Hwang M, Jin L, et al: MG53 constitutes a primary determinant of cardiac ischemic preconditioning. Circulation. 121:2565–2574. 2010. View Article : Google Scholar : PubMed/NCBI
28	Song R, Peng W, Zhang Y, Lv F, Wu HK, Guo J, Cao Y, Pi Y, Zhang X, Jin L, et al: Central role of E3 ubiquitin ligase MG53 in insulin resistance and metabolic disorders. Nature. 494:375–379. 2013. View Article : Google Scholar : PubMed/NCBI
29	Cai C, Masumiya H, Weisleder N, Matsuda N, Nishi M, Hwang M, Ko JK, Lin P, Thornton A, Zhao X, et al: MG53 nucleates assembly of cell membrane repair machinery. Nat Cell Biol. 11:56–64. 2009. View Article : Google Scholar : PubMed/NCBI
30	Qi J, Yang B, Ren C, Fu J and Zhang J: Swimming exercise alleviated insulin resistance by regulating tripartite motif family protein 72 expression and AKT signal pathway in sprague-dawley rats fed with high-fat diet. J Diabetes Res. 2016:15643862016. View Article : Google Scholar : PubMed/NCBI
31	Hirosumi J, Tuncman G, Chang L, Görgün CZ, Uysal KT, Maeda K, Karin M and Hotamisligil GS: A central role for JNK in obesity and insulin resistance. Nature. 420:333–336. 2002. View Article : Google Scholar : PubMed/NCBI
32	Yi Z, Langlais P, De Filippis EA, Luo M, Flynn CR, Schroeder S, Weintraub ST, Mapes R and Mandarino LJ: Global assessment of regulation of phosphorylation of insulin receptor substrate-1 by insulin in vivo in human muscle. Diabetes. 56:1508–1516. 2007. View Article : Google Scholar : PubMed/NCBI
33	Yu C, Chen Y, Cline GW, Zhang D, Zong H, Wang Y, Bergeron R, Kim JK, Cushman SW, Cooney GJ, et al: Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. J Biol Chem. 277:50230–50236. 2002. View Article : Google Scholar : PubMed/NCBI
34	Kruszynska YT, Worrall DS, Ofrecio J, Frias JP, Macaraeg G and Olefsky JM: Fatty acid-induced insulin resistance: Decreased muscle PI3K activation but unchanged Akt phosphorylation. J Clin Endocrinol Metab. 87:226–234. 2002. View Article : Google Scholar : PubMed/NCBI
35	Copps KD, Hancer NJ, Opare-Ado L, Qiu W, Walsh C and White MF: Irs1 serine 307 promotes insulin sensitivity in mice. Cell Metab. 11:84–92. 2010. View Article : Google Scholar : PubMed/NCBI
36	Tebay LE, Robertson H, Durant ST, Vitale SR, Penning TM, Dinkova-Kostova AT and Hayes JD: Mechanisms of activation of the transcription factor Nrf2 by redox stressors, nutrient cues, and energy status and the pathways through which it attenuates degenerative disease. Free Radic Biol Med. 88:108–146. 2015. View Article : Google Scholar : PubMed/NCBI
37	Chanas SA, Jiang Q, McMahon M, McWalter GK, McLellan LI, Elcombe CR, Henderson CJ, Wolf CR, Moffat GJ, Itoh K, et al: Loss of the Nrf2 transcription factor causes a marked reduction in constitutive and inducible expression of the glutathione S-transferase Gsta1, Gsta2, Gstm1, Gstm2, Gstm3 and Gstm4 genes in the livers of male and female mice. Biochem J. 365:405–416. 2002. View Article : Google Scholar : PubMed/NCBI
38	Asghar M, George L and Lokhandwala MF: Exercise decreases oxidative stress and inflammation and restores renal dopamine D1 receptor function in old rats. Am J Physiol Renal Physiol. 293:F914–F919. 2007. View Article : Google Scholar : PubMed/NCBI
39	Done AJ and Traustadóttir T: Nrf2 mediates redox adaptations to exercise. Redox Biol. 10:191–199. 2016. View Article : Google Scholar : PubMed/NCBI
40	Muthusamy VR, Kannan S, Sadhaasivam K, Gounder SS, Davidson CJ, Boeheme C, Hoidal JR, Wang L and Rajasekaran NS: Acute exercise stress activates Nrf2/ARE signaling and promotes antioxidant mechanisms in the myocardium. Free Radic Biol Med. 52:366–376. 2012. View Article : Google Scholar : PubMed/NCBI
41	Zhao X, Bian Y, Sun Y, Li L, Wang L, Zhao C, Shen Y, Song Q, Qu Y, Niu S, et al: Effects of moderate exercise over different phases on age-related physiological dysfunction in testes of SAMP8 mice. Exp Gerontol. 48:869–880. 2013. View Article : Google Scholar : PubMed/NCBI
42	Sen C, Packer L and Hänninen O: Handbook of oxidants and antioxidants in exercise. Elsevier Science. 2000.PubMed/NCBI
43	Kim JS and Yi HK: Intermittent bout exercise training down-regulates age-associated inflammation in skeletal muscles. Exp Gerontol. 72:261–268. 2015. View Article : Google Scholar : PubMed/NCBI
44	Cechella JL, Leite MR, Dobrachinski F, da Rocha JT, Carvalho NR, Duarte MM, Soares FA, Bresciani G, Royes LF and Zeni G: Moderate swimming exercise and caffeine supplementation reduce the levels of inflammatory cytokines without causing oxidative stress in tissues of middle-aged rats. Amino Acids. 46:1187–1195. 2014. View Article : Google Scholar : PubMed/NCBI
45	Isanejad A, Saraf ZH, Mahdavi M, Gharakhanlou R, Shamsi MM and Paulsen G: The effect of endurance training and downhill running on the expression of IL-1ß, IL-6, and TNF-α and HSP72 in rat skeletal muscle. Cytokine. 73:302–308. 2015. View Article : Google Scholar : PubMed/NCBI
46	Jeong JH, Park HG, Lee YR and Lee WL: Moderate exercise training is more effective than resveratrol supplementation for ameliorating lipid metabolic complication in skeletal muscle of high fat diet-induced obese mice. J Exerc Nutrition Biochem. 19:131–137. 2015. View Article : Google Scholar : PubMed/NCBI
47	Tantiwong P, Shanmugasundaram K, Monroy A, Ghosh S, Li M, DeFronzo RA, Cersosimo E, Sriwijitkamol A, Mohan S and Musi N: NF-B activity in muscle from obese and type 2 diabetic subjects under basal and exercise-stimulated conditions. Am J Physiol Endocrinol Metab. 299:E794–E801. 2010. View Article : Google Scholar : PubMed/NCBI
48	Knudsen JG, Joensen E, Bertholdt L, Jessen H, van Hauen L, Hidalgo J and Pilegaard H: Skeletal muscle IL-6 and regulation of liver metabolism during high-fat diet and exercise training. Physiol Rep. 4:e127882016. View Article : Google Scholar : PubMed/NCBI
49	Chowdhry S, Nazmy MH, Meakin PJ, Dinkova-Kostova AT, Walsh SV, Tsujita T, Dillon JF, Ashford ML and Hayes JD: Loss of Nrf2 markedly exacerbates nonalcoholic steatohepatitis. Free Radic Biol Med. 48:357–371. 2010. View Article : Google Scholar : PubMed/NCBI
50	Liu Z, Dou W, Ni Z, Wen Q, Zhang R, Qin M, Wang X, Tang H, Cao Y, Wang J and Zhao S: Deletion of Nrf2 leads to hepatic insulin resistance via the activation of NF-B in mice fed a high-fat diet. Mol Med Rep. 14:1323–1331. 2016. View Article : Google Scholar : PubMed/NCBI