Role of exercise and rapamycin on the expression of energy metabolism genes in liver tissues of rats fed a high‑fat diet

Tu,Genghong; Dai,Chunyan; Qu,Haofei; Wang,Yunzhen; Liao,Bagen

doi:10.3892/mmr.2020.11362

Role of exercise and rapamycin on the expression of energy metabolism genes in liver tissues of rats fed a high‑fat diet

Authors:
- Genghong Tu
- Chunyan Dai
- Haofei Qu
- Yunzhen Wang
- Bagen Liao
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Affiliations: Department of Sports Medicine, Guangzhou Sport University, Guangzhou, Guangdong 510150, P.R. China
Published online on: July 28, 2020 https://doi.org/10.3892/mmr.2020.11362
Pages: 2932-2940
Copyright: © Tu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The mTOR pathway serves an important role in the development of insulin resistance induced by obesity. Exercise improves obesity‑associated insulin resistance and hepatic energy metabolism; however, the precise mechanism of this process remains unknown. Therefore, the present study investigated the role of rapamycin, an inhibitor of mTOR, on exercise‑induced expression of hepatic energy metabolism genes in rats fed a high‑fat diet (HFD). A total of 30 male rats were divided into the following groups: Normal group (n=6) fed chow diets and HFD group (n=24) fed an HFD for 6 weeks. The HFD rats performed exercise adaptation for 1 week and were randomly divided into the four following groups (each containing six rats): i) Group of HFD rats with sedentary (H group); ii) group of HFD rats with exercise (HE group); iii) group of HFD rats with rapamycin (HR group); and iv) group of HFD rats with exercise and rapamycin (HER group). Both HE and HER rats were placed on incremental treadmill training for 4 weeks (from week 8‑11). Both HR and HER rats were injected with rapamycin intraperitoneally at the dose of 2 mg/kg once a day for 2 weeks (from week 10‑11). All rats were sacrificed following a 12‑16 h fasting period at the end of week 11. The levels of mitochondrial and oxidative enzyme activities, as well as of the expression of genes involved in energy metabolism were assessed in liver tissues. Biochemical assays and oil red staining were used to assess the content of hepatic triglycerides (TGs). The results indicated that exercise, but not rapamycin, reduced TG content in the liver of HFD rats. Further analysis indicated that rapamycin reduced the activity of cytochrome c oxidase, but not the activities of succinate dehydrogenase and β‑hydroxyacyl‑CoA dehydrogenase in the liver of HFD rats. Exercise significantly upregulated the mRNA expression of peroxisome proliferator‑activated receptor γ coactivator 1 β, while rapamycin exhibited no effect on the mRNA expression levels of hepatic transcription factors associated with energy metabolism enzymes in the liver of HFD rats. Collectively, the results indicated that exercise reduced TG content and upregulated mitochondrial metabolic gene expression in the liver of HFD rats. Moreover, this mechanism may not involve the mTOR pathway.

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1	Lara-Castro C and Garvey WT: Intracellular lipid accumulation in liver and muscle and the insulin resistance syndrome. Endocrinol Metab Clin North Am. 37:2932–856. 2008. View Article : Google Scholar
2	Samuel VT and Shulman GI: Mechanisms for insulin resistance: Common threads and missing links. Cell. 148:852–871. 2012. View Article : Google Scholar : PubMed/NCBI
3	Di Meo S, Iossa S and Venditti P: Improvement of obesity-linked skeletal muscle insulin resistance by strength and endurance training. J Endocrinol. 234:R159–R181. 2017. View Article : Google Scholar : PubMed/NCBI
4	Golabi P, Locklear CT, Austin P, Afdhal S, Byrns M, Gerber L and Younossi ZM: Effectiveness of exercise in hepatic fat mobilization in non-alcoholic fatty liver disease: Systematic review. World J Gastroenterol. 22:6318–6327. 2016. View Article : Google Scholar : PubMed/NCBI
5	Laplante M and Sabatini DM: mTOR signaling in growth control and disease. Cell. 149:274–293. 2012. View Article : Google Scholar : PubMed/NCBI
6	Guillén C and Benito M: mTORC1 overactivation as a key aging factor in the progression to type 2 diabetes mellitus. Front Endocrinol (Lausanne). 9:6212018. View Article : Google Scholar : PubMed/NCBI
7	Lushchak O, Strilbytska O, Piskovatska V, Storey KB, Koliada A and Vaiserman A: The role of the TOR pathway in mediating the link between nutrition and longevity. Mech Ageing Dev. 164:127–138. 2017. View Article : Google Scholar : PubMed/NCBI
8	Kimball SR: Integration of signals generated by nutrients, hormones, and exercise in skeletal muscle. Am J Clin Nutr. 99:237S–242S. 2014. View Article : Google Scholar : PubMed/NCBI
9	Li J, Kim SG and Blenis J: Rapamycin: One drug, many effects. Cell Metab. 19:373–379. 2014. View Article : Google Scholar : PubMed/NCBI
10	Sabatini DM: Twenty-five years of mTOR: Uncovering the link from nutrients to growth. Proc Natl Acad Sci USA. 114:11818–11825. 2017. View Article : Google Scholar : PubMed/NCBI
11	El Ouarrat D, Isaac R, Lee YS, Oh DY, Wollam J, Lackey D, Riopel M, Bandyopadhyay G, Seo JB, Sampath-Kumar R and Olefsky JM: TAZ Is a negative regulator of PPARgamma activity in adipocytes and TAZ deletion improves insulin sensitivity and glucose tolerance. Cell Metab. 31:162–173 e165. 2020. View Article : Google Scholar : PubMed/NCBI
12	Peterson TR, Sengupta SS, Harris TE, Carmack AE, Kang SA, Balderas E, Guertin DA, Madden KL, Carpenter AE, Finck BN and Sabatini DM: mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell. 146:408–420. 2011. View Article : Google Scholar : PubMed/NCBI
13	Sengupta S, Peterson TR, Laplante M, Oh S and Sabatini DM: mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. Nature. 468:1100–1104. 2010. View Article : Google Scholar : PubMed/NCBI
14	Li S, Brown MS and Goldstein JL: Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, but not inhibition of gluconeogenesis. Proc Natl Acad Sci USA. 107:3441–3446. 2010. View Article : Google Scholar : PubMed/NCBI
15	Fletcher JA, Meers GM, Linden MA, Kearney ML, Morris EM, Thyfault JP and Rector RS: Impact of various exercise modalities on hepatic mitochondrial function. Med Sci Sports Exerc. 46:1089–1097. 2014. View Article : Google Scholar : PubMed/NCBI
16	Houde VP, Brûlé S, Festuccia WT, Blanchard PG, Bellmann K, Deshaies Y and Marette A: Chronic rapamycin treatment causes glucose intolerance and hyperlipidemia by upregulating hepatic gluconeogenesis and impairing lipid deposition in adipose tissue. Diabetes. 59:1338–1348. 2010. View Article : Google Scholar : PubMed/NCBI
17	Caron A, Mouchiroud M, Gautier N, Labbé SM, Villot R, Turcotte L, Secco B, Lamoureux G, Shum M, Gélinas Y, et al: Loss of hepatic DEPTOR alters the metabolic transition to fasting. Mol Metab. 6:447–458. 2017. View Article : Google Scholar : PubMed/NCBI
18	Kucejova B, Duarte J, Satapati S, Fu X, Ilkayeva O, Newgard CB, Brugarolas J and Burgess SC: Hepatic mTORC1 opposes impaired insulin action to control mitochondrial metabolism in obesity. Cell Rep. 16:508–519. 2016. View Article : Google Scholar : PubMed/NCBI
19	Kenerson HL, Subramanian S, McIntyre R, Kazami M and Yeung RS: Livers with constitutive mTORC1 activity resist steatosis independent of feedback suppression of Akt. PLoS One. 10:e01170002015. View Article : Google Scholar : PubMed/NCBI
20	Liao B and Xu Y: Exercise improves skeletal muscle insulin resistance without reduced basal mTOR/S6K1 signaling in rats fed a high-fat diet. Eur J Appl Physiol. 111:2743–2752. 2011. View Article : Google Scholar : PubMed/NCBI
21	Bass A, Brdiczka D, Eyer P, Hofer S and Pette D: Metabolic differentiation of distinct muscle types at the level of enzymatic organization. Eur J Biochem. 10:198–206. 1969. View Article : Google Scholar : PubMed/NCBI
22	Osumi T and Hashimoto T: Occurrence of two 3-hydroxyacyl-CoA dehydrogenases in rat liver. Biochim Biophys Acta. 574:258–267. 1979. View Article : Google Scholar : PubMed/NCBI
23	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
24	Leontieva OV, Paszkiewicz GM and Blagosklonny MV: Comparison of rapamycin schedules in mice on high-fat diet. Cell Cycle. 13:3350–3356. 2014. View Article : Google Scholar : PubMed/NCBI
25	Lamming DW, Ye L, Katajisto P, Goncalves MD, Saitoh M, Stevens DM, Davis JG, Salmon AB, Richardson A, Ahima RS, et al: Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science. 335:1638–1643. 2012. View Article : Google Scholar : PubMed/NCBI
26	Khamzina L, Veilleux A, Bergeron S and Marette A: Increased activation of the mammalian target of rapamycin pathway in liver and skeletal muscle of obese rats: Possible involvement in obesity-linked insulin resistance. Endocrinology. 146:1473–1481. 2005. View Article : Google Scholar : PubMed/NCBI
27	Volkers M, Doroudgar S, Nguyen N, Konstandin MH, Quijada P, Din S, Ornelas L, Thuerauf DJ, Gude N, Friedrich K, et al: PRAS40 prevents development of diabetic cardiomyopathy and improves hepatic insulin sensitivity in obesity. EMBO Mol Med. 6:57–65. 2014. View Article : Google Scholar : PubMed/NCBI
28	Makki K, Taront S, Molendi-Coste O, Bouchaert E, Neve B, Eury E, Lobbens S, Labalette M, Duez H, Staels B, et al: Beneficial metabolic effects of rapamycin are associated with enhanced regulatory cells in diet-induced obese mice. PLoS One. 9:e926842014. View Article : Google Scholar : PubMed/NCBI
29	Salmon AB: About-face on the metabolic side effects of rapamycin. Oncotarget. 6:2585–2586. 2015. View Article : Google Scholar : PubMed/NCBI
30	Liu Y, Diaz V, Fernandez E, Strong R, Ye L, Baur JA, Lamming DW, Richardson A and Salmon AB: Rapamycin-induced metabolic defects are reversible in both lean and obese mice. Aging (Albany NY). 6:742–754. 2014. View Article : Google Scholar : PubMed/NCBI
31	Fang Y, Westbrook R, Hill C, Boparai RK, Arum O, Spong A, Wang F, Javors MA, Chen J, Sun LY and Bartke A: Duration of rapamycin treatment has differential effects on metabolism in mice. Cell Metab. 17:456–462. 2013. View Article : Google Scholar : PubMed/NCBI
32	Reifsnyder PC, Flurkey K, Te A and Harrison DE: Rapamycin treatment benefits glucose metabolism in mouse models of type 2 diabetes. Aging (Albany NY). 8:3120–3130. 2016. View Article : Google Scholar : PubMed/NCBI
33	Kenerson HL, Yeh MM and Yeung RS: Tuberous sclerosis complex-1 deficiency attenuates diet-induced hepatic lipid accumulation. PLoS One. 6:e180752011. View Article : Google Scholar : PubMed/NCBI
34	Binsch C, Jelenik T, Pfitzer A, Dille M, Müller-Lühlhoff S, Hartwig S, Karpinski S, Lehr S, Kabra DG, Chadt A, et al: Absence of the kinase S6k1 mimics the effect of chronic endurance exercise on glucose tolerance and muscle oxidative stress. Mol Metab. 6:1443–1453. 2017. View Article : Google Scholar : PubMed/NCBI
35	Kim JA, Wei Y and Sowers JR: Role of mitochondrial dysfunction in insulin resistance. Circ Res. 102:401–414. 2008. View Article : Google Scholar : PubMed/NCBI
36	Softic S, Meyer JG, Wang GX, Gupta MK, Batista TM, Lauritzen HPMM, Fujisaka S, Serra D, Herrero L, Willoughby J, et al: Dietary sugars alter hepatic fatty acid oxidation via transcriptional and post-translational modifications of mitochondrial proteins. Cell Metab. 30:735–753 e734. 2019. View Article : Google Scholar : PubMed/NCBI
37	Ramanathan A and Schreiber SL: Direct control of mitochondrial function by mTOR. Proc Natl Acad Sci USA. 106:22229–22232. 2009. View Article : Google Scholar : PubMed/NCBI
38	Schieke SM, Phillips D, McCoy JP Jr, Aponte AM, Shen RF, Balaban RS and Finkel T: The mammalian target of rapamycin (mTOR) pathway regulates mitochondrial oxygen consumption and oxidative capacity. J Biol Chem. 281:27643–27652. 2006. View Article : Google Scholar : PubMed/NCBI
39	Han L, Shen WJ, Bittner S, Kraemer FB and Azhar S: PPARs: Regulators of metabolism and as therapeutic targets in cardiovascular disease. Part II: PPAR-b/δ and PPAR-g. Future Cardiol. 13:279–296. 2017. View Article : Google Scholar : PubMed/NCBI
40	Villena JA: New insights into PGC-1 coactivators: Redefining their role in the regulation of mitochondrial function and beyond. FEBS J. 282:647–672. 2015. View Article : Google Scholar : PubMed/NCBI
41	Souza-Mello V: Peroxisome proliferator-activated receptors as targets to treat non-alcoholic fatty liver disease. World J Hepatol. 7:1012–1019. 2015. View Article : Google Scholar : PubMed/NCBI
42	Shimano H and Sato R: SREBP-regulated lipid metabolism: Convergent physiology-divergent pathophysiology. Nat Rev Endocrinol. 13:710–730. 2017. View Article : Google Scholar : PubMed/NCBI
43	Wang Y, Viscarra J, Kim SJ and Sul HS: Transcriptional regulation of hepatic lipogenesis. Nat Rev Mol Cell Biol. 16:678–689. 2015. View Article : Google Scholar : PubMed/NCBI
44	Chambers KT, Chen Z, Crawford PA, Fu X, Burgess SC, Lai L, Leone TC, Kelly DP and Finck BN: Liver-specific PGC-1beta deficiency leads to impaired mitochondrial function and lipogenic response to fasting-refeeding. PLoS One. 7:e526452012. View Article : Google Scholar : PubMed/NCBI
45	Chau GC, Im DU, Kang TM, Bae JM, Kim W, Pyo S, Moon EY and Um SH: mTOR controls ChREBP transcriptional activity and pancreatic β cell survival under diabetic stress. J Cell Biol. 216:2091–2105. 2017. View Article : Google Scholar : PubMed/NCBI
46	Iizuka K: Recent progress on the role of ChREBP in glucose and lipid metabolism. Endocrine J. 60:543–555. 2013. View Article : Google Scholar
47	Iso T, Sunaga H, Matsui H, Kasama S, Oshima N, Haruyama Furukawa N, Nakajima K, Machida T, Murakami M, et al: Serum levels of fatty acid binding protein 4 and fat metabolic markers in relation to catecholamines following exercise. Clin Biochem. 50:896–902. 2017. View Article : Google Scholar : PubMed/NCBI
48	Aye IL, Rosario FJ, Powell TL and Jansson T: Adiponectin supplementation in pregnant mice prevents the adverse effects of maternal obesity on placental function and fetal growth. Proc Natl Acad Sci USA. 112:12858–12863. 2015. View Article : Google Scholar : PubMed/NCBI