نشریه فیزیولوژی ورزش و فعالیت بدنی

نشریه فیزیولوژی ورزش و فعالیت بدنی

تأثیر تمرین هوازی تناوبی به‌همراه مکمل‌یاری بتائین نانو امولسیفای‌شده بر بیان ژن‌های mTORC1، PI3K و کلسی نورین در سلول‌های کبدی موش‌های صحرایی چاق

نوع مقاله : مقاله پژوهشی

نویسندگان
گروه فیزیولوژی ورزش، واحد کرج، دانشگاه آزاد اسلامی، کرج، ایران
چکیده
زمینه و هدف: چاقی، یکی از معضلات مهم بهداشتی درمانی در جوامع امروزی است که با گسترة وسیعی از بیماری‌ها از جمله دیابت، اختلالات متابولیک و کبد چرب در ارتباط است. گسترش روزافزون چاقی و سبک زندگی بی‌تحرک و ابتلا به بیماری‌های مرتبط با آن سبب شده است تا فعالیت ورزشی منظم به‌عنوان زیربنای درمان چاقی مطرح شود. همچنین شواهد اخیر نشان می‌دهند که مصرف بتائین از طریق تأثیر بر سوخت‌وساز کبدی چربی و گلوکز، احتمالاً در بهبود چاقی مؤثر باشد. از این‌رو در پژوهش حاضر، تأثیر تمرین هوازی تناوبی به‌همراه مکمل‌یاری با بتائین نانو امولسیفای‌شده بر بیان ژن‌های کمپلکس-1 هدف راپامایسین پستانداران (mTORC1)، فسفاتیدیل اینوزیتول-3 کیناز (PI3K) و کلسی نورین در سلول‌های هپاتوسیتی موش‌های صحرایی چاق بررسی می‌شود.
مواد و روش‌ها: در این تحقیق تجربی، 25 سر موش صحرایی نر نژاد ویستار به پنج گروه (پنج سر موش در هر گروه) شامل . سالم، 2. چاق، 3. چاق + مکمل، 4. چاق + تمرین و 5. چاق + مکمل+ تمرین تقسیم شدند. گروه‌های چاق به مدت 12 هفته با رژیم غذایی پرچرب و کلسترول تغذیه شدند. تمرین هوازی تناوبی با شدت متوسط به مدت هشت هفته شامل دویدن روی نوار گردان به مدت 30 دقیقه و پنج روز در هفته همراه با اضافه بار تدریجی انجام شد؛ پروتکل تمرینی در هفتة اول شامل 10 وهله فعالیت یک‌دقیقه‌ای (با سرعت 10 متر در دقیقه) با تناوب‌های استراحتی دودقیقه‌ای (با سرعت پنج متر در دقیقه) بود که سرعت دویدن در وهله‌های فعالیتی در هفتة چهارم تا هشتم به 16 متر در دقیقه رسید. از روش فراصوت با دامنة بالا برای تهیة نانوامولسیون بتائین استفاده شد که پایداری سرمی و فراهمی زیستی آن را افزایش می‌دهد. گاواژ مکمل نانوامولسیفای‌شدة بتائین با دوز 50 میلی‌گرم/کیلوگرم وزن بدن قبل تمرین صورت گرفت. در پایان دورة پژوهش، بیان ژن‌های mTORC1، PI3K و کلسی نورین در کبد با روش Real-Time PCR اندازه‌گیری شد و داده‌ها از طریق آزمون‌های آماری t-مستقل و آنوای دوعاملی و آزمون تعقیبی بونفرونی در سطح معناداری 05/0 P≤ تحلیل شد.
نتایج: چاقی سبب کاهش معنادار mTORC1 و PI3K و همچنین افزایش کلسی نورین شد (0001/0=P). تمرین هوازی تناوبی به افزایش معنادار mTORC1 و PI3K و کاهش معنادار کلسی نورین منجر شد (0001/0=P). مکمل‌یاری بتائین نیز سطوح mTORC1 (002/0=P) و PI3K (0001/0=P) را افزایش و کلسی نورین (001/0=P) را کاهش داد. همچنین در تعامل تمرین و مکمل اثر آماری معناداری بر سطوح mTORC1 (0001/0=P)، PI3K (0001/0=P) و کلسی نورین (021/0=P) مشاهده شد.
نتیجه‏گیری: به‌نظر می‌رسد که تمرین هوازی تناوبی با شدت متوسط و مکمل‌یاری بتائین، به‌طور مستقل و همچنین در کنار یکدیگر، با تأثیر بر بیان ژن‌های mTORC1، PI3K و کلسی نورین، از طریق تنظیم سوخت‌وساز چربی کبدی احتمالاً نقش مهمی در بهبود کبد چرب ناشی از چاقی دارند.
کلیدواژه‌ها
موضوعات

عنوان مقاله English

The effect of interval aerobic exercise combined with nano-emulsified Betaine supplementation on the gene expression of mTORC1, PI3K, and calcineurin in hepatocytes of obese rats

نویسندگان English

Mahdieh Poursoltani Zarandi
Amir Sarshin
Alireza Rahimi
Foad Feizolahi
Department of exercise physiology, Karaj branch, Islamic Azad University, Karaj, Iran
چکیده English

Background and Purpose: Obesity is one of the major health problems in today's societies, which is associated with a wide range of diseases, including diabetes, metabolic disorders, and fatty liver. The increasing prevalence of obesity and sedentary lifestyles and the development of related diseases have led to the emergence of regular exercise as the basis for obesity treatment. Recent evidence also suggests that betaine consumption may be effective in improving obesity by affecting hepatic lipid and glucose metabolism. Therefore, in the present study, the effect of interval aerobic exercise combined with nano-emulsified betaine supplementation on the genes expression of mammalian target of rapamycin complex-1 (mTORC1), phosphatidyl inositol-3 kinase (PI3K), and calcineurin in hepatocyte cells of obese rats was investigated.
Materials and Methods: In this experimental study, 25 male Wistar rats were divided into five groups (five rats in each group): 1) healthy, 2) obese, 3) obese + supplement, 4) obese + exercise, 5) obese + supplement + exercise. Rats in obese groups were fed a high-fat and cholesterol diet for 12 weeks. Moderate-intensity interval aerobic training was performed for 8 weeks, included treadmill running for 30 minutes, 5 days a week, with gradual overload. The training protocol in the first week included ten 1-minute activity intervals (at a speed of 10 meters per minute) with 2-minute rest intervals (at a speed of 5 meters per minute), and the running speed in the activity intervals reached 16 meters per minute during fourth to eighth weeks. High-amplitude ultrasound was used to prepare betaine nanoemulsion, which increases its serum stability and bioavailability. Nanoemulsified betaine supplement was administered by gavage at a dose of 50 mg/kg body weight before exercise. At the end of the study period, the expression of mTORC1, PI3K, and calcineurin genes in the liver were measured by using Real-Time PCR, and the data were analyzed using independent t-tests, two-way ANOVA, and Bonferroni post-hoc test.
Results: Obesity significantly decreased mTORC1 and PI3K and also increased calcineurin (p=0.0001). Interval aerobic exercise significantly increased mTORC1 and PI3K and significantly decreased calcineurin (p=0.0001). Betaine supplementation also increased mTORC1 (p=0.002) and PI3K (p=0.0001) levels and decreased calcineurin (p=0.0001). Furthermore, a statistically significant interaction effects of exercise and supplementation on mTORC1 (p=0.0001), PI3K (p=0.0001) and calcineurin (p=0.021) levels were observed.
Conclusion: Based on our findings, it seems that moderate-intensity interval aerobic exercise and betaine supplementation, independently and together, might play an important role in improving obesity-induced fatty liver by affecting the expression of mTORC1, PI3K, and calcineurin genes through regulating hepatic fat metabolism.

کلیدواژه‌ها English

Obesity
Interval training
Betaine
mTOR
Calcineurin
1.Brunt EM, Wong VW, Nobili V, Day CP, Sookoian S, Maher JJ, Bugianesi E, Sirlin CB, Neuschwander-Tetri BA, Rinella ME. Nonalcoholic fatty liver disease. Nature reviews Disease primers. 2015;1(1):1-22. https://doi.org/10.1038/nrdp.2015.80. 2.Chu H, Du C, Yang Y, Feng X, Zhu L, Chen J, Yang F. MC-LR aggravates liver lipid metabolism disorders in obese mice fed a high-fat diet via PI3K/AKT/mTOR/SREBP1 signaling pathway. Toxins. 2022;14(12):833. https://doi.org/10.3390/toxins14120833. 3.Liu DD, Han CC, Wan HF, He F, Xu HY, Wei SH, Du XH, Xu F. Effects of inhibiting PI3K-Akt-mTOR pathway on lipid metabolism homeostasis in goose primary hepatocytes. Animal. 2016;10(8):1319-27. https://doi.org/10.1017/S1751731116000380. 4.Houde VP, Bruˆlé S, Festuccia WT, Blanchard PG, Bellmann K, Deshaies Y, Marette A. Chronic rapamycin treatment causes glucose intolerance and hyperlipidemia by upregulating hepatic gluconeogenesis and impairing lipid deposition in adipose tissue. Diabetes. 2010;59(6):1338-48. https://doi.org/10.2337/db09-1324. 5.Stephenson EJ, Redd JR, Snyder D, Tran QT, Lu B, Peloquin MJ, Mulcahy MC, Harvey I, Fisher K, Han JC, Qi N. Skeletal muscle mTORC1 activation increases energy expenditure and reduces longevity in mice. bioRxiv. 2019:720540. https://doi.org/10.1101/720540. 6.Danowska M, Strączkowski M. The Ca2+/Calmodulin-dependent calcineurin/NFAT signaling pathway in the pathogenesis of insulin resistance in skeletal muscle. Experimental and Clinical Endocrinology & Diabetes. 2023;131(11):589-94. https://doi.org/10.1055/a-2174-7958. 7.Chakkera HA, Kudva Y, Kaplan B. Calcineurin inhibitors: pharmacologic mechanisms impacting both insulin resistance and insulin secretion leading to glucose dysregulation and diabetes mellitus. Clinical Pharmacology & Therapeutics. 2017;101(1):114-20. https://doi.org/10.1002/cpt.546. 8.Weber K, Schilling JD. Lysosomes integrate metabolic-inflammatory cross-talk in primary macrophage inflammasome activation. Journal of Biological Chemistry. 2014;289(13):9158-71. https://doi.org/10.1074/jbc.M113.531202. 9.Chimin P, Andrade ML, Belchior T, Paschoal VA, Magdalon J, Yamashita AS, Castro É, Castoldi A, Chaves-Filho AB, Yoshinaga MY, Miyamoto S. Adipocyte mTORC1 deficiency promotes adipose tissue inflammation and NLRP3 inflammasome activation via oxidative stress and de novo ceramide synthesis [S]. Journal of Lipid Research. 2017;58(9):1797-807. https://doi.org/10.1194/jlr.M074518. 10.Wong VW, Singal AK. Emerging medical therapies for non-alcoholic fatty liver disease and for alcoholic hepatitis. Translational Gastroenterology and Hepatology. 2019;4:53. https://doi.org/10.21037/tgh.2019.06.06. 11.Ruan L, Wang G, Qing Lv Z, Li S, Liu Q, Ren Y, Zhang Q, Lv X, Wu R, Jin Z. The effect of varied exercise intensity on antioxidant function, aortic endothelial function, and serum lipids in rats with non-alcoholic fatty liver disease. Investigación Clínica. 2022;63(4):327-43. https://doi.org/10.54817/ic.v63n4a01. 12.Yu Q, Xia Z, Liong EC, Tipoe GL. 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. Molecular medicine reports. 2019;20(6):4963-72. https://doi.org/10.3892/mmr.2019.10787. 13.Allen DL, Uyenishi JJ, Cleary AS, Mehan RS, Lindsay SF, Reed JM. Calcineurin activates interleukin-6 transcription in mouse skeletal muscle in vivo and in C2C12 myotubes in vitro. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology. 2010;298(1): R198-210. https://doi.org/10.1152/ajpregu.00325.2009. 14.Eklund M, Bauer E, Wamatu J, Mosenthin R. Potential nutritional and physiological functions of betaine in livestock. Nutrition research reviews. 2005;18(1):31-48. https://doi.org/10.1079/NRR200493. 15.Sivanesan S, Taylor A, Zhang J, Bakovic M. Betaine and choline improve lipid homeostasis in obesity by participation in mitochondrial oxidative demethylation. Frontiers in Nutrition. 2018;5:61. https://doi.org/10.3389/fnut.2018.00061. 16.Du J, Shen L, Tan Z, Zhang P, Zhao X, Xu Y, Gan M, Yang Q, Ma J, Jiang AA, Tang G. Betaine supplementation enhances lipid metabolism and improves insulin resistance in mice fed a high-fat diet. Nutrients. 2018;10(2):131. https://doi.org/10.3390/nu10020131. 17.Gao X, Zhang H, Guo XF, Li K, Li S, Li D. Effect of betaine on reducing body fat—a systematic review and meta-analysis of randomized controlled trials. Nutrients. 2019;11(10):2480. https://doi.org/10.3390/nu11102480. 18.Schwab U, Törrönen A, Toppinen L, Alfthan G, Saarinen M, Aro A, Uusitupa M. Betaine supplementation decreases plasma homocysteine concentrations but does not affect body weight, body composition, or resting energy expenditure in human subjects1, 2, 3. The American journal of clinical nutrition. 2002;76(5):961-967. https://doi.org/10.1093/ajcn/76.5.961. 19.Alvarenga L, Ferreira MS, Kemp JA, Mafra D. The role of betaine in patients with chronic kidney disease: a narrative review. Current Nutrition Reports. 2022;11(3):395-406. https://doi.org/10.1007/s13668-022-00426-z. 20.Norouzzadeh M, Kalantar H, Khorsandi L, Mohtadi S, Khodayar MJ. Betaine ameliorates arsenic-induced kidney injury in mice by mitigating oxidative stress-mediated inflammation. Archives of Biochemistry and Biophysics. 2024;758:110076. https://doi.org/10.1016/j.abb.2024.110076. 21.Veskovic M, Mladenovic D, Milenkovic M, Tosic J, Borozan S, Gopcevic K, Labudovic-Borovic M, Dragutinovic V, Vucevic D, Jorgacevic B, Isakovic A. Betaine modulates oxidative stress, inflammation, apoptosis, autophagy, and Akt/mTOR signaling in methionine-choline deficiency-induced fatty liver disease. European journal of pharmacology. 2019;848:39-48. https://doi.org/10.1016/j.ejphar.2019.01.043. 22.Xu J, Nie Z, Qiu X, Zhang J, Han S. Effects of betaine supplementation on inflammatory markers: a systematic review and meta-analysis of randomised controlled trials. International Journal of Food Sciences and Nutrition. 2023;74(7):721-9. https://doi.org/10.1080/09637486.2023.2257906. 23.Wang DQ, Schmitz F, Kopin AS, Carey MC. Targeted disruption of the murine cholecystokinin-1 receptor promotes intestinal cholesterol absorption and susceptibility to cholesterol cholelithiasis. The Journal of clinical investigation. 2004;114(4):521-528. https://doi.org/10.1172/JCI16801. 24.Li J, Huang L, Xiong W, Qian Y, Song M. Aerobic exercise improves non-alcoholic fatty liver disease by down-regulating the protein expression of the CNPY2-PERK pathway. Biochemical and Biophysical Research Communications. 2022;603:35-40. https://doi.org/10.1016/j.bbrc.2022.03.008. 25.Chen W, Zhang X, Xu M, Jiang L, Zhou M, Liu W, Chen Z, Wang Y, Zou Q, Wang L. Betaine prevented high-fat diet-induced NAFLD by regulating the FGF10/AMPK signaling pathway in ApoE−/− mice. European journal of nutrition. 2021;60:1655-68. https://doi.org/10.1007/s00394-020-02362-6. 26.Rasineni K, Lee SM, McVicker BL, Osna NA, Casey CA, Kharbanda KK. Susceptibility of asialoglycoprotein receptor-deficient mice to lps/galactosamine liver injury and protection by betaine administration. Biology. 2020;10(1):19. https://doi.org/10.3390/biology10010019. 27.Koroleva MY, Yurtov EV. Nanoemulsions: the properties, methods of preparation and promising applications. Russian Chemical Reviews. 2012;81(1):21. https://doi.org/10.1070/RC2012v081n01ABEH004219. 28.Pucek-Kaczmarek A, Celary D, Bazylińska U. Natural-Origin Betaine Surfactants as Promising Components for the Stabilization of Lipid Carriers. International Journal of Molecular Sciences. 2024;25(2):955. https://doi.org/10.3390/ijms25020955. 29.Trang K, Grant SF. Genetics and epigenetics in the obesity phenotyping scenario. Reviews in endocrine and metabolic disorders. 2023;24(5):775-93. https://doi.org/10.1007/s11154-023-09804-6. 30.Li N, Shi H, Guo Q, Gan Y, Zhang Y, Jia J, Zhang L, Zhou Y. Aerobic Exercise Prevents Chronic Inflammation and Insulin Resistance in Skeletal Muscle of High-Fat Diet Mice. Nutrients. 2022;14(18):3730. https://doi.org/10.3390/nu14183730. 31.da Rocha AL, Pinto AP, Teixeira GR, Pereira BC, Oliveira LC, Silva AC, Morais GP, Cintra DE, Pauli JR, da Silva AS. Exhaustive training leads to hepatic fat accumulation. Journal of cellular physiology. 2017;232(8):2094-103. https://doi.org/10.1002/jcp.25625. 32.de Melo DG, da Cruz Rodrigues VC, de Sá Pereira GJ, de Campos TD, dos Santos Canciglieri R, Pauli JR, da Silva AS, da Costa Fernandes CJ, de Moura LP. Effects of aerobic exercise on the regulation of mitochondrial carrier homolog-2 and its influence on the catabolic and anabolic activity of lipids in the mesenteric adipose tissue of obese mice. Life Sciences. 2024;345:122567. https://doi.org/10.1016/j.lfs.2024.122567. 33.Abulfadle KA, Saied AA. Role of obestatin in improvement of obesity-induced metabolic and kidney function changes in exercised rats. Am J Biomed Sci. 2019;11(2):74-89. https://doi.org/10.5099/aj190200074. 34.Olli K, Lahtinen S, Rautonen N, Tiihonen K. Betaine reduces the expression of inflammatory adipokines caused by hypoxia in human adipocytes. British journal of nutrition. 2013;109(1):43-49. https://doi.org/10.1017/S0007114512000888. 35.Zhao G, He F, Wu C, Li P, Li N, Deng J, Zhu G, Ren W, Peng Y. Betaine in inflammation: mechanistic aspects and applications. Frontiers in immunology. 2018;9:1070. https://doi.org/ 10.3389/fimmu.2018.01070. 36.Yu J, Laybutt DR, Youngson NA, Morris MJ. Concurrent betaine administration enhances exercise-induced improvements to glucose handling in obese mice. Nutrition, Metabolism and Cardiovascular Diseases. 2022;32(10):2439-49. https://doi.org/10.1016/j.numecd.2022.08.012. 37.Jang A, Kim D, Sung KS, Jung S, Kim HJ, Jo C. The effect of dietary α-lipoic acid, betaine, l-carnitine, and swimming on the obesity of mice induced by a high-fat diet. Food & Function. 2014;5(8):1966-74. https://doi.org/10.1039/c4fo00246f. 38.Popov DV, Lysenko EA, Miller TF, Bachinin AV, Perfilov DV, Vinogradova OL. The effect of single aerobic exercise on the regulation of mitochondrial biogenesis in skeletal muscles of trained men: A time-course study. Human Physiology. 2015;41:296-303. https://doi.org/10.1134/S0362119715030123. 39.Takahashi H, Kotani K, Tanaka K, Egucih Y, Anzai K. Therapeutic approaches to nonalcoholic fatty liver disease: exercise intervention and related mechanisms. Frontiers in endocrinology. 2018;9:588. https://doi.org/10.3389/fendo.2018.00588. 40.Cornu M, Oppliger W, Albert V, Robitaille AM, Trapani F, Quagliata L, Fuhrer T, Sauer U, Terracciano L, Hall MN. Hepatic mTORC1 controls locomotor activity, body temperature, and lipid metabolism through FGF21. Proceedings of the National Academy of Sciences. 2014;111(32):11592-9. https://doi.org/10.1073/pnas.1412047111. 41.Sun JP, Shi L, Wang F, Qin J, Ke B. Modified Linggui Zhugan Decoction ameliorates glycolipid metabolism and inflammation via PI3K-Akt/mTOR-S6K1/AMPK-PGC-1 α signaling pathways in obese type 2 diabetic rats. Chinese journal of integrative medicine. 2022:1-8. https://doi.org/10.1007/s11655-020-3285-2. 42.Rius-Pérez S, Torres-Cuevas I, Millán I, Ortega ÁL, Pérez S. PGC‐1α, inflammation, and oxidative stress: an integrative view in metabolism. Oxidative medicine and cellular longevity. 2020;2020(1):1452696. https://doi.org/10.1155/2020/1452696. 43.Jung GY, Won SB, Kim J, Jeon S, Han A, Kwon YH. Betaine alleviates hypertriglycemia and tau hyperphosphorylation in db/db mice. Toxicological Research. 2013;29:7-14. https://doi.org/10.3892/mmr.2017.7295. 44.Yang W, Huang L, Gao J, Wen S, Tai Y, Chen M, Huang Z, Liu R, Tang C, Li J. Betaine attenuates chronic alcohol induced fatty liver by broadly regulating hepatic lipid metabolism. Molecular medicine reports. 2017;16(4):5225-34. https://doi.org/10.5487/TR.2013.29.1.007. 45.Ma J, Meng X, Kang SY, Zhang J, Jung HW, Park YK. Regulatory effects of the fruit extract of Lycium chinense and its active compound, betaine, on muscle differentiation and mitochondrial biogenesis in C2C12 cells. Biomedicine & Pharmacotherapy. 2019;118:109297. https://doi.org/10.1016/j.biopha.2019.109297. 46.Fromenty B, Roden M. Mitochondrial alterations in fatty liver diseases. Journal of hepatology. 2023;78(2):415-29. https://doi.org/10.1016/j.jhep.2022.09.020.

  • تاریخ دریافت 24 تیر 1404
  • تاریخ بازنگری 26 مرداد 1404
  • تاریخ پذیرش 11 شهریور 1404
  • تاریخ اولین انتشار 11 شهریور 1404
  • تاریخ انتشار 01 فروردین 1405