Sport Physiology

Sport Physiology

The Effect of 8 Weeks of Aerobic Training and High-Fat Diet on PGC-1α, FNDC5, and UCP-1 Gene Expression in Muscle Tissue of Male Wistar Rats

Document Type : Research Paper

Authors
1 Department of Exercise Physiology, Faculty of Humanities and Social Sciences, University of Kurdistan, Sanandaj, Iran
2 Department of Biology, Faculty of Basic Sciences, Islamic Azad University, Zanjan Branch, Zanjan, Iran
3 5Department of Physical Education and Sport Sciences, University of Halabja, Halabja, Kurdistan region, Iraq.
Abstract
Background and Purpose
Obesity is a major health concern in modern societies, increasing the risk of cardiovascular diseases, diabetes, and metabolic disorders. Lifestyle modifications and regular physical activity are recognized as effective strategies for obesity prevention and management. Exercise plays a crucial role in weight control and metabolic health by influencing energy balance, improving body composition, and reducing fat accumulation. Research indicates that exercise can combat obesity through muscle tissue modifications and the secretion of myokines like irisin. PGC-1α, a key regulatory molecule in skeletal muscle, enhances FNDC5 expression, leading to irisin production. Irisin stimulates UCP-1 in adipose tissue, promoting white-to-brown fat conversion and thermogenesis. While studies have investigated exercise's effects on these genes, findings remain inconsistent. Some report significant increases in UCP-1 and FNDC5 after aerobic or resistance training, while others show minimal changes. For instance, high-intensity interval training (HIIT) elevated FNDC5 in healthy males, whereas combined training had no effect in non-athletes. Aerobic exercise also improved FNDC5 expression in obese rats. Given the role of high-fat diets (HFD) in visceral fat accumulation and varied metabolic responses to exercise, further research is needed. This study examines how progressive aerobic training combined with HFD affects PGC-1α, FNDC5, and UCP-1 levels in rats, assessing its potential to prevent weight gain via white-to-brown fat conversion.
Materials and Methods
Animals and GroupingForty male Wistar rats (8 weeks old, 180±10 g) were obtained from Pasteur Institute of Karaj. After one week of acclimatization, they were randomly divided into four groups (n=10/group): Control (CO): Standard diet, High-fat diet (HFD), Exercise (T): Aerobic training + standard diet, Exercise + HFD (T+HFD)Housing ConditionsRats were housed in polycarbonate cages (4/cage) at 22±2°C, 45±5% humidity, with a 12-hour light/dark cycle. Food and water were provided ad libitum.Diets: Standard diet: 18-23% protein, 4-6% fat, 45-55% carbohydrates, HFD: 60% fat-derived calories (soybean oil), 16% protein, 24% carbohydrates (pellet form, Razi Serum Research Institute)Progressive Aerobic Training Protocol: Duration: 8 weeks, 5 sessions/week, Intensity: 45–85% VO₂maxProgram:Weeks 1–4: Gradual increase in duration (15→35 min) and speed (12→27 m/min). Weeks 5–8: Weekly 10-min duration increments; speed fixed at 27 m/min. warm-up/cool-down: 10 m/min. minimal electric shocks were used for ethical compliance.
Results
 PGC-1α: HFD caused a significant 1.66-fold decrease (p=0.0001), while exercise (T) induced a 5.4-fold increase (p=0.0001). The T+HFD group showed no significant difference vs. CO (1.16-fold, p>0.05). HFD had the lowest PGC-1α levels (p<0.0001). FNDC5: Non-significant 0.86-fold reduction in HFD (p=0.141). Exercise (T) led to a 5.52-fold rise (p=0.001); T+HFD increased 1.47-fold (p=0.019). T group had the highest expression (p<0.0001). UCP1: No significant difference between HFD and CO (1.15-fold, p=0.337). Exercise (T) elevated expression 2.35-fold (p<0.0001) and 2.04-fold vs. HFD (p<0.0001).
Conclusion
HFD reduces PGC-1α expression, but aerobic exercise counteracts this effect. Exercise alone most effectively upregulates FNDC5 and UCP1. Combined training and HFD (T+HFD) only partially mitigates HFD’s negative impacts. These findings demonstrate that aerobic training can attenuate HFD-induced metabolic damage by positively modulating fat metabolism-related genes.
Article Message
This study demonstrates a critical interaction between diet and exercise at the molecular level. While a high-fat diet suppresses the expression of key genes regulating mitochondrial energy expenditure (PGC-1α, FNDC5), an 8-week progressive aerobic exercise program can effectively counteract this effect. Exercise significantly increased the expression of these genes, which are involved in the browning of fat and thermogenesis. This suggests that regular aerobic exercise provides a powerful protective effect against weight gain and obesity, even in the presence of a high-calorie diet, by enhancing the body's innate energy-burning pathways.
Ethical Considerations
The protocol (Code: IR.UOK.REC.1397.024) was approved by the Ethics Committee of Kurdistan University, complying with laboratory animal guidelines.
Authors’ Contributions
Conceptualization: Mohammad Rahman Rahimi, Mehdi Rahnama and Sanaz Mahmazi
Data Collection: Mohammad Rahman Rahimi and Naser Ghanbari
Data Analysis: Mohammad Rahman Rahimi, Naser Ghanbari, Sanaz Mahmazi
Manuscript Writing: Mohammad Rahman Rahimi, Naser Ghanbari
Review and Editing: Mohammad Rahman Rahimi, Naser Ghanbari, Dara Latif Saifalddin
Responsible for Funding: Mohammad Rahman Rahimi
Literature Review: Mohammad Rahman Rahimi, Naser Ghanbari, Dara Latif Saifalddin
Project Manager: Mohammad Rahman Rahimi
Conflict of Interest
According to the authors' declaration, this article has no conflicts of interest.
Acknowledgments
We sincerely thank all participants who assisted us in conducting this research. The research costs were covered by the authors.
 
 
Keywords

Subjects


1. Miles L. Physical activity and health. Nutrition bulletin. 2007;32(4):314-63. https://doi.org/10.1111/j.1467-3010.2007.00668.x
2. Boström P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, et al. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature. 2012;463–8. https://doi.org/10.1038/nature10777
3. Turner N, Kowalski G, Leslie SJ, Risis S, Yang C, Lee-Young RS, et al. Distinct patterns of tissue-specific lipid accumulation during the induction of insulin resistance in mice by high-fat feeding. Diabetologia. 2013;56(7):1638-48. https://doi.org/10.1007/s00125-013-2913-1
4. Booth FW, Ruegsegger GN, Toedebusch RG, Yan Z. Endurance exercise and the regulation of skeletal muscle metabolism. Progress in Molecular Biology and Translational Science. 2015;135:129-51. https://doi.org/10.1016/bs.pmbts.2015.07.016
5. Richter EA, Hargreaves M. Exercise, GLUT4, and skeletal muscle glucose uptake. Physiological Reviews. 2013; 93(3): 993-1017. https://doi.org/10.1152/physrev.00038.2012
6. Gollnick P, Armstrong R, Saubert 4th C, Piehl K, Saltin B. Enzyme activity and fiber composition in skeletal muscle of untrained and trained men. Journal of Applied Physiology. 1972;33(3):312-9. https://doi.org/10.1152/jappl.1972.33.3.312
7. Rahimi MR, Mehrwand Z. The impact of resistance training on IL-6, TNF-a, and CRP levels in the elderly: a systematic review and meta-analysis study. International Journal of Sport Studies for Health. 2023;6(2). https://doi.org/10.61838/kman.intjssh.6.2.1
8. Rahimi MR, Ketabi S, Saeedi N. The effect of 8 weeks of green tea extract supplementation and resistance training on the concentration of adipokines apelin and chemerin in obese women. Metabolism and Exercise. 2022;12(1):17-33. https://doi.org/10.22124/jme.2023.14847.263
9. Rahimi MR, Faraji H, Samzadeh Kermani F. The effect of exercise training on vaspin serum levels in obese people and type 2 diabetes patients: a meta-analysis study. Journal of Sport and Exercise Physiology. 2025;18(1):102-24. https://doi.org/10.48308/joeppa.2024.236449.1282
10. Ghanbari N, Rahimi MR, Mahmazi S, Rahnema M. Effect of eight weeks caffeine supplementation and high fat diet on PGC1-α, Fndc-5 and UCP-1 gene expression in male wistar rats. Journal of Advances in Medical and Biomedical Research|. 2021;2676:6264. https://doi.org/10.30699/jambs.29.136.271
11. Handschin C, Spiegelman BM. The role of exercise and PGC1α in inflammation and chronic disease. Nature. 2008;454:463–9. https://doi.org/10.1038/nature07206
12. Roca-Rivada A, Castelao C, Senin LL, Landrove MO, Baltar J, Crujeiras AB, et al. FNDC5/irisin is not only a myokine but also an adipokine. PloS One. 2013;8(4). https://doi.org/10.1371/journal.pone.0060563
13. Wenz T, Rossi SG, Rotundo RL, Spiegelman BM, Moraes CT. Increased muscle PGC-1α expression protects from sarcopenia and metabolic disease during aging. Proceedings of the National Academy of Sciences. 2009;106(48):20405-10. https://doi.org/10.1073/pnas.091157010
14. Kazemi Nasab F, Marandi M, Ghaedi K, Esfarjani F, Nasr-Esfahani MH. The effect of endurance training and high-fat diet on PGC-1a/FNDC5/irisin pathway in male C57BL/6 mice. Sport Physiology. 2019;11(41):63-80.  https://doi.org/10.22089/spj.2017.4295.1573
15. Norheim F, Langleite TM, Hjorth M, Holen T, Kielland A, Stadheim HK, et al. The effects of acute and chronic exercise on PGC‐1α, irisin and browning of subcutaneous adipose tissue in humans. The FEBS Journal. 2014;281(3):739-49. https://doi.org/10.1111/febs.12619
16. Daneshyar S, Kordi Mr, Gaeini A, Kadivar M, Afshari S. The effect of endurance training on gene expression of uncoupling protein 1 (UCP-1) in white visceral adipose tissue of retroperitoneal depot of male Wistar rats. Razi Journal of Medical Sciences. 2015;22(136):35-45. [In Persian].Available at: https://rjms.iums.ac.ir/article-1-3995-en.html
17. Eaton M, Granata C, Barry J, Safdar A, Bishop D, Little JP. Impact of a single bout of high-intensity interval exercise and short-term interval training on interleukin-6, FNDC5, and METRNL mRNA expression in human skeletal muscle. Journal of Sport and Health Science. 2018;7(2):191-6. https://doi.org/10.1016/j.jshs.2017.01.003
18. Jeon Y, Ha K, Seo DY, Yeo JY, Choi SJ, Han J. Effects of aerobic exercise on the expressions of skeletal muscle fiber type-related genes and FNDC-5 in high-fat diet-induced obese rats. International Journal of Applied Sports Sciences. 2017;29(1):42-53. https://doi.org/10.24985/ijass.2017.29.1.42
19. Timmons JA, Baar K, Davidsen PK, Atherton PJ. Is irisin a human exercise gene? Nature. 2012;488(7413):E9-E10. https://doi.org/10.1038/nature11364
20. Reisi J, Rajabi H, Ghaedi K, Marandi S-M, Dehkhoda M-R. Effect of acute resistance training on plasma irisin protein level and expression of muscle FNDC5 and adipose tissue UCP1 genes in male rats. Journal of Isfahan Medical School. 2013;31(256). Available at: https://jims.mui.ac.ir/article_14172.html
21. Høydal MA, Wisløff U, Kemi OJ, Ellingsen Ø. Running speed and maximal oxygen uptake in rats and mice: practical implications for exercise training. European Journal of Preventive Cardiology. 2007;14(6):753-60. https://doi.org/10.1097/HJR.0b013e3281eacef1
22. Sparks LM, Xie H, Koza RA, Mynatt R, Hulver MW, Bray GA, et al. A high-fat diet coordinately downregulates genes required for mitochondrial oxidative phosphorylation in skeletal muscle. Diabetes. 2005;54(7):1926-33. https://doi.org/10.2337/diabetes.54.7.1926
23. Ghaderi M, Mohebbi H, Soltani B. The Effect of obesity and its subsequent intense endurance training on serum irisin concentration and expression of subcutaneous adipose tissue UCP1 mRNA and these factors' relation with leptin changes in wistar rats. Journal of Sport Biosciences. 2019;11(3):283-98.  https://doi.org/10.22059/jsb.2019.240606.1203
24. Derbré F, Gomez-Cabrera MC, Nascimento AL, Sanchis-Gomar F, Martinez-Bello VE, Tresguerres JA, et al. Age associated low mitochondrial biogenesis may be explained by lack of response of PGC-1α to exercise training. Age. 2012;34(3):669-79. https://doi.org/10.1007/s11357-011-9264-y
25. Sadeghipour HR, Salesi M, Rabiezade A. Effects of 4 week endurance training on PGC-1α expression in adipose tissue, ANGPTL8 serum concentrations and beta cells function of STZ diabetic rats. Journal of Fasa University of Medical Sciences. 2019;8(4):1068-78. https://doi.org/20.1001.1.22285105.2019.8.4.7.3
26. Lanzi CR, Perdicaro DJ, Tudela JG, Muscia V, Fontana AR, Oteiza PI, et al. Grape pomace extract supplementation activates FNDC5/irisin in muscle and promotes white adipose browning in rats fed a high-fat diet. Food & Function. 2020;11(2):1537-46. https://doi.org/10.1039/C9FO02463H
27. El-Desoky F, Gaber AE-H, Holah NS, Esam E, Daba MHY, Abd Elrahman AY, et al. Protective effect of caffeine and curcumin versus silymarin on nonalcoholic steatohepatitis in rats. Menoufia Medical Journal. 2020;33(1):196. https://dx.doi.org/10.4103/mmj.mmj_253_18
28. Pedersen BK. Muscles and their myokines. Journal of Experimental Biology. 2011;214(2):337-46. https://doi.org/10.1242/jeb.048074
29. Guo Q, Zhang B, Du H, Zhu R, Sun X, Fan X, et al. High-fat diet and palmitate inhibits FNDC5 expression via AMPK-Zfp57 pathway in mouse muscle cells. Chemico-Biological Interactions. 2023;369:110265. https://doi.org/10.1016/j.cbi.2022.110265
30. Hejazi K, Attarzadeh Hosseini SR, Fathi M, Mosaferi Ziaaldini M, Zaeemi M. Comparison the effect of eight weeks aerobic training with moderate and high intensities on serum levels of Irisin and Uncoupling Protein 1 (UCP-1) in white adipose tissue in obese male rats. Journal of Gorgan University of Medical Sciences. 2018;20(3):31-9. Available at: http://goums.ac.ir/journal/article-1-3453-en.html
31. Hoseinzadeh M, Rashidlamir A, Hejazi SM. The effect of progressive resistance and endurance training on gastrocnemius muscle’s FNDC5 gene expression in male rats. Journal of Sabzevar University of Medical Sciences. 2018;25(5):629-637. Available at: https://jsums.medsab.ac.ir/article_1117.html
32. Kang Y-S, Kim J-C, Kim J-S, Kim SH. Effects of swimming exercise on serum irisin and bone FNDC5 in rat models of high-fat diet-induced osteoporosis. Journal of Sports Science & Medicine. 2019;18(4):596. Available at: https://pubmed.ncbi.nlm.nih.gov/31827343/
33. Lally JS, Ford RJ, Johar J, Crane JD, Kemp BE, Steinberg GR. Skeletal muscle AMPK is essential for the maintenance of FNDC5 expression. Physiological Reports. 2015;3(5):e12343. https://doi.org/10.14814/phy2.12343
34. Ringholm S, Grunnet Knudsen J, Leick L, Lundgaard A, Munk Nielsen M, Pilegaard H. PGC-1α is required for exercise-and exercise training-induced UCP1 up-regulation in mouse white adipose tissue. PloS One. 2013;8(5):e64123. https://doi.org/10.1371/journal.pone.0064123
35. Afshari S, Mohammad AM, Daneshyar S. Comparison of moderate and high volume aerobic training on gene expression of uncoupling protein 1 (UCP-1) in subcutaneous white adipose tissue of wistar rats. Iranian Journal of Endocrinology and Metabolism. 2017;19(1):34-40. [In Persian]. https://dor.isc.ac/dor/20.1001.1.16834844.1396.19.1.5.1
36. Jun H-J, Joshi Y, Patil Y, Noland RC, Chang JS. NT-PGC-1α activation attenuates high-fat diet–induced obesity by enhancing brown fat thermogenesis and adipose tissue oxidative metabolism. Diabetes. 2014;63(11):3615-25. https://doi.org/10.2337/db13-1837
37. Pérez S, Rius‐Pérez S, Finamor I, Martí‐Andrés P, Prieto I, García R, et al. Obesity causes PGC‐1α deficiency in the pancreas leading to marked IL‐6 upregulation via NF‐κB in acute pancreatitis. The Journal of Pathology. 2019;247(1):48-59. https://doi.org/10.1002/path.5166
38. Boström P, Wu J, Jedrychowski MP, Korde A, 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, Spiegelman BM. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature. 2012;481(7382):463-8. https://doi.org/10.1038/nature10777
end
Volume 17, Issue 67
Summer 2025
Pages 61-78

  • Receive Date 09 January 1404
  • Revise Date 19 August 1404
  • Accept Date 01 September 1404