Daneshvar Medicine

Daneshvar Medicine

The Effect of Aerobic Exercise and Probiotic Intervention on HMGB1-RAGE Gene Expression in Visceral Adipose Tissue of Obese Rats

Document Type : Original Article

Authors
mahta Meshkinfam 1
ahmad kaki 2
Elaheh Larki Ghorbani 3
1 M.Sc. Student, Department of Sport Physiology, Ahvaz Branch, Islamic Azad University, Ahvaz, Iran
2 Department of Sports Physiology, Faculty of Humanities, Ahvaz Branch, Islamic Azad University, Ahvaz, Iran
3 Physical Education Teacher, Department of Education, District 2, Ahvaz, Khuzestan Province, Iran
10.22070/daneshmed.2025.20743.1621
Abstract
Background and Objective: Chronic inflammation caused by obesity is one of the key factors in the development of metabolic disorders. The HMGB1-RAGE signaling pathway is recognized as a crucial molecular axis in the initiation and persistence of metabolic inflammation in visceral adipose tissue. This study aimed to investigate the effects of aerobic exercise and probiotic supplementation on the gene expression levels of HMGB1 and RAGE in the visceral adipose tissue of obese male Wistar rats.
Materials and Methods: In this experimental study, 40 male Wistar rats were divided into two groups: standard diet and high-fat diet containing fructose. After 24 weeks of obesity induction, they were assigned to five subgroups: control, obese, obese + exercise, obese + probiotic, and obese + exercise + probiotic. Aerobic exercise was performed on a treadmill for 8 weeks, and probiotics were administered orally. At the end of the study, gene expression levels of HMGB1 and RAGE in visceral adipose tissue were measured using Real-Time PCR.
Results: The results showed that the high-fat and fructose diet significantly increased the expression of HMGB1 and RAGE genes compared to the healthy group (P<0.001). In contrast, aerobic exercise, probiotic supplementation, and especially their combination significantly reduced the expression of these genes (P<0.05). Additionally, anthropometric indices and lipid profiles improved in the intervention groups.
Conclusion: Aerobic exercise and probiotics, particularly when combined, can reduce obesity-induced chronic inflammation by inhibiting the HMGB1-RAGE inflammatory pathway in visceral adipose tissue. These findings emphasize the effectiveness of non-pharmacological lifestyle interventions in preventing and managing obesity-related metabolic complications.
Keywords
HMGB1
RAGE
Aerobic exercise
Probiotic
Visceral adipose tissue
1.         Hotamisligil, G.S., Inflammation and metabolic disorders. Nature, 2006. 444(7121): p. 860–867.
2.         Gregor, M.F. and G.S. Hotamisligil, Inflammatory mechanisms in obesity. Annual review of immunology, 2011. 29(1): p. 415–445.
3.         Feng, Z., et al., Role of RAGE in obesity-induced adipose tissue inflammation and insulin resistance. Cell Death Discovery, 2021. 7(1): p. 305.
4.         Kang, R., et al., HMGB1 in health and disease. Molecular aspects of medicine, 2014. 40: p. 1–116.
5.         Andersson, U. and K.J. Tracey, HMGB1 is a therapeutic target for sterile inflammation and infection. Annual review of immunology, 2011. 29(1): p. 139–162.
6.         Song, F., et al., RAGE regulates the metabolic and inflammatory response to high-fat feeding in mice. Diabetes, 2014. 63(6): p. 1948–1965.
7.         Petersen, A.M.W. and B.K. Pedersen, The anti-inflammatory effect of exercise. Journal of applied physiology, 2005. 98(4): p. 1154–1162.
8.         Fu, P., et al., Aerobic exercise promotes the functions of brown adipose tissue in obese mice via a mechanism involving COX2 in the VEGF signaling pathway. Nutrition & Metabolism, 2021. 18(1): p. 56.
9.         Lira, V.A., et al., PGC-1α regulation by exercise training and its influences on muscle function and insulin sensitivity. American Journal of Physiology-Endocrinology and Metabolism, 2010. 299(2): p. E145–E161.
10.       Plaza-Díaz, J., et al., Evidence of the anti-inflammatory effects of probiotics and synbiotics in intestinal chronic diseases. Nutrients, 2017. 9(6): p. 555.
11.       Chen, Y.-Y., et al., Phyllanthus emblica L. polysaccharides ameliorate colitis via microbiota modulation and dual inhibition of the RAGE/NF-κB and MAPKs signaling pathways in rats. International Journal of Biological Macromolecules, 2024. 258: p. 129043.
12.       Milton-Laskibar, I., et al., Gut microbiota induced by pterostilbene and resveratrol in high-fat-high-fructose fed rats: Putative role in steatohepatitis onset. Nutrients, 2021. 13(5): p. 1738.
13.       Gómez-García, I., et al., Oral Administration of an Opuntia ficus-indica Fruit Extract Induces Changes in Gut Microbiota Composition: Relationship with Its Anti-Obesity and Anti-Steatotic Effects in Rats Fed a High-Fat High-Fructose Diet. Foods, 2025. 14(16): p. 2891.
14.       Rocha-Rodrigues, S., et al., Effects of physical exercise on myokines expression and brown adipose-like phenotype modulation in rats fed a high-fat diet. Life sciences, 2016. 165: p. 100–108.
15.       Livak, K.J. and T.D. Schmittgen, Analysis of relative gene expression data using real-time quantitative PCR and the 2− ΔΔCT method. methods, 2001. 25(4): p. 402–408.
16.       Feng, Z., L. Zhu, and J. Wu, RAGE signalling in obesity and diabetes: focus on the adipose tissue macrophage. Adipocyte, 2020. 9(1): p. 563–566.
17.       Vianello, E., et al., The advanced glycation end-products (AGE)–receptor for AGE system (RAGE): An inflammatory pathway linking obesity and cardiovascular diseases. International Journal of Molecular Sciences, 2025. 26(8): p. 3707.
18.       Zhang, J., et al., HMGB1, an innate alarmin, plays a critical role in chronic inflammation of adipose tissue in obesity. Molecular and cellular endocrinology, 2017. 454: p. 103–111.
19.       Guzmán-Ruiz, R., et al., Alarmin high-mobility group B1 (HMGB1) is regulated in human adipocytes in insulin resistance and influences insulin secretion in β-cells. International journal of obesity, 2014. 38(12): p. 1545–1554.
20.       Chylikova, J., et al., M1/M2 macrophage polarization in human obese adipose tissue. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub, 2018. 162(2): p. 79–82.
21.       Li, X., et al., Adipose tissue macrophages as potential targets for obesity and metabolic diseases. Frontiers in Immunology, 2023. 14: p. 1153915.
22.       Wu, H. and C.M. Ballantyne, Metabolic inflammation and insulin resistance in obesity. Circulation research, 2020. 126(11): p. 1549–1564.
23.       Zatterale, F., et al., Chronic adipose tissue inflammation linking obesity to insulin resistance and type 2 diabetes. Frontiers in physiology, 2020. 10: p. 1607.
24.       Wilson, R.A., et al., Pharmacological antagonism of receptor for advanced glycation end products signaling promotes thermogenesis, healthful body mass and composition, and metabolism in mice. Obesity, 2023. 31(7): p. 1825–1843.
25.       Ishii, Y., et al., Synthesized HMGB1 peptide prevents the progression of inflammation, steatosis, fibrosis, and tumor occurrence in a non‐alcoholic steatohepatitis mouse model. Hepatology Research, 2022. 52(12): p. 985–997.
26.       Guo, Q., et al., Aerobic Exercise Prevents High-Fat-Diet-Induced Adipose Tissue Dysfunction in Male Mice. Nutrients, 2024. 16(20): p. 3451.
27.       Han, X., et al., Aerobic exercise ameliorates insulin resistance in C57BL/6 J mice via activating Sestrin3. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 2023. 1869(1): p. 166568.
28.       Guo, Y., et al., Effects of different exercise modalities on inflammatory markers in the obese and overweight populations: unraveling the mystery of exercise and inflammation. Frontiers in physiology, 2024. 15: p. 1405094.
29.       Pedersen, B.K. and M.A. Febbraio, Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiological reviews, 2008.
30.       Bravo, G.M., et al., High-Intensity Interval Training Decreases Circulating HMGB1 in Individuals with Insulin Resistance; Plasma Lipidomics Identifies Associated Cardiometabolic Benefits. bioRxiv, 2024: p. 2024.08. 21.608998.
31.       Li, N., et al., Aerobic exercise prevents chronic inflammation and insulin resistance in skeletal muscle of high-fat diet mice. Nutrients, 2022. 14(18): p. 3730.
32.       Lira, F.S.d., et al., Exercise training decreases adipose tissue inflammation in cachectic rats. Hormone and Metabolic Research, 2012. 44(02): p. 91–98.
33.       Guo, Y., et al., Depot-specific adaption of adipose tissue for different exercise approaches in high-fat diet/streptozocin-induced diabetic mice. Frontiers in physiology, 2023. 14: p. 1189528.
34.       de Sousa Neto, I.V., et al., Pleiotropic and multi-systemic actions of physical exercise on PGC-1α signaling during the aging process. Ageing research reviews, 2023. 87: p. 101935.
35.       Zhao, L., The gut microbiota and obesity: from correlation to causality. Nature Reviews Microbiology, 2013. 11(9): p. 639–647.
36.       Hemarajata, P. and J. Versalovic, Effects of probiotics on gut microbiota: mechanisms of intestinal immunomodulation and neuromodulation. Therapeutic advances in gastroenterology, 2013. 6(1): p. 39–51.
37.       Cao, Z., et al., Luteolin attenuates APEC-induced oxidative stress and inflammation via inhibiting the HMGB1/TLR4/NF-κB signal axis in the ileum of chicks. Animals, 2022. 13(1): p. 83.
38.       Cronin, O., et al., The effect of exercise interventions on inflammatory biomarkers in healthy, physically inactive subjects: a systematic review. QJM: An International Journal of Medicine, 2017. 110(10): p. 629–637.
39.       Rocha-Rodrigues, S., et al., Impact of physical exercise on visceral adipose tissue fatty acid profile and inflammation in response to a high-fat diet regimen. The international journal of biochemistry & cell biology, 2017. 87: p. 114–124.
Daneshvar Medicine
Volume 33, Issue 2 - Serial Number 177
July and August 2025
Pages 13-22