Evaluating the effects of metformin on irisin and serum biochemical parameters in male sprague-dawley rats fed by a high-fat emulsion diet

Authors

1 Department of Biology, Faculty of Basic Sciences, Research Sciences Branch, Islamic Azad University, Tehran, Iran

2 Endocrinology and Metabolism Research Center, Tehran University of Medical Sciences Tehran, Iran

Abstract
Irisin is a myokine secreted mostly by muscles after exercise, and its secretion level changes in metabolic disorders. The aim of present study was to investigate the effect of metformin on changes in the levels of plasma irisin, blood glucose and insulin resistance in male Sprague-Dawley rats receiving a high-fat emulsion diet. Twenty-four rats were divided into a normal control group (n = 8) and a high-fat diet group (n = 16). Then, high-fat diet group was divided into two subgroups, including high-fat diet control group (n = 8) and metformin group (n = 8). The normal control group received a standard diet. The high-fat diet control group received a high-fat emulsion diet containing corn oil by gavage on a daily basis for six weeks, and the metformin group received a high-fat emulsion diet with metformin (250 mg/kg/daily). At the end of the six-week period, factors such as glucose, insulin, irisin, Adiponectin, insulin resistance, liver enzymes, tumor necrosis factor α (TNF-α), serum lipid profile, lipid profile and lipid peroxidation in liver were measured and PGC-1α gene expression were examined in adipose tissue by Real-time PCR method. Liver histological tests with hematoxylin-eosin staining were performed to evaluate fat accumulation in liver tissue. Blood glucose level, insulin resistance, adiponectin, serum irisin level and liver lipid profile in the group receiving high-fat diet compared to the normal control group increased significantly (P <0. 05). Treatment with metformin caused a significant decrease in the level of these parameters compared to the high-fat diet group (P <0. 05) and an increase in the expression of PGC-1α gene in adipose tissue was observed in this group. As insulin resistance increased in rats receiving the high-fat diet, serum irisin level also increased, and with improving blood glucose and insulin resistance by metformin, serum irisin level was decreased. These results suggested that the elevated irisin levels may be a compensatory response to insulin resistance and impaired glucose metabolism. Hence, irisin could be considered as a potential target for the treatment of type 2 diabetes.





Keywords


Aatsinki, S.M., Buler, M., Salomaki, H., Koulu, M., Pavek, P. & Hakkola, J. 2014. Metformin induces PGC-1α expression and selectively affects hepatic PGC-1α functions. British Journal of Pharmacology 171: 2351-2363.
Arias-Loste, M.T., Ranchal, I., Romero-Gómez, M. & Crespo, J. 2014. Irisin, a link among fatty liver disease, physical inactivity and insulin resistance. International Journal of Molecular Sciences 15: 23163-23178.
Asrih, M. & Jornayvaz, F.R. 2015. Metabolic syndrome and nonalcoholic fatty liver disease: Is insulinresistance the link? Molecular and Cellular Endocrinology 418: 55-65.
Bułdak, L., Łabuzek, K. & Bułdak, R.J. 2014. Metformin affects macrophages’ phenotype and improvesthe activity of glutathione peroxidase, superoxide dismutase, catalase and decreases malondialdehyde concentration in a partially AMPK-independent manner in LPS-stimulatedhuman monocytes/macrophages. Pharmacological Reports 66: 418-429
Buzzetti, E., Pinzani, M. & Tsochatzis, E.A. 2015. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism 65: 1038-1048.
Dai, J., Liu, M., Ai, Q., Lin, L., Wud, K., Deng, X., Jing, Y., Jia, M. Wane, J. & Zhang, L. 2014. Involvement of catalase in the protective benefits of metformin in mice with oxidative liver injury. Chemico-Biological Interactions 216: 34-42.
Del Rio, D., Stewart, A.J. & Pellegrini, N. 2005. A review of recent studies on malondialdehyde as toxic molecule and biological marker of oxidative stress. Nutrition, Metabolism & Cardiovascular Diseases 15: 315-328.
Dowman, J.K., Tomlinson, J.W. & Newsome, P.N. 2010. Pathogenesis of non-alcoholic fatty liver disease. QJM: An International Journal of Medicine 103: 71-83.
Dupont, J., Carpenter, M.P., Schaefer, E.J., Meydani, S.N., Elson, C.E., Woods, M. & Gorbach, S.L. 1990. Food uses and health effects of corn oil. Journal of the American College of Nutrilion 9: 438-470.
Esfade H., Mirabolghasemi G., Azarnia M. 2019. The joint effect of hydro-alcoholic extract of nettle root and metformin on ovarian tissue of diabetic model of Wistar rat. Nova Biologica Reperta 6: 131-139.
Esterbauer, H., Schaur, R.J. & Zollner, H. 1991. Chemistrt and biochemistry of 4-Hydroxynonenal, Malonaldehyde and related aldehydes. Free Radical Biology & Medicin 11: 81-128.
Finck, B.N. & Kelly, D.P. 2006. PGC-1 coactivators: inducible regulators of energy metabolism in health and disease. Journal of Clinical Investigation: 116: 615-622.
Gizaw, M., Anandakumar, P. & Debela, T. 2017. Review on the role of irisin in insulin resistance and type 2 diabetes mellitus. Journal of Pharmacopuncture 20: 235-242.
Hariri, N. & Thibault, L. 2010. High-fat diet-induced obesity in animal models. Nutrition Research Reviews 23: 270-299.
Hebbard, L. & George, J. 2011. Animal models of nonalcoholic fatty liver disease. Nature Reviews Gastroenterology & Hepatology 8: 34-44.
Hesselink, M. K., Schrauwen-Hinderling, V. & Schrauwen, P. 2016. Skeletal muscle mitochondria as a target to prevent or treat type 2 diabetes mellitus. Nature reviews endocrinology 12: 633-645.
Huerta, A.E., Prieto-Hontoria, P.L., Fernandez-Galilea, M., Sainz, N., Cuervo, M., Martinez, J.A. & Moreno-Aliaga, M.J. 2015. Circulating irisin and glucose metabolism in overweight/obese women: effects of α-lipoic acid and eicosapentaenoic acid. Journal of Physiology and Biochemistry 71: 547-558.
Jian-Gao, F., Xiao-Dong, D., Zeng-Jie, X., Xiao-Ying, Z. & Tian, L.Y. 2003. Preventie effects of Metformin on rats with Nonalcoholic steatohepatitis. Hepatology 34: 501-502.
Karise, I., Bargut, T.C., Del Sol, M., Pacilio, M. & Mandarim-de-Lacerda, C.A. 2019. Metformin enhances mitochondrial biogenesis and thermogenesis in brown adipocytes of mice. Biomedicine & Pharmacotherapy 111: 1156-1165.
Karkhaneh, L., Yaghmaei, P., Parivar, K., Sadeghizadeh, M. & Ebrahim-Habibi, A. 2016. Effect of trans-chalcone on atheroma plaque formation, liver fibrosis and adiponectin gene expression in cholesterol-fed NMRI mice. Pharmacological Reports 462: 1-8.
Kleiner, S., Mepani, R.J., Laznik, D., Ye, L., Jurczak, M.J., Jornayvaz, F.R. & Spiegelman, B.M. 2012. Development of insulin resistance in mice lacking PGC-1α in adipose tissues. Proceedings of the National Academy of Sciences 109: 9635-9640.
Lee, H.J., Lee, J.O., Kim, N., Kim, J.K., Kim, H.I., Lee, Y.W. & Kim, H.S. 2015. Irisin, a novel myokine, regulates glucose uptake in skeletal muscle cells via AMPK. Molecular Endocrinology 29: 873-881.
Lovati, M. R., Manzoni, C., Castiglioni, S., Parolari, A., Magni, C. & Duranti, M. 2012. Lupin seed γ-conglutin lowers blood glucose in hyperglycaemic rats and increases glucose consumption of HepG2 cells. British Journal of Nutrition 107: 67-73.
Moreno-Navarrete, J.M., Ortega, F., Serrano, M., Guerra, E., Pardo, G., Tinahones, F. & Fernández-Real, J.M. 2013. Irisin is expressed and produced by human muscle and adipose tissue in association with obesity and insulin resistance. The Journal of Clinical Endocrinology & Metabolism 98: 769-778.
Negre-Salvayre, A., Auge, N., Ayala, V., Basaga, H., Boada, J., Brenke, R. & Zarkovic, N. 2010. Pathological aspects of lipid peroxidation. Free Radical Research 44: 1125-1171.
Paschos, P. & Paletas, K. 2009. Non alcoholic fatty liver disease and metabolic syndrome. Hippokratia 13: 9-19.
Patterson, E., Wall, R., Fitzgerald, G.F., Ross, R.P. & Stanton, C. 2011. Health Implications of High Dietary Omega-6 Polyunsaturated Fatty Acids. Journal of Nutrition and Metabolism 2012: 1-16.
Perakakis, N., Triantafyllou, G.A., Fernández-Real, J.M., Huh, J.Y., Park, K.H., Seufert, J. & Mantzoros, C.S. 2017. Physiology and role of irisin in glucose homeostasis. Nature Reviews Endocrinology 13: 324-337.
Popov, V.B. & Lim, J.K. 2015. Treatment of nonalcoholic fatty liver disease: the role of medical, surgical, and endoscopic weight loss. Journal of Clinical and Translational Hepatology 3: 230-238.
Puigserver, P. & Spiegelman, B.M. 2003. Peroxisome proliferator-activated receptor γ coactivator 1a (PGC-1a): transcriptional coactivator and metabolic regulator. Endocrine Reviews 24: 78-90.
Raso, G.M., Esposito, E., Iacono, A., Pacilio, M., Cuzzocrea, S., Canani, R.B. & Meli, R. 2009. Comparative therapeutic effects of metformin and vitamin E in a model of non-alcoholic steatohepatitis in the young rat. European Journal of Pharmacology 604: 125-131.
Robertson, G., Leclercq, I. & Farrell, G.C. 2001. II. Cytochrome P-450 enzymes and oxidative stress. American Journal of Physiology-Gastrointestinal and Liver Physiology 281: 1135-1139.
Rolo, A.P., Teodoro, J.S. & Palmeira, C.M. 2012. Role of oxidative stress in the pathogenesis of nonalcoholic steatohepatitis. Free Radical Biology & Medicine 52: 59-69.
Schommers, P., Thurau, A., Bultmann-Mellin, I., Guschlbauer, M., Klatt, A.R., Rozman, J. & Wiesner, R.J. 2017. Metformin causes a futile intestinal–hepatic cycle which increases energy expenditure and slows down development of a type 2 diabetes-like state. Molecular Metabolism 6: 737-747.
Sesti, G., Andreozzi, F., Fiorentino, T.V., Mannino, G.C., Sciacqua, A., Marini, M.A. & Perticone, F. 2014. High circulating irisin levels are associated with insulin resistance and vascular atherosclerosis in a cohort of nondiabetic adult subjects. Acta Diabetologica 51: 705-713.
Stengel, A., Hofmann, T., Geobel-Stengel, M., Elbelt, U., Kobelt, P. & Klapp, B.F. 2013. Circulating levels of irisin in patients with anorexia nervosa and different stages of obesity- Correlation with body mass index. Peptides 39: 125-130.
Varela-Rodríguez, B. M., Pena-Bello, L., Juiz-Valiña, P., Vidal-Bretal, B., Cordido, F. & Sangiao-Alvarellos, S. 2016. FNDC5 expression and circulating irisin levels are modified by diet and hormonal conditions in hypothalamus, adipose tissue and muscle. Scientific Reports 6: 1-13.
Woo, S.L., Xu, H., Li, H., Zhao, Y., Hu, X., Zhao, J. & Wu, C. 2014. Metformin ameliorates hepatic steatosis and inflammation without altering adipose phenotype in diet-induced obesity. Plos One 9: 1-13.
Yang, Q., Liang, X., Sun, X., Zhang, L., Fu, X., Rogers, C.J. & Du, M. 2016. AMPK/α-ketoglutarate axis dynamically mediates DNA demethylation in the Prdm16 promoter and brown adipogenesis. Cell Metabolism 24: 542-554.
Zou, Y., Li, J., Lu, C., Wang, J., Ge, J., Huang, Y. & Wang, Y. 2006. High-fat emulsion-induced rat model of nonalcoholic steatohepatitis. Life Sciences 79: 1100-1107.
Volume 9, Issue 3 - Serial Number 33
Autumn 2022
Pages 169-181

  • Receive Date 08 June 2026
  • Publish Date 08 June 2026