Metformin treatment prevents experimental metabolic syndrome-induced  femoral bone marrow adiposity in rats

Authors

  • Siro Lasalvia Laboratorio de Investigaciones en Osteopatías y Metabolismo Mineral (LIOMM), Facultad de Ciencias Exactas, Universidad Nacional de La Plata. Buenos Aires, Argentina https://orcid.org/0009-0004-7051-1065
  • Claudia Sedlinsky Laboratorio de Investigaciones en Osteopatías y Metabolismo Mineral (LIOMM), Facultad de Ciencias Exactas, Universidad Nacional de La Plata. Buenos Aires, Argentina https://orcid.org/0009-0006-1825-9397
  • León Schurman Laboratorio de Investigaciones en Osteopatías y Metabolismo Mineral (LIOMM), Facultad de Ciencias Exactas, Universidad Nacional de La Plata. Buenos Aires, Argentina https://orcid.org/0009-0008-9614-3036
  • Antonio Desmond McCarthy Laboratorio de Investigaciones en Osteopatías y Metabolismo Mineral (LIOMM), Facultad de Ciencias Exactas, Universidad Nacional de La Plata. Buenos Aires, Argentina https://orcid.org/0000-0002-9175-6596
  • Nahuel Ezequiel Wanionok Laboratorio de Investigaciones en Osteopatías y Metabolismo Mineral (LIOMM), Facultad de Ciencias Exactas, Universidad Nacional de La Plata. Buenos Aires, Argentina https://orcid.org/0009-0006-1614-6292

DOI:

https://doi.org/10.17843/rpmesp.2024.411.13333

Keywords:

Metformin, metabolic syndrome, adipocytes, mesenchymal stem cells, bone tissue

Abstract

Objetive. To determine the effect of metformin (MET) treatment on adipogenic predisposition of bone marrow progenitor cells (BMPC), bone marrow adiposity and  bone biomechanical properties. Materials and methods. 20 young adult male Wistar rats were sorted into four groups. Each of the groups received the following in drinking water: 100% water (C); 20% fructose (F); metformin 100 mg/kg wt/day (M); or fructose plus metformin (FM). After five weeks the animals were sacrificed. Both humeri were dissected to obtain BMPC, and both femurs were dissected to evaluate medullary adiposity (histomorphometry) and biomechanical properties (3-point bending). BMPC were cultured in vitro in adipogenic medium to evaluate RUNX2, PPAR-γ and RAGE expression by RT-PCR, lipase activity and triglyceride accumulation. Results. The fructose-rich diet (group F) caused an increase in both triglycerides in vitro, and medullary adiposity in vivo; being partially or totally prevented by co-treatment with metformin (group FM). No differences were found in femoral biomechanical tests in vivo, nor in lipase activity and RUNX2/PPAR-γ ratio in vitro. DRF increased RAGE expression in BMPC, being prevented by co-treatment with MET. Conclusions. Metabolic syndrome induced by a fructose-rich diet increases femoral medullary adiposity and, in part, the adipogenic predisposition of BMPC. In turn, this can be totally or partially prevented by oral co-treatment with MET.

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References

Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, et al. Harmonizing the metabolic syndrome: a joint interim statement of the international diabetes federation task force on epidemiology and prevention; national heart, lung, and blood institute; American heart association; world heart federation; international atherosclerosis society; and international association for the study of obesity. Circulation. 2009;120(6):1640–5. doi: 10.1161/circulationaha.109.192644.

Yamaoka, K, Tango T. Effects of lifestyle modification on metabolic syndrome: a systematic review and meta-analysis. BMC Med. 2012; 10,138. doi: 10.1186/1741-7015-10-138.

Chin KY, Wong SK, Ekeuku SO, Pang KL. Relationship Between Metabolic Syndrome and Bone Health - An Evaluation of Epidemiological Studies and Mechanisms Involved. Diabetes Metab Syndr Obes. 2020;13:3667-3690. doi: 10.2147/DMSO.S275560.

Hwang DK, Choi HJ. The relationship between low bone mass and metabolic syndrome in Korean women. Osteoporos Int. 2010; 21(3):425-31. doi: 10.1007/s00198-009-0990-2.

Chen DZ, Xu QM, Wu XX, Cai C, Zhang LJ, Shi KQ, et al. The Combined Effect of Nonalcoholic Fatty Liver Disease and Metabolic Syndrome on Osteoporosis in Postmenopausal Females in Eastern China. Int J Endocrinol. 2018; 2018:2314769. doi: 10.1155/2018/2314769.

Kim H, Oh HJ, Choi H, Choi WH, Lim SK, Kim JG. The association between bone mineral density and metabolic syndrome: a Korean

population-based study. J Bone Miner Metab 2013; 31(5):571-8. doi: 10.1007/s00774-013-0446-9.

Muka T, Trajanoska K, Kiefte-de Jong JC, Oei L, Uitterlinden AG, Hofman A, et al. The Association between Metabolic Syndrome,

Bone Mineral Density, Hip Bone Geometry and Fracture Risk: The Rotterdam Study. PLoS One. 2015;10(6):e0129116. doi: 10.1371/

journal.pone.0129116.

von Muhlen D, Safii S, Jassal SK, Svartberg J, Barrett-Connor E. Associations between the metabolic syndrome and bone health in older men and women: the Rancho Bernardo Study. Osteoporos Int. 2007;18(10):1337-44. doi: 10.1007/s00198-007-0385-1.

Qin L, Yang Z, Zhang W, Gu H, Li X, Zhu L, et al. Metabolic syndrome and osteoporotic fracture: a population-based study in China. BMC Endocr Disord. 2016;16(1):27. doi: 10.1186/s12902-016-0106-x.

Wanionok NE, McCarthy AD. Síndrome metabólico, metformina y hueso. Actual Osteol [Internet]. 2023 [citado el 19 de febrero de 2024];18(3):169-182. Disponible en: https://ojs.osteologia.org.ar/ojs33010/index.php/osteologia/article/view/68.

Fazeli PK, Horowitz MC, MacDougald OA, Scheller EL, Rodeheffer MS, Rosen CJ, et al. Marrow fat and bone--new perspectives. J Clin Endocrinol Metab. 2013;98(3), 935–945. doi: 10.1210/jc.2012-3634.

Felice JI, Gangoiti MV, Molinuevo MS, McCarthy AD, Cortizo AM. Effects of a metabolic syndrome induced by a fructose-rich diet on bone metabolism in rats. Metabolism. 2014; 63(2):296-305. doi: 10.1016/j.metabol.2013.11.002.

Felice JI, Schurman L, McCarthy AD, Sedlinsky C, Aguirre JI, Cortizo AM. Effects of fructose-induced metabolic syndrome on rat skeletal cells and tissue, and their responses to metformin treatment. Diabetes Res Clin Pract. 2017;126:202-213. doi: 10.1016/j.diabres.2017.02.011.

Cortizo AM, Sedlinsky C, McCarthy AD, Blanco A, Schurman L. Osteogenic actions of the anti-diabetic drug metformin on osteoblasts in culture. Eur J Pharmacol. 2006;536(1-2):38-46. doi: 10.1016/j.ejphar.2006.02.030.

American Diabetes Association. Treatment effects on measures of body composition in the TODAY clinical trial. Diabetes Care. 2013;36(6):1742–1748. doi: 10.2337/dc12-2534.

Lee MG, Choi YH, Lee I. Effects of diabetes mellitus induced by alloxan on the pharmacokinetics of metformin in rats: restoration of pharmacokinetic parameters to the control state by insulin treatment. J Pharm Pharm Sci. 2008;11(1):88-103. doi: 10.18433/j35p4x.

Schwartz AV, Pan Q, Aroda VR, Crandall JP, Kriska A, Piromalli C, et al. Long-term effects of lifestyle and metformin interventions in DPP on bone density. Osteoporos Int. 2021;32(11):2279-2287. doi: 10.1007/s00198-021-05989-1.

Marycz K, Tomaszewski KA, Kornicka K, Henry BM, Wroński S, Tarasiuk J, et al. Metformin Decreases Reactive Oxygen Species, Enhances Osteogenic Properties of Adipose-Derived Multipotent Mesenchymal Stem Cells In Vitro, and Increases Bone Density In Vivo. Oxid Med Cell Longev. 2016;2016:9785890. doi: 10.1155/2016/9785890.

Wang C, Li H, Chen SG, He JW, Sheng CJ, Cheng XY, et al. The skeletal effects of thiazolidinedione and metformin on insulin-resistant mice. J Bone Miner Metab. 2012;30(6):630-7. doi: 10.1007/s00774-012-0374-0.

Gao Y, Li Y, Xue J, Jia Y, Hu J. Effect of the anti-diabetic drug metformin on bone mass in ovariectomized rats. Eur J Pharmacol. 2010;635(1-3):231-6. doi: 10.1016/j.ejphar.2010.02.051.

Tolosa MJ, Chuguransky SR, Sedlinsky C, Schurman L, McCarthy AD, Molinuevo MS, et al. Insulin-deficient diabetes-induced bone microarchitecture alterations are associated with a decrease in the osteogenic potential of bone marrow progenitor cells: preventive effects of metformin. Diabetes Res Clin Pract. 2013;101:177–86. doi: 10.1016/j.diabres.2013.05.016.

Molinuevo MS, Schurman L, McCarthy AD, Cortizo AM, Tolosa MJ, Gangoiti MV, et al. Effect of metformin on bone marrow progenitor

cell differentiation: in vivo and in vitro studies. J Bone Miner Res. 2010;25:211–6. doi: 10.1359/jbmr.090732.

McCarthy AD, Cortizo AM, Sedlinsky C. Metformin revisited: Does this regulator of AMP-activated protein kinase secondarily affect bone metabolism and prevent diabetic osteopathy? World J Diabetes. 2016;7(6):122-133. doi: 10.4239/wjd.v7.i6.122.

UFAW. The UFAW handbook on the care and management of laboratory and other research animals. 8th ed. United Kingdom: Wiley-Blackwell; 2011. doi: 10.1002/9781444318777.ch8.

Mamikutty N, Thent ZC, Sapri SR, Sahruddin NN, Mohd Yusof MR, Haji Suhaimi F. The establishment of metabolic syndrome model by induction of fructose drinking water in male Wistar rats. Biomed Res Int. 2014; 2014:263897. doi: 10.1155/2014/263897.

Dupas J, Feray A, Goanvec C, Guernec A, Samson N, Bougaran P, et al. Metabolic Syndrome and Hypertension Resulting from Fructose Enriched Diet in Wistar Rats. Biomed Res Int. 2017;2017:2494067. doi: 10.1155/2017/2494067.

Choi YH, Lee MG, Lee I. Effects of diabetes mellitus induced by alloxan on the pharmacokinetics of metformin in rats: restoration of pharmacokinetic parameters to the control state by insulin treatment. J Pharm Pharm Sci. 2008;11(1):88–103. doi: 10.18433/j35p4x.

Melo BP, Zacarias AC, Oliveira JCC, de Souza LMC, Sabino J, Ferreira AVM, et al. Thirty days of combined consumption of a high-fat diet and fructose-rich beverages promotes insulin resistance and modulates inflammatory response and histomorphometry parameters of liver, pancreas, and adipose tissue in Wistar rats. Nutrition. 2021;91-92:111403. doi: 10.1016/j.nut.2021.111403.

Álvarez-Lloret P, Fernández JM, Molinuevo MS, Lino AB, Ferretti JL, Capozza RF, et al. Multi-Scale Approach for the Evaluation of Bone Mineralization in Strontium Ranelate-Treated Diabetic Rats. Biol Trace Elem Res. 2018;186(2):457-466. doi: 10.1007/s12011-018-1322-1.

Jiating L, Buyun J, Yinchang Z. Role of Metformin on Osteoblast Differentiation in Type 2 Diabetes. Biomed Res Int. 2019;2019:9203934. doi: 10.1155/2019/9203934.

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Published

2024-03-26

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Original Article

How to Cite

1.
Lasalvia S, Sedlinsky C, Schurman L, McCarthy AD, Wanionok NE. Metformin treatment prevents experimental metabolic syndrome-induced  femoral bone marrow adiposity in rats. Rev Peru Med Exp Salud Publica [Internet]. 2024 Mar. 26 [cited 2024 Apr. 15];41(1):28-36. Available from: https://rpmesp.ins.gob.pe/index.php/rpmesp/article/view/13333

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