Emerging Therapeutic Targets for Metabolic Syndrome: Lessons from Animal Models

Author(s): Himadri Singh, Samuel Joshua Pragasam, Vijayalakshmi Venkatesan*.

Journal Name: Endocrine, Metabolic & Immune Disorders - Drug Targets

Volume 19 , Issue 4 , 2019

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Graphical Abstract:


Abstract:

Background: Metabolic syndrome is a cluster of medical conditions that synergistically increase the risk of heart diseases and diabetes. The current treatment strategy for metabolic syndrome focuses on treating its individual components. A highly effective agent for metabolic syndrome has yet to be developed. To develop a target for metabolic syndrome, the mechanism encompassing different organs - nervous system, pancreas, skeletal muscle, liver and adipose tissue - needs to be understood. Many animal models have been developed to understand the pathophysiology of metabolic syndrome. Promising molecular targets have emerged while characterizing these animals. Modulating these targets is expected to treat some components of metabolic syndrome.

Objective: To discuss the emerging molecular targets in an animal model of metabolic syndrome.

Methods: A literature search was performed for the retrieval of relevant articles.

Conclusion: Multiple genes/pathways that play important role in the development of Metabolic Syndrome are discussed.

Keywords: Obesity, diabetes, metabolic syndrome, inflammation, NCDs, animal models.

[1]
Venkatesan, V.; Madhira, S.L.; Malakapalli, V.M.; Chalasani, M.; Shaik, S.N.; Seshadri, V.; Kodavalla, V.; Bhonde, R.R.; Nappanveettil, G. Obesity, insulin resistance, and metabolic syndrome: a study in WNIN/Ob rats from a pancreatic perspective. BioMed Res. Int., 2013, 2013617569.
[2]
Madhira, S.L.; Challa, S.S.; Chalasani, M.; Nappanveethl, G.; Bhonde, R.R.; Ajumeera, R.; Venkatesan, V. Promise(s) of mesenchymal stem cells as an in vitro model system to depict pre-diabetic/diabetic milieu in WNIN/GR-Ob mutant rats. PLoS One, 2012, 7(10), e4806.
[3]
Madhira, S.L.; Nappanveethl, G.; Kodavalla, V.; Venkatesan, V. Comparison of adipocyte-specific gene expression from WNIN/Ob mutant obese rats, lean control, and parental control. Mol. Cell. Biochem., 2011, 357(1-2), 217-225.
[4]
Grundy, S.M.; Cleeman, J.I.; Daniels, S.R.; Donato, K.A.; Eckel, R.H.; Franklin, B.A.; Gordon, D.J.; Krauss, R.M.; Savage, P.J.; Smith, S.C., Jr; Spertus, J.A.; Costa, F.; Smith, S.C., Jr; Spertus, J.A. Diagnosis and management of the metabolic syndrome: An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation, 2005, 112(17), 2735-2752.
[5]
Grundy, S.M. Metabolic syndrome: a multiplex cardiovascular risk factor. J. Clin. Endocrinol. Metab., 2007, 92(2), 399-404.
[6]
Tune, J.D.; Goodwill, A.G.; Sassoon, D.J.; Mather, K.J. Cardiovascular consequences of metabolic syndrome. Transl. Res., 2017, 183, 57-70.
[7]
Kaur, J. A comprehensive review on metabolic syndrome. Cardiol. Res. Pract., 2014, 2014943162.
[8]
Speakman, J.; Hambly, C.; Mitchell, S.; Król, E. Animal models of obesity. Obes. Rev., 2007, 8(Suppl. 1), 55-61.
[9]
Wong, S.K.; Chin, K-Y.; Suhaimi, F.H.; Fairus, A.; Ima-Nirwana, S. Animal models of metabolic syndrome: a review. Nutr. Metab. (Lond.), 2016, 13(1), 65.
[10]
Scroyen, I.; Hemmeryckx, B.; Lijnen, H.R. From mice to men--mouse models in obesity research: what can we learn? Thromb. Haemost., 2013, 110(4), 634-640.
[11]
Madsen, A.N.; Hansen, G.; Paulsen, S.J.; Lykkegaard, K.; Tang-Christensen, M.; Hansen, H.S.; Levin, B.E.; Larsen, P.J.; Knudsen, L.B.; Fosgerau, K.; Vrang, N. Long-term characterization of the diet-induced obese and diet-resistant rat model: A polygenetic rat model mimicking the human obesity syndrome. J. Endocrinol., 2010, 206(3), 287-296.
[12]
Lobley, G.E.; Bremner, D.M.; Holtrop, G.; Johnstone, A.M.; Maloney, C. Impact of high-protein diets with either moderate or low carbohydrate on weight loss, body composition, blood pressure and glucose tolerance in rats. Br. J. Nutr., 2007, 97(6), 1099-1108.
[13]
Miesel, A.; Müller, H.; Thermann, M.; Heidbreder, M.; Dominiak, P.; Raasch, W. Overfeeding-induced obesity in spontaneously hypertensive rats: an animal model of the human metabolic syndrome. Ann. Nutr. Metab., 2010, 56(2), 127-142.
[14]
Vickers, S.P.; Jackson, H.C.; Cheetham, S.C. The utility of animal models to evaluate novel anti-obesity agents. Br. J. Pharmacol., 2011, 164(4), 1248-1262.
[15]
Buettner, R.; Parhofer, K.G.; Woenckhaus, M.; Wrede, C.E.; Kunz-Schughart, L.A.; Schölmerich, J.; Bollheimer, L.C. Defining high-fat-diet rat models: Metabolic and molecular effects of different fat types. J. Mol. Endocrinol., 2006, 36(3), 485-501.
[16]
Srinivasan, K.; Ramarao, P. Animal models in type 2 diabetes research: an overview. Indian J. Med. Res., 2007, 125(3), 451-472.
[17]
Watanabe, M.; Houten, S.M.; Mataki, C.; Christoffolete, M.A.; Kim, B.W.; Sato, H.; Messaddeq, N.; Harney, J.W.; Ezaki, O.; Kodama, T.; Schoonjans, K.; Bianco, A.C.; Auwerx, J. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature, 2006, 439(7075), 484-489.
[18]
Zhang, Y.; Guo, K.; LeBlanc, R.E.; Loh, D.; Schwartz, G.J.; Yu, Y.H. Increasing dietary leucine intake reduces diet-induced obesity and improves glucose and cholesterol metabolism in mice via multimechanisms. Diabetes, 2007, 56(6), 1647-1654.
[19]
Noguchi, Y.; Nishikata, N.; Shikata, N.; Kimura, Y.; Aleman, J.O.; Young, J.D.; Koyama, N.; Kelleher, J.K.; Takahashi, M.; Stephanopoulos, G. Ketogenic essential amino acids modulate lipid synthetic pathways and prevent hepatic steatosis in mice. PLoS One, 2010, 5(8), e12057.
[20]
Bultman, S.J.; Michaud, E.J.; Woychik, R.P. Molecular characterization of the mouse agouti locus. Cell, 1992, 71(7), 1195-1204.
[21]
Zhang, Y.; Proenca, R.; Maffei, M.; Barone, M.; Leopold, L.; Friedman, J.M. Positional cloning of the mouse obese gene and its human homologue. Nature, 1994, 372(6505), 425-432.
[22]
Chen, H.; Charlat, O.; Tartaglia, L.A.; Woolf, E.A.; Weng, X.; Ellis, S.J.; Lakey, N.D.; Culpepper, J.; Moore, K.J.; Breitbart, R.E.; Duyk, G.M.; Tepper, R.I.; Morgenstern, J.P. Evidence that the diabetes gene encodes the leptin receptor: Identification of a mutation in the leptin receptor gene in db/db mice. Cell, 1996, 84(3), 491-495.
[23]
Cefalu, W.T. Animal models of type 2 diabetes: clinical presentation and pathophysiological relevance to the human condition. ILAR J., 2006, 47(3), 186-198.
[24]
Kanasaki, K.; Koya, D. Biology of obesity: Lessons from animal models of obesity. J. Biomed. Biotechnol., 2011, 2011197636.
[25]
Lutz, T.A.; Woods, S.C. Overview of animal models of obesity. Curr. Protoc. Pharmacol.,2018, Chapter 5, Unit 5.6.1.
[26]
Singh, H.; Ajumeera, R.; Malakapalli, V.; Chalasani, M.; Pothani, S.; Venkatesan, V. WNIN mutant obese rats develop acute pancreatitis with the enhanced inflammatory milieu. Cell. Mol. Med. Res., 2017, 1(1), 20-31.
[27]
Harishankar, N.; Kumar, P.U.; Sesikeran, B.; Giridharan, N. Obesity associated pathophysiological & histological changes in WNIN obese mutant rats. Indian J. Med. Res., 2011, 134, 330-340.
[28]
Barrett, P.; Mercer, J.G.; Morgan, P.J. Preclinical models for obesity research. Dis. Model. Mech., 2016, 9(11), 1245-1255.
[29]
Beltrán-Sánchez, H.; Harhay, M.O.; Harhay, M.M.; McElligott, S. Prevalence and trends of metabolic syndrome in the adult U.S. population, 1999-2010. J. Am. Coll. Cardiol., 2013, 62(8), 697-703.
[30]
Pandit, K.; Goswami, S.; Ghosh, S.; Mukhopadhyay, P.; Chowdhury, S. Metabolic syndrome in South Asians. Indian J. Endocrinol. Metab., 2012, 16(1), 44-55.
[31]
Alhassan, S.; Kiazand, A.; Balise, R.R.; King, A.C.; Reaven, G.M.; Gardner, C.D. Metabolic syndrome: do clinical criteria identify similar individuals among overweight premenopausal women? Metabolism, 2008, 57(1), 49-56.
[32]
Khristich, T.N.; Kendzerskaia, T.B. [Pancreas at metabolic syndrome]. Eksp. Klin. Gastroenterol., 2010, (8), 83-91.
[33]
Puddu, A.; Sanguineti, R.; Mach, F.; Dallegri, F.; Viviani, G.L.; Montecucco, F. Update on the protective molecular pathways improving pancreatic beta-cell dysfunction. Mediators Inflamm., 2013, 2013750540.
[34]
Maedler, K.; Sergeev, P.; Ris, F.; Oberholzer, J.; Joller-Jemelka, H.I.; Spinas, G.A.; Kaiser, N.; Halban, P.A.; Donath, M.Y. Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets. J. Clin. Invest., 2002, 110(6), 851-860.
[35]
Böni-Schnetzler, M.; Thorne, J.; Parnaud, G.; Marselli, L.; Ehses, J.A.; Kerr-Conte, J.; Pattou, F.; Halban, P.A.; Weir, G.C.; Donath, M.Y. Increased interleukin (IL)-1β messenger ribonucleic acid expression in β -cells of individuals with type 2 diabetes and regulation of IL-1β in human islets by glucose and autostimulation. J. Clin. Endocrinol. Metab., 2008, 93(10), 4065-4074.
[36]
Donath, M.Y.; Dalmas, É.; Sauter, N.S.; Böni-Schnetzler, M. Inflammation in obesity and diabetes: islet dysfunction and therapeutic opportunity. Cell Metab., 2013, 17(6), 860-872.
[37]
Keller, M.P.; Attie, A.D. Physiological insights gained from gene expression analysis in obesity and diabetes. Annu. Rev. Nutr., 2010, 30, 341-364.
[38]
Singh, H.; Parthasarathy, V.; Farouk, M.; Venkatesan, V. Progenitor cells may aid successful islet compensation in metabolically healthy obese individuals. Med. Hypotheses, 2016, 86, 97-99.
[39]
Keller, M.P.; Choi, Y.; Wang, P.; Davis, D.B.; Rabaglia, M.E.; Oler, A.T.; Stapleton, D.S.; Argmann, C.; Schueler, K.L.; Edwards, S.; Steinberg, H.A.; Chaibub Neto, E.; Kleinhanz, R.; Turner, S.; Hellerstein, M.K.; Schadt, E.E.; Yandell, B.S.; Kendziorski, C.; Attie, A.D. A gene expression network model of type 2 diabetes links cell cycle regulation in islets with diabetes susceptibility. Genome Res., 2008, 18(5), 706-716.
[40]
Singh, H.; Giridharan, N.; Bhonde, R.; Venkatesan, V. Deriving at candidate genes of metabolic stress from pancreas of WNIN/GR-Ob mutant rats. Islets, 2013, 5(4), 133-138.
[41]
Singh, H.; Ganneru, S.; Malakapalli, V.; Chalasani, M.; Nappanveettil, G.; Bhonde, R.R.; Venkatesan, V. Islet adaptation to obesity and insulin resistance in WNIN/GR-Ob rats. Islets, 2014, 6(5-6), e998099.
[42]
Prentki, M.; Nolan, C.J. Islet beta cell failure in type 2 diabetes. J. Clin. Invest., 2006, 116(7), 1802-1812.
[43]
Singh, H.; Venkatesan, V. Treatment of ‘diabesity’: Beyond pharmacotherapy. Curr. Drug Targets, 2018, 19(14), 1672-1682.
[44]
Bansal, V.S.; Raja, C.P.; Venkataraman, K.; Vijayalakshmi, M.A. Genes involved in pancreatic islet cell rejuvenation. Indian J. Med. Res., 2013, 137(4), 695-703.
[45]
Singh, H.; Venkatesan, V. Beta-cell management in type 2 diabetes: beneficial role of nutraceuticals. Endocr. Metab. Immune Disord. Drug Targets, 2016, 16(2), 89-98.
[46]
Pereda, J.; Pérez, S.; Escobar, J.; Arduini, A.; Asensi, M.; Serviddio, G.; Sabater, L.; Aparisi, L.; Sastre, J. Obese rats exhibit high levels of fat necrosis and isoprostanes in taurocholate-induced acute pancreatitis. PLoS One, 2012, 7(9), e44383.
[47]
Grundy, S.M. Adipose tissue and metabolic syndrome: too much, too little or neither. Eur. J. Clin. Invest., 2015, 45(11), 1209-1217.
[48]
Lefebvre, A.M.; Laville, M.; Vega, N.; Riou, J.P.; van Gaal, L.; Auwerx, J.; Vidal, H. Depot-specific differences in adipose tissue gene expression in lean and obese subjects. Diabetes, 1998, 47(1), 98-103.
[49]
Sarjeant, K.; Stephens, J.M. Adipogenesis. Cold Spring Harb. Perspect. Biol., 2012, 4(9), a008417.
[50]
Rosen, E.D.; MacDougald, O.A. Adipocyte differentiation from the inside out. Nat. Rev. Mol. Cell Biol., 2006, 7(12), 885-896.
[51]
Hammad, S.S.; Jones, P.J. Dietary fatty acid composition modulates obesity and interacts with obesity-related genes. Lipids, 2017, 52(10), 803-822.
[52]
Schwartz, M.W.; Porte, D. Jr Diabetes, obesity, and the brain. Science, 2005, 307(5708), 375-379.
[53]
Raji, C.A.; Ho, A.J.; Parikshak, N.N.; Becker, J.T.; Lopez, O.L.; Kuller, L.H.; Hua, X.; Leow, A.D.; Toga, A.W.; Thompson, P.M. Brain structure and obesity. Hum. Brain Mapp., 2010, 31(3), 353-364.
[54]
Sinha, J.K.; Ghosh, S.; Swain, U.; Giridharan, N.V.; Raghunath, M. Increased macromolecular damage due to oxidative stress in the neocortex and hippocampus of WNIN/Ob, a novel rat model of premature aging. Neuroscience, 2014, 269, 256-264.
[55]
Reddy, S.S.; Shruthi, K.; Reddy, V.S.; Raghu, G.; Suryanarayana, P.; Giridharan, N.V.; Reddy, G.B. Altered ubiquitin-proteasome system leads to neuronal cell death in a spontaneous obese rat model. Biochim. Biophys. Acta, 2014, 1840(9), 2924-2934.
[56]
Froy, O. Circadian rhythms and obesity in mammals. ISRN Obes., 2012, 2012437198.
[57]
Turek, F.W.; Joshu, C.; Kohsaka, A.; Lin, E.; Ivanova, G.; McDearmon, E.; Laposky, A.; Losee-Olson, S.; Easton, A.; Jensen, D.R.; Eckel, R.H.; Takahashi, J.S.; Bass, J. Obesity and metabolic syndrome in circadian Clock mutant mice. Science, 2005, 308(5724), 1043-1045.
[58]
Grundy, S.M. Metabolic syndrome: Connecting and reconciling cardiovascular and diabetes worlds. J. Am. Coll. Cardiol., 2006, 47(6), 1093-1100.
[59]
Ebong, I.A.; Goff, D.C., Jr; Rodriguez, C.J.; Chen, H.; Bertoni, A.G. Mechanisms of heart failure in obesity. Obes. Res. Clin. Pract., 2014, 8(6), e540-e548.
[60]
Bugger, H.; Abel, E.D. Molecular mechanisms for myocardial mitochondrial dysfunction in the metabolic syndrome. Clin. Sci. (Lond.), 2008, 114(3), 195-210.
[61]
Laskowski, K.R.; Russell, R.R., III Uncoupling proteins in heart failure. Curr. Heart Fail. Rep., 2008, 5(2), 75-79.
[62]
Kozak, L.P.; Anunciado-Koza, R. UCP1: Its involvement and utility in obesity. Int. J. Obes., 2008, 32(Suppl. 7), S32-S38.
[63]
Bae, M-S.; Han, J-H.; Kim, J-H.; Kim, Y-J.; Lee, K-J.; Kwon, K-Y. The relationship between metabolic syndrome and pulmonary function. Korean J. Fam. Med., 2012, 33(2), 70-78.
[64]
Baffi, C.W.; Wood, L.; Winnica, D.; Strollo, P.J., Jr; Gladwin, M.T.; Que, L.G.; Holguin, F. Metabolic syndrome and the lung. Chest, 2016, 149(6), 1525-1534.
[65]
Singh, S.; Prakash, Y.S.; Linneberg, A.; Agrawal, A. Insulin and the lung: connecting asthma and metabolic syndrome. J. Allergy (Cairo), 2013, 2013627384.
[66]
Kwak, H.J.; Park, D.W.; Seo, J.Y.; Moon, J.Y.; Kim, T.H.; Sohn, J.W.; Shin, D.H.; Yoon, H.J.; Park, S.S.; Kim, S.H. The Wnt/β-catenin signaling pathway regulates the development of airway remodeling in patients with asthma. Exp. Mol. Med., 2015, 47(12), e198.
[67]
Caplan, A.I.; Bruder, S.P. Mesenchymal stem cells: Building blocks for molecular medicine in the 21st century. Trends Mol. Med., 2001, 7(6), 259-264.
[68]
Drewa, T.; Joachimiak, R.; Kaznica, A.; Flisinski, M.; Brymora, A.; Manitius, J. Bone marrow progenitors from animals with chronic renal failure lack capacity of in vitro proliferation. Transplant. Proc., 2008, 40(5), 1668-1673.
[69]
Wang, J.; Xiao, Z. Mesenchymal stem cells in pathogenesis of myelodysplastic syndromes. Stem Cell Investig., 2014, 1(8), 16-19.
[70]
Garayoa, M.; Garcia, J.L.; Santamaria, C.; Garcia-Gomez, A.; Blanco, J.F.; Pandiella, A.; Hernández, J.M.; Sanchez-Guijo, F.M.; del Cañizo, M-C.; Gutiérrez, N.C.; San Miguel, J.F. Mesenchymal stem cells from multiple myeloma patients display distinct genomic profile as compared with those from normal donors. Leukemia, 2009, 23(8), 1515-1527.
[71]
Geyh, S.; Rodríguez-Paredes, M.; Jäger, P.; Khandanpour, C.; Cadeddu, R-P.; Gutekunst, J.; Wilk, C.M.; Fenk, R.; Zilkens, C.; Hermsen, D.; Germing, U.; Kobbe, G.; Lyko, F.; Haas, R.; Schroeder, T. Functional inhibition of mesenchymal stromal cells in acute myeloid leukemia. Leukemia, 2016, 30(3), 683-691.
[72]
Kastrinaki, M-C.; Sidiropoulos, P.; Roche, S.; Ringe, J.; Lehmann, S.; Kritikos, H.; Vlahava, V-M.; Delorme, B.; Eliopoulos, G.D.; Jorgensen, C.; Charbord, P.; Häupl, T.; Boumpas, D.T.; Papadaki, H.A. Functional, molecular and proteomic characterisation of bone marrow mesenchymal stem cells in rheumatoid arthritis. Ann. Rheum. Dis., 2008, 67(6), 741-749.
[73]
Fu, M-H.; Li, C-L.; Lin, H-L.; Chen, P-C.; Calkins, M.J.; Chang, Y-F.; Cheng, P-H.; Yang, S-H. Stem cell transplantation therapy in Parkinson’s disease. Springerplus, 2015, 4(1), 597.
[74]
Coe, L.M.; Irwin, R.; Lippner, D.; McCabe, L.R. The bone marrow microenvironment contributes to type I diabetes induced osteoblast death. J. Cell. Physiol., 2011, 226(2), 477-483.
[75]
Phadnis, S.M.; Ghaskadbi, S.M.; Hardikar, A.A.; Bhonde, R.R. Mesenchymal stem cells derived from bone marrow of diabetic patients portrait unique markers influenced by the diabetic microenvironment. Rev. Diabet. Stud., 2009, 6(4), 260-270.
[76]
Guan, C-C.; Yan, M.; Jiang, X-Q.; Zhang, P.; Zhang, X-L.; Li, J.; Ye, D-X.; Zhang, F-Q. Sonic hedgehog alleviates the inhibitory effects of high glucose on the osteoblastic differentiation of bone marrow stromal cells. Bone, 2009, 45(6), 1146-1152.
[77]
Luo, J-D.; Hu, T-P.; Wang, L.; Chen, M-S.; Liu, S-M.; Chen, A.F. Sonic hedgehog improves delayed wound healing via enhancing cutaneous nitric oxide function in diabetes. Am. J. Physiol. Endocrinol. Metab., 2009, 297(2), E525-E531.
[78]
Thomas, M.K.; Rastalsky, N.; Lee, J.H.; Habener, J.F. Hedgehog signaling regulation of insulin production by pancreatic beta-cells. Diabetes, 2000, 49(12), 2039-2047.
[79]
Dashti, M.; Peppelenbosch, M.P.; Rezaee, F. Hedgehog signalling as an antagonist of ageing and its associated diseases. BioEssays, 2012, 34(10), 849-856.
[80]
Kanda, S.; Mochizuki, Y.; Suematsu, T.; Miyata, Y.; Nomata, K.; Kanetake, H. Sonic hedgehog induces capillary morphogenesis by endothelial cells through phosphoinositide 3-kinase. J. Biol. Chem., 2003, 278(10), 8244-8249.
[81]
Paulis, L.; Fauconnier, J.; Cazorla, O.; Thireau, J.; Soleti, R.; Vidal, B.; Ouillé, A.; Bartholome, M.; Bideaux, P.; Roubille, F.; Le Guennec, J.Y.; Andriantsitohaina, R.; Martínez, M.C.; Lacampagne, A. Activation of Sonic hedgehog signaling in ventricular cardiomyocytes exerts cardioprotection against ischemia reperfusion injuries. Sci. Rep., 2015, 5(1), 7983.
[82]
Matsushita, K.; Dzau, V.J. Mesenchymal stem cells in obesity: Insights for translational applications. Lab. Invest., 2017, 97(10), 1158-1166.
[83]
Almalki, S.G.; Agrawal, D.K. Key transcription factors in the differentiation of mesenchymal stem cells. Differentiation, 2016, 92(1-2), 41-51.
[84]
Godisela, K.K.; Reddy, S.S.; Kumar, C.U.; Saravanan, N.; Reddy, P.Y.; Jablonski, M.M.; Ayyagari, R.; Reddy, G.B. Impact of obesity with impaired glucose tolerance on retinal degeneration in a rat model of metabolic syndrome. Mol. Vis., 2017, 23, 263-274.
[85]
Reddy, P.Y.; Giridharan, N.V.; Reddy, G.B. Activation of sorbitol pathway in metabolic syndrome and increased susceptibility to cataract in Wistar-Obese rats. Mol. Vis., 2012, 18, 495-503.
[86]
Shin, D. Association between metabolic syndrome, radiographic knee osteoarthritis, and intensity of knee pain: results of a national survey. J. Clin. Endocrinol. Metab., 2014, 99(9), 3177-3183.
[87]
Vincent, H.K.; Heywood, K.; Connelly, J.; Hurley, R.W. Obesity and weight loss in the treatment and prevention of osteoarthritis. PM R, 2012, 4(Suppl. 5), S59-S67.
[88]
King, L.K.; March, L.; Anandacoomarasamy, A. Obesity & osteoarthritis. Indian J. Med. Res., 2013, 138(2), 185-193.
[89]
Blanco, F.J.; Rego, I.; Ruiz-Romero, C. The role of mitochondria in osteoarthritis. Nat. Rev. Rheumatol., 2011, 7(3), 161-169.
[90]
Zhuo, Q.; Yang, W.; Chen, J.; Wang, Y. Metabolic syndrome meets osteoarthritis. Nat. Rev. Rheumatol., 2012, 8(12), 729-737.
[91]
Deng, C.; Bianchi, A.; Presle, N.; Moulin, D.; Koufany, M.; Guillaume, C.; Kempf, H.; Pizard, A. Eplerenone treatment alleviates the development of joint lesions in a new rat model of spontaneous metabolic-associated osteoarthritis. Ann. Rheum. Dis., 2018, 77(2), 315-316.


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VOLUME: 19
ISSUE: 4
Year: 2019
Page: [481 - 489]
Pages: 9
DOI: 10.2174/1871530319666181130142642
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