Osteopontin (OPN) is a multifaceted matricellular protein, with well-recognized roles in both the physiological and pathological processes in the body. OPN is expressed in the main organs and cell types, in which it induces different biological actions. During physiological conditioning, OPN acts as both an intracellular protein and soluble excreted cytokine, regulating tissue remodeling and immune-infiltrate in adipose tissue the heart and the kidney. In contrast, the increased expression of OPN has been correlated with the severity of the cardiovascular and renal outcomes associated with obesity. Indeed, OPN expression is at the "cross roads" of visceral fat extension, cardiovascular diseases (CVDs) and renal disorders, in which OPN orchestrates the molecular interactions, leading to chronic low-grade inflammation. The common factor associated with OPN overexpression in adipose, cardiac and renal tissues seems attributable to the concomitant increase in visceral fat size and the increase in infiltrated OPN+ macrophages. This review underlines the current knowledge on the molecular interactions between obesity and the cardiac-renal disorders ruled by OPN.

Department of Biomedical Sciences for Health Università degli Studi di Milano 20133 Milan Italy

Institute of Medical Biochemistry and Laboratory Diagnostic 1st Faculty of Medicine Charles University and General University Hospital Prague 12108 Prague Czech Republic

U O C SMEL 1 of Clinical Pathology IRCCS Policlinico San Donato 20097 San Donato Milanese Italy

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Icer M.A., Gezmen-Karadag M. The multiple functions and mechanisms of osteopontin. Clin. Biochem. 2018;59:17–24. doi: 10.1016/j.clinbiochem.2018.07.003. PubMed DOI

Omar B., Banke E., Guirguis E., Akesson L., Manganiello V., Lyssenko V., Groop L., Gomez M.F., Degerman E. Regulation of the pro-inflammatory cytokine osteopontin by GIP in adipocytes—A role for the transcription factor NFAT and phosphodiesterase 3B. Biochem. Biophys. Res. Commun. 2012;425:812–817. doi: 10.1016/j.bbrc.2012.07.157. PubMed DOI PMC

Frangogiannis N.G. Matricellular proteins in cardiac adaptation and disease. Physiol. Rev. 2012;92:635–688. doi: 10.1152/physrev.00008.2011. PubMed DOI PMC

Mazzali M., Kipari T., Ophascharoensuk V., Wesson J.A., Johnson R., Hughes J. Osteopontin—A molecule for all seasons. QJM. 2002;95:3–13. doi: 10.1093/qjmed/95.1.3. PubMed DOI

Ashkar S., Weber G.F., Panoutsakopoulou V., Sanchirico M.E., Jansson M., Zawaideh S., Rittling S.R., Denhardt D.T., Glimcher M.J., Cantor H. Eta-1 (osteopontin): An early component of type-1 (cell-mediated) immunity. Science. 2000;287:860–864. doi: 10.1126/science.287.5454.860. PubMed DOI

Kazanecki C.C., Uzwiak D.J., Denhardt D.T. Control of osteopontin signaling and function by post-translational phosphorylation and protein folding. J. Cell. Biochem. 2007;102:912–924. doi: 10.1002/jcb.21558. PubMed DOI

Gimba E.R., Tilli T.M. Human osteopontin splicing isoforms: Known roles, potential clinical applications and activated signaling pathways. Cancer Lett. 2013;331:11–17. doi: 10.1016/j.canlet.2012.12.003. PubMed DOI

Viloria K., Hill N.J. Embracing the complexity of matricellular proteins: The functional and clinical significance of splice variation. Biomol. Concepts. 2016;7:117–132. doi: 10.1515/bmc-2016-0004. PubMed DOI

Murphy-Ullrich J.E., Sage E.H. Revisiting the matricellular concept. Matrix Biol. 2014;37:1–14. doi: 10.1016/j.matbio.2014.07.005. PubMed DOI PMC

Morris A.H., Kyriakides T.R. Matricellular proteins and biomaterials. Matrix Biol. 2014;37:183–191. doi: 10.1016/j.matbio.2014.03.002. PubMed DOI PMC

Denhardt D.T., Noda M., O’Regan A.W., Pavlin D., Berman J.S. Osteopontin as a means to cope with environmental insults: Regulation of inflammation, tissue remodeling, and cell survival. J. Clin. Investig. 2001;107:1055–1061. doi: 10.1172/JCI12980. PubMed DOI PMC

Seo K.W., Lee S.J., Ye B.H., Kim Y.W., Bae S.S., Kim C.D. Mechanical stretch enhances the expression and activity of osteopontin and MMP-2 via the Akt1/AP-1 pathways in VSMC. J. Mol. Cell. Cardiol. 2015;85:13–24. doi: 10.1016/j.yjmcc.2015.05.006. PubMed DOI

Pollard C.M., Desimine V.L., Wertz S.L., Perez A., Parker B.M., Maning J., McCrink K.A., Shehadeh L.A., Lymperopoulos A. Deletion of Osteopontin Enhances beta(2)-Adrenergic Receptor-Dependent Anti-Fibrotic Signaling in Cardiomyocytes. Int. J. Mol. Sci. 2019;20:1396. doi: 10.3390/ijms20061396. PubMed DOI PMC

Theocharis A.D., Skandalis S.S., Gialeli C., Karamanos N.K. Extracellular matrix structure. Adv. Drug. Deliv. Rev. 2016;97:4–27. doi: 10.1016/j.addr.2015.11.001. PubMed DOI

Bostan Gayret O., Tasdemir M., Erol M., Tekin Nacaroglu H., Zengi O., Yigit O. Are there any new reliable markers to detect renal injury in obese children? Ren. Fail. 2018;40:416–422. doi: 10.1080/0886022X.2018.1489284. PubMed DOI PMC

Fitter S., Zannettino A.C.W. Osteopontin in the pathophysiology of obesity: Is Opn a fat cell foe? Obes. Res. Clin. Pract. 2018;12:249–250. doi: 10.1016/j.orcp.2018.06.004. PubMed DOI

Schinzari F., Tesauro M., Bertoli A., Valentini A., Veneziani A., Campia U., Cardillo C. Calcification biomarkers and vascular dysfunction in obesity and type 2 diabetes: Influence of oral hypoglycemic agents. Am. J. Physiol. Endocrinol. Metab. 2019;317:E658–E666. doi: 10.1152/ajpendo.00204.2019. PubMed DOI

Wang T., He C. Pro-inflammatory cytokines: The link between obesity and osteoarthritis. Cytokine Growth Factor Rev. 2018;44:38–50. doi: 10.1016/j.cytogfr.2018.10.002. PubMed DOI

Luczak M., Suszynska-Zajczyk J., Marczak L., Formanowicz D., Pawliczak E., Wanic-Kossowska M., Stobiecki M. Label-Free Quantitative Proteomics Reveals Differences in Molecular Mechanism of Atherosclerosis Related and Non-Related to Chronic Kidney Disease. Int. J. Mol. Sci. 2016;17:631. doi: 10.3390/ijms17050631. PubMed DOI PMC

Brankovic M., Martijn Akkerhuis K., Mouthaan H., Constantinescu A., Caliskan K., van Ramshorst J., Germans T., Umans V., Kardys I. Utility of temporal profiles of new cardio-renal and pulmonary candidate biomarkers in chronic heart failure. Int. J. Cardiol. 2019;276:157–165. doi: 10.1016/j.ijcard.2018.08.001. PubMed DOI

Matsuzawa Y. The metabolic syndrome and adipocytokines. FEBS Lett. 2006;580:2917–2921. doi: 10.1016/j.febslet.2006.04.028. PubMed DOI

Sawaki D., Czibik G., Pini M., Ternacle J., Suffee N., Mercedes R., Marcelin G., Surenaud M., Marcos E., Gual P., et al. Visceral Adipose Tissue Drives Cardiac Aging Through Modulation of Fibroblast Senescence by Osteopontin Production. Circulation. 2018;138:809–822. doi: 10.1161/CIRCULATIONAHA.117.031358. PubMed DOI

Singh M., Ananthula S., Milhorn D.M., Krishnaswamy G., Singh K. Osteopontin: A novel inflammatory mediator of cardiovascular disease. Front. Biosci. 2007;12:214–221. doi: 10.2741/2059. PubMed DOI

Singh M., Dalal S., Singh K. Osteopontin: At the cross-roads of myocyte survival and myocardial function. Life Sci. 2014;118:1–6. doi: 10.1016/j.lfs.2014.09.014. PubMed DOI PMC

Yamate T., Kohri K., Umekawa T., Konya E., Ishikawa Y., Iguchi M., Kurita T. Interaction between osteopontin on madin darby canine kidney cell membrane and calcium oxalate crystal. Urol. Int. 1999;62:81–86. doi: 10.1159/000030363. PubMed DOI

Kaleta B. The role of osteopontin in kidney diseases. Inflamm. Res. 2019;68:93–102. doi: 10.1007/s00011-018-1200-5. PubMed DOI

Clemente N., Raineri D., Cappellano G., Boggio E., Favero F., Soluri M.F., Dianzani C., Comi C., Dianzani U., Chiocchetti A. Osteopontin bridging innate and adaptive immunity in autoimmune diseases. J. Immunol. Res. 2016;2016:7675437. doi: 10.1155/2016/7675437. PubMed DOI PMC

Fisher L.W., Torchia D.A., Fohr B., Young M.F., Fedarko N.S. Flexible structures of SIBLING proteins, bone sialoprotein, and osteopontin. Biochem. Biophys. Res. Commun. 2001;280:460–465. doi: 10.1006/bbrc.2000.4146. PubMed DOI

Kiefer F.W., Zeyda M., Todoric J., Huber J., Geyeregger R., Weichhart T., Aszmann O., Ludvik B., Silberhumer G.R., Prager G., et al. Osteopontin expression in human and murine obesity: Extensive local up-regulation in adipose tissue but minimal systemic alterations. Endocrinology. 2008;149:1350–1357. doi: 10.1210/en.2007-1312. PubMed DOI

Herum K.M., Romaine A., Wang A., Melleby A.O., Strand M.E., Pacheco J., Braathen B., Duner P., Tonnessen T., Lunde I.G., et al. Syndecan-4 protects the heart from the profibrotic effects of thrombin-cleaved osteopontin. J. Am. Heart. Assoc. 2020;9:e013518. doi: 10.1161/JAHA.119.013518. PubMed DOI PMC

Gomez-Ambrosi J., Catalan V., Ramirez B., Rodriguez A., Colina I., Silva C., Rotellar F., Mugueta C., Gil M.J., Cienfuegos J.A., et al. Plasma osteopontin levels and expression in adipose tissue are increased in obesity. J. Clin. Endocrinol. Metab. 2007;92:3719–3727. doi: 10.1210/jc.2007-0349. PubMed DOI

Nagaraju C.K., Robinson E.L., Abdesselem M., Trenson S., Dries E., Gilbert G., Janssens S., Van Cleemput J., Rega F., Meyns B., et al. Myofibroblast phenotype and reversibility of fibrosis in patients with end-stage heart failure. J. Am. Coll. Cardiol. 2019;73:2267–2282. doi: 10.1016/j.jacc.2019.02.049. PubMed DOI

Sarosiek K., Jones E., Chipitsyna G., Al-Zoubi M., Kang C., Saxena S., Gandhi A.V., Sendiky J., Yeo C.J., Arafat H.A. Osteopontin (OPN) isoforms, diabetes, obesity, and cancer; what is one got to do with the other? A new role for OPN. J. Gastrointest. Surg. 2015;19:639–650. doi: 10.1007/s11605-014-2735-6. PubMed DOI

Podzimkova J., Palecek T., Kuchynka P., Marek J., Danek B.A., Jachymova M., Kalousova M., Zima T., Linhart A. Plasma osteopontin levels in patients with dilated and hypertrophic cardiomyopathy. Herz. 2019;44:347–353. doi: 10.1007/s00059-017-4645-3. PubMed DOI

Pan W., Liang J., Tang H., Fang X., Wang F., Ding Y., Huang H., Zhang H. Differentially expressed microRNA profiles in exosomes from vascular smooth muscle cells associated with coronary artery calcification. Int. J. Biochem. Cell Biol. 2020;118:105645. doi: 10.1016/j.biocel.2019.105645. PubMed DOI

Crewe C., An Y.A., Scherer P.E. The ominous triad of adipose tissue dysfunction: Inflammation, fibrosis, and impaired angiogenesis. J. Clin. Investig. 2017;127:74–82. doi: 10.1172/JCI88883. PubMed DOI PMC

Lin D., Chun T.H., Kang L. Adipose extracellular matrix remodelling in obesity and insulin resistance. Biochem. Pharmacol. 2016;119:8–16. doi: 10.1016/j.bcp.2016.05.005. PubMed DOI PMC

Lancha A., Rodriguez A., Catalan V., Becerril S., Sainz N., Ramirez B., Burrell M.A., Salvador J., Fruhbeck G., Gomez-Ambrosi J. Osteopontin deletion prevents the development of obesity and hepatic steatosis via impaired adipose tissue matrix remodeling and reduced inflammation and fibrosis in adipose tissue and liver in mice. PLoS ONE. 2014;9:e98398. doi: 10.1371/journal.pone.0098398. PubMed DOI PMC

Schuch K., Wanko B., Ambroz K., Castelo-Rosa A., Moreno-Viedma V., Grun N.G., Leitner L., Staffler G., Zeyda M., Stulnig T.M. Osteopontin affects macrophage polarization promoting endocytic but not inflammatory properties. Obesity. 2016;24:1489–1498. doi: 10.1002/oby.21510. PubMed DOI

Leitner L., Schuch K., Jurets A., Itariu B.K., Keck M., Grablowitz V., Aszmann O.C., Prager G., Staffler G., Zeyda M., et al. Immunological blockade of adipocyte inflammation caused by increased matrix metalloproteinase-cleaved osteopontin in obesity. Obesity. 2015;23:779–785. doi: 10.1002/oby.21024. PubMed DOI

Chen C., Li R., Ross R.S., Manso A.M. Integrins and integrin-related proteins in cardiac fibrosis. J. Mol. Cell. Cardiol. 2016;93:162–174. doi: 10.1016/j.yjmcc.2015.11.010. PubMed DOI PMC

Lindsey M.L., Iyer R.P., Jung M., DeLeon-Pennell K.Y., Ma Y. Matrix metalloproteinases as input and output signals for post-myocardial infarction remodeling. J. Mol. Cell. Cardiol. 2016;91:134–140. doi: 10.1016/j.yjmcc.2015.12.018. PubMed DOI PMC

Lu L., Guo J., Hua Y., Huang K., Magaye R., Cornell J., Kelly D.J., Reid C., Liew D., Zhou Y., et al. Cardiac fibrosis in the ageing heart: Contributors and mechanisms. Clin. Exp. Pharmacol. Physiol. 2017;44:55–63. doi: 10.1111/1440-1681.12753. PubMed DOI

Iyer R.P., Jung M., Lindsey M.L. Using the laws of thermodynamics to understand how matrix metalloproteinases coordinate the myocardial response to injury. Met. Med. 2015;2:75–82. PubMed PMC

Frangogiannis N.G. The extracellular matrix in myocardial injury, repair, and remodeling. J. Clin. Investig. 2017;127:1600–1612. doi: 10.1172/JCI87491. PubMed DOI PMC

Sorop O., Heinonen I., van Kranenburg M., van de Wouw J., de Beer V.J., Nguyen I.T.N., Octavia Y., van Duin R.W.B., Stam K., van Geuns R.J., et al. Multiple common comorbidities produce left ventricular diastolic dysfunction associated with coronary microvascular dysfunction, oxidative stress, and myocardial stiffening. Cardiovasc. Res. 2018;114:954–964. doi: 10.1093/cvr/cvy038. PubMed DOI PMC

Li L., Zhao Q., Kong W. Extracellular matrix remodeling and cardiac fibrosis. Matrix. Biol. 2018;68–69:490–506. doi: 10.1016/j.matbio.2018.01.013. PubMed DOI

Passmore M., Nataatmadja M., Fung Y.L., Pearse B., Gabriel S., Tesar P., Fraser J.F. Osteopontin alters endothelial and valvular interstitial cell behaviour in calcific aortic valve stenosis through HMGB1 regulation. Eur. J. Cardiothorac. Surg. 2015;48:e20–e29. doi: 10.1093/ejcts/ezv244. PubMed DOI

Li G., Qiao W., Zhang W., Li F., Shi J., Dong N. The shift of macrophages toward M1 phenotype promotes aortic valvular calcification. J. Thorac. Cardiovasc. Surg. 2017;153:1318–1327. doi: 10.1016/j.jtcvs.2017.01.052. PubMed DOI

Trostel J., Truong L.D., Roncal-Jimenez C., Miyazaki M., Miyazaki-Anzai S., Kuwabara M., McMahan R., Andres-Hernando A., Sato Y., Jensen T., et al. Different effects of global osteopontin and macrophage osteopontin in glomerular injury. Am. J. Physiol. Renal. Physiol. 2018;315:F759–F768. doi: 10.1152/ajprenal.00458.2017. PubMed DOI PMC

Frangogiannis N.G. Cardiac fibrosis: Cell biological mechanisms, molecular pathways and therapeutic opportunities. Mol. Aspects Med. 2019;65:70–99. doi: 10.1016/j.mam.2018.07.001. PubMed DOI

Toba H., Lindsey M.L. Extracellular matrix roles in cardiorenal fibrosis: Potential therapeutic targets for CVD and CKD in the elderly. Pharm. Ther. 2019;193:99–120. doi: 10.1016/j.pharmthera.2018.08.014. PubMed DOI PMC

Zhang Y., Reif G., Wallace D.P. Extracellular matrix, integrins, and focal adhesion signaling in polycystic kidney disease. Cell. Signal. 2020;72:109646. doi: 10.1016/j.cellsig.2020.109646. PubMed DOI PMC

Feng D., Ngov C., Henley N., Boufaied N., Gerarduzzi C. Characterization of matricellular protein expression signatures in mechanistically diverse mouse models of kidney injury. Sci. Rep. 2019;9:16736. doi: 10.1038/s41598-019-52961-5. PubMed DOI PMC

Nogueira A., Pires M.J., Oliveira P.A. Pathophysiological mechanisms of renal fibrosis: A review of animal models and therapeutic strategies. Vivo. 2017;31:1–22. doi: 10.21873/invivo.11019. PubMed DOI PMC

Zeyda M., Gollinger K., Todoric J., Kiefer F.W., Keck M., Aszmann O., Prager G., Zlabinger G.J., Petzelbauer P., Stulnig T.M. Osteopontin is an activator of human adipose tissue macrophages and directly affects adipocyte function. Endocrinology. 2011;152:2219–2227. doi: 10.1210/en.2010-1328. PubMed DOI

Nomiyama T., Perez-Tilve D., Ogawa D., Gizard F., Zhao Y., Heywood E.B., Jones K.L., Kawamori R., Cassis L.A., Tschop M.H., et al. Osteopontin mediates obesity-induced adipose tissue macrophage infiltration and insulin resistance in mice. J. Clin. Investig. 2007;117:2877–2888. doi: 10.1172/JCI31986. PubMed DOI PMC

West M. Dead adipocytes and metabolic dysfunction: Recent progress. Curr. Opin. Endocrinol. Diabetes Obes. 2009;16:178–182. doi: 10.1097/MED.0b013e3283292327. PubMed DOI

Dort J., Fabre P., Molina T., Dumont N.A. Macrophages are key regulators of stem cells during skeletal muscle regeneration and diseases. Stem. Cells. Int. 2019;2019:4761427. doi: 10.1155/2019/4761427. PubMed DOI PMC

Zuo L., Tozawa K., Okada A., Yasui T., Taguchi K., Ito Y., Hirose Y., Fujii Y., Niimi K., Hamamoto S., et al. A paracrine mechanism involving renal tubular cells, adipocytes and macrophages promotes kidney stone formation in a simulated metabolic syndrome environment. J. Urol. 2014;191:1906–1912. doi: 10.1016/j.juro.2014.01.013. PubMed DOI

Aouadi M., Tencerova M., Vangala P., Yawe J.C., Nicoloro S.M., Amano S.U., Cohen J.L., Czech M.P. Gene silencing in adipose tissue macrophages regulates whole-body metabolism in obese mice. Proc. Natl. Acad. Sci. USA. 2013;110:8278–8283. doi: 10.1073/pnas.1300492110. PubMed DOI PMC

Prieur X., Mok C.Y., Velagapudi V.R., Nunez V., Fuentes L., Montaner D., Ishikawa K., Camacho A., Barbarroja N., O’Rahilly S., et al. Differential lipid partitioning between adipocytes and tissue macrophages modulates macrophage lipotoxicity and M2/M1 polarization in obese mice. Diabetes. 2011;60:797–809. doi: 10.2337/db10-0705. PubMed DOI PMC

Luna-Luna M., Medina-Urrutia A., Vargas-Alarcon G., Coss-Rovirosa F., Vargas-Barron J., Perez-Mendez O. Adipose tissue in metabolic syndrome: Onset and progression of atherosclerosis. Arch. Med. Res. 2015;46:392–407. doi: 10.1016/j.arcmed.2015.05.007. PubMed DOI

Luna-Luna M., Cruz-Robles D., Avila-Vanzzini N., Herrera-Alarcon V., Martinez-Reding J., Criales-Vera S., Sandoval-Zarate J., Vargas-Barron J., Martinez-Sanchez C., Tovar-Palacio A.R., et al. Differential expression of osteopontin, and osteoprotegerin mRNA in epicardial adipose tissue between patients with severe coronary artery disease and aortic valvular stenosis: Association with HDL subclasses. Lipids Health Dis. 2017;16:156. doi: 10.1186/s12944-017-0550-2. PubMed DOI PMC

Chapman J., Miles P.D., Ofrecio J.M., Neels J.G., Yu J.G., Resnik J.L., Wilkes J., Talukdar S., Thapar D., Johnson K., et al. Osteopontin is required for the early onset of high fat diet-induced insulin resistance in mice. PLoS ONE. 2010;5:e13959. doi: 10.1371/journal.pone.0013959. PubMed DOI PMC

Kahles F., Findeisen H.M. Does osteopontin induce adipose tissue inflammation by local macrophage proliferation? Mol. Metab. 2016;5:1147–1148. doi: 10.1016/j.molmet.2016.10.002. PubMed DOI PMC

Kahles F., Findeisen H.M., Bruemmer D. Osteopontin: A novel regulator at the cross roads of inflammation, obesity and diabetes. Mol. Metab. 2014;3:384–393. doi: 10.1016/j.molmet.2014.03.004. PubMed DOI PMC

Mohamed I.A., Mraiche F. Targeting osteopontin, the silent partner of Na+/H+ exchanger isoform 1 in cardiac remodeling. J. Cell. Physiol. 2015;230:2006–2018. doi: 10.1002/jcp.24958. PubMed DOI

Landecho M.F., Tuero C., Valenti V., Bilbao I., de la Higuera M., Fruhbeck G. Relevance of leptin and other adipokines in obesity-associated cardiovascular risk. Nutrients. 2019;11:2664. doi: 10.3390/nu11112664. PubMed DOI PMC

Rubis P., Wisniowska-Smialek S., Dziewiecka E., Rudnicka-Sosin L., Kozanecki A., Podolec P. Prognostic value of fibrosis-related markers in dilated cardiomyopathy: A link between osteopontin and cardiovascular events. Adv. Med. Sci. 2018;63:160–166. doi: 10.1016/j.advms.2017.10.004. PubMed DOI

Yousefi K., Irion C.I., Takeuchi L.M., Ding W., Lambert G., Eisenberg T., Sukkar S., Granzier H.L., Methawasin M., Lee D.I., et al. Osteopontin promotes left ventricular diastolic dysfunction through a mitochondrial pathway. J. Am. Coll. Cardiol. 2019;73:2705–2718. doi: 10.1016/j.jacc.2019.02.074. PubMed DOI PMC

Coculescu B.I., Manole G., Dinca G.V., Coculescu E.C., Berteanu C., Stocheci C.M. Osteopontin-a biomarker of disease, but also of stage stratification of the functional myocardial contractile deficit by chronic ischaemic heart disease. J. Enzyme. Inhib. Med. Chem. 2019;34:783–788. doi: 10.1080/14756366.2019.1587418. PubMed DOI PMC

Matloch Z., Cinkajzlova A., Mraz M., Haluzik M. The role of inflammation in epicardial adipose tissue in heart diseases. Curr. Pharm. Des. 2018;24:297–309. doi: 10.2174/1381612824666180110102125. PubMed DOI

Iacobellis G., Lonn E., Lamy A., Singh N., Sharma A.M. Epicardial fat thickness and coronary artery disease correlate independently of obesity. Int. J. Cardiol. 2011;146:452–454. doi: 10.1016/j.ijcard.2010.10.117. PubMed DOI

Iacobellis G., Bianco A.C. Epicardial adipose tissue: Emerging physiological, pathophysiological and clinical features. Trends Endocrinol. Metab. 2011;22:450–457. doi: 10.1016/j.tem.2011.07.003. PubMed DOI PMC

Vianello E., Dozio E., Arnaboldi F., Marazzi M.G., Martinelli C., Lamont J., Tacchini L., Sigruner A., Schmitz G., Corsi Romanelli M.M. Epicardial adipocyte hypertrophy: Association with M1-polarization and toll-like receptor pathways in coronary artery disease patients. Nutr. Metab. Cardiovasc. Dis. 2016;26:246–253. doi: 10.1016/j.numecd.2015.12.005. PubMed DOI

Villasante Fricke A.C., Iacobellis G. Epicardial adipose tissue: Clinical biomarker of cardio-metabolic risk. Int. J. Mol. Sci. 2019;20:5989. doi: 10.3390/ijms20235989. PubMed DOI PMC

Tardelli M., Zeyda K., Moreno-Viedma V., Wanko B., Grun N.G., Staffler G., Zeyda M., Stulnig T.M. Osteopontin is a key player for local adipose tissue macrophage proliferation in obesity. Mol. Metab. 2016;5:1131–1137. doi: 10.1016/j.molmet.2016.09.003. PubMed DOI PMC

Pierzynova A., Sramek J., Cinkajzlova A., Kratochvilova H., Lindner J., Haluzik M., Kucera T. The number and phenotype of myocardial and adipose tissue CD68+ cells is associated with cardiovascular and metabolic disease in heart surgery patients. Nutr. Metab. Cardiovasc. Dis. 2019;29:946–955. doi: 10.1016/j.numecd.2019.05.063. PubMed DOI

Madaro L., Passafaro M., Sala D., Etxaniz U., Lugarini F., Proietti D., Alfonsi M.V., Nicoletti C., Gatto S., De Bardi M., et al. Denervation-activated STAT3-IL-6 signalling in fibro-adipogenic progenitors promotes myofibres atrophy and fibrosis. Nat. Cell. Biol. 2018;20:917–927. doi: 10.1038/s41556-018-0151-y. PubMed DOI PMC

Lombardi R., Chen S.N., Ruggiero A., Gurha P., Czernuszewicz G.Z., Willerson J.T., Marian A.J. Cardiac fibro-adipocyte progenitors express desmosome proteins and preferentially differentiate to adipocytes upon deletion of the desmoplakin gene. Circ. Res. 2016;119:41–54. doi: 10.1161/CIRCRESAHA.115.308136. PubMed DOI PMC

Capote J., Kramerova I., Martinez L., Vetrone S., Barton E.R., Sweeney H.L., Miceli M.C., Spencer M.J. Osteopontin ablation ameliorates muscular dystrophy by shifting macrophages to a pro-regenerative phenotype. J. Cell. Biol. 2016;213:275–288. doi: 10.1083/jcb.201510086. PubMed DOI PMC

Singh M., Foster C.R., Dalal S., Singh K. Role of osteopontin in heart failure associated with aging. Heart Fail. Rev. 2010;15:487–494. doi: 10.1007/s10741-010-9158-6. PubMed DOI

Uezumi A., Ito T., Morikawa D., Shimizu N., Yoneda T., Segawa M., Yamaguchi M., Ogawa R., Matev M.M., Miyagoe-Suzuki Y., et al. Fibrosis and adipogenesis originate from a common mesenchymal progenitor in skeletal muscle. J. Cell. Sci. 2011;124:3654–3664. doi: 10.1242/jcs.086629. PubMed DOI

Berezin A.E., Kremzer A.A. Circulating osteopontin as a marker of early coronary vascular calcification in type two diabetes mellitus patients with known asymptomatic coronary artery disease. Atherosclerosis. 2013;229:475–481. doi: 10.1016/j.atherosclerosis.2013.06.003. PubMed DOI

Iglesias P., Diez J.J. Adipose tissue in renal disease: Clinical significance and prognostic implications. Nephrol. Dial. Transplant. 2010;25:2066–2077. doi: 10.1093/ndt/gfq246. PubMed DOI

Xie Z., Singh M., Singh K. Osteopontin modulates myocardial hypertrophy in response to chronic pressure overload in mice. Hypertension. 2004;44:826–831. doi: 10.1161/01.HYP.0000148458.03202.48. PubMed DOI

Wajchenberg B.L., Giannella-Neto D., da Silva M.E., Santos R.F. Depot-specific hormonal characteristics of subcutaneous and visceral adipose tissue and their relation to the metabolic syndrome. Horm. Metab. Res. 2002;34:616–621. doi: 10.1055/s-2002-38256. PubMed DOI

Wajchenberg B.L. Subcutaneous and visceral adipose tissue: Their relation to the metabolic syndrome. Endocr. Rev. 2000;21:697–738. doi: 10.1210/edrv.21.6.0415. PubMed DOI

Mulyadi L., Stevens C., Munro S., Lingard J., Bermingham M. Body fat distribution and total body fat as risk factors for microalbuminuria in the obese. Ann. Nutr. Metab. 2001;45:67–71. doi: 10.1159/000046708. PubMed DOI

Toita R., Kawano T., Murata M., Kang J.H. Anti-obesity and anti-inflammatory effects of macrophage-targeted interleukin-10-conjugated liposomes in obese mice. Biomaterials. 2016;110:81–88. doi: 10.1016/j.biomaterials.2016.09.018. PubMed DOI