Top

Published in:

01-09-2013

Direct effects of adipokines on the heart: focus on adiponectin

Authors: Min Park, Gary Sweeney

Published in: Heart Failure Reviews | Issue 5/2013

Abstract

Cardiovascular disease, including heart failure, is a principal cause of death in individuals with obesity and diabetes. However, the mechanisms of obesity- and diabetes-induced heart disease are multifaceted and remain to be clearly defined. Of relevance to this review, there is currently great research and clinical interest in the endocrine effects of adipokines on the myocardium and their role in heart failure. We will discuss the potential significance of adipokines in the pathogenesis of heart failure via their ability to regulate remodeling events including metabolism, hypertrophy, fibrosis, and cell death. As an excellent example, we will first focus on adiponectin which is best known to confer numerous cardioprotective effects. However, we comprehensively discuss the existing literature that highlights it would be naive to assume that this was always the case. We also focus on lipocalin-2 which mediates pro-inflammatory and pro-apoptotic effects. It is important when studying actions of adipokines to integrate cellular and mechanistic analyses and translate these to physiologically relevant in vivo models and clinical studies. However, assimilating studies on numerous cardiac remodeling events which ultimately dictate cardiac dysfunction into a unifying conclusion is challenging. Nevertheless, there is undoubted potential for the use of adipokines as robust biomarkers and appropriate therapeutic targets in heart failure.

Gaddam KK, Ventura HO, Lavie CJ (2011) Metabolic syndrome and heart failure–the risk, paradox, and treatment. Curr Hypertens Rep 13(2):142–148. doi:10.1007/s11906-011-0179-x PubMedCrossRef

Mazzone T, Chait A, Plutzky J (2008) Cardiovascular disease risk in type 2 diabetes mellitus: insights from mechanistic studies. Lancet 371(9626):1800–1809. doi:10.1016/S0140-6736(08)60768-0 PubMedCrossRef

Poirier P, Giles TD, Bray GA, Hong Y, Stern JS, Pi-Sunyer FX, Eckel RH (2006) Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss: an update of the 1997 American Heart Association Scientific Statement on Obesity and Heart Disease from the Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism. Circulation 113(6):898–918. doi:10.1161/CIRCULATIONAHA.106.171016 PubMedCrossRef

Anker SD, von Haehling S (2011) The obesity paradox in heart failure: accepting reality and making rational decisions. Clin Pharmacol Ther 90(1):188–190. doi:10.1038/clpt.2011.72 PubMedCrossRef

Abel ED, Litwin SE, Sweeney G (2008) Cardiac remodeling in obesity. Physiol Rev 88(2):389–419PubMedCrossRef

Boudina S, Abel ED (2010) Diabetic cardiomyopathy, causes and effects. Rev Endocr Metab Disord 11(1):31–39. doi:10.1007/s11154-010-9131-7 PubMedCrossRef

Smith CC, Yellon DM (2011) Adipocytokines, cardiovascular pathophysiology and myocardial protection. Pharmacol Ther 129(2):206–219. doi:10.1016/j.pharmthera.2010.09.003 PubMedCrossRef

Walsh K (2009) Adipokines, myokines and cardiovascular disease. Circulation 73(1):13–18CrossRef

Sattar N (2012) Biomarkers for diabetes prediction, pathogenesis or pharmacotherapy guidance? Past, present and future possibilities. Diabet Med J Br Diabet Assoc 29(1):5–13. doi:10.1111/j.1464-5491.2011.03480.x CrossRef

10.

Yanavitski M, Givertz MM (2011) Novel biomarkers in acute heart failure. Curr Heart Fail Rep 8(3):206–211. doi:10.1007/s11897-011-0065-5 PubMedCrossRef

11.

Marette A, Sweeney G (2011) Recent insights in cardiovascular complications of diabetes. Expert Rev Endocrinol Metab 6(5):689–696CrossRef

12.

Abel ED, Sweeney G (2012) Modulation of the cardiovascular system by leptin. Biochimie. doi:10.1016/j.biochi.2012.03.019

13.

Sweeney G (2010) Cardiovascular effects of leptin. Nat Rev Cardiol 7(1):22–29. doi:10.1038/nrcardio.2009.224 PubMedCrossRef

14.

Tycinska AM, Lisowska A, Musial WJ, Sobkowicz B (2012) Apelin in acute myocardial infarction and heart failure induced by ischemia. Clin Chim Acta Int J Clin Chem 413(3–4):406–410. doi:10.1016/j.cca.2011.11.021 CrossRef

15.

Bhalla V, Kalogeropoulos A, Georgiopoulou V, Butler J (2010) Serum resistin: physiology, pathophysiology and implications for heart failure. Biomarkers Med 4(3):445–452. doi:10.2217/bmm.10.17 CrossRef

16.

Xu A, Vanhoutte PM (2012) Adiponectin and adipocyte fatty acid binding protein in the pathogenesis of cardiovascular disease. Am J Physiol Heart Circ Physiol 302(6):H1231–H1240. doi:10.1152/ajpheart.00765.2011 PubMedCrossRef

17.

Fang X, Sweeney G (2006) Mechanisms regulating energy metabolism by adiponectin in obesity and diabetes. Biochem Soc Trans 34(Pt 5):798–801PubMed

18.

Yamauchi T, Kadowaki T (2008) Physiological and pathophysiological roles of adiponectin and adiponectin receptors in the integrated regulation of metabolic and cardiovascular diseases. Int J Obes (Lond) 32(Suppl 7):S13–S18. doi:10.1038/ijo.2008.233 CrossRef

19.

Waki H, Yamauchi T, Kamon J, Kita S, Ito Y, Hada Y, Uchida S, Tsuchida A, Takekawa S, Kadowaki T (2005) Generation of globular fragment of adiponectin by leukocyte elastase secreted by monocytic cell line THP-1. Endocrinology 146(2):790–796PubMedCrossRef

20.

Wang Y, Lam KS, Chan L, Chan KW, Lam JB, Lam MC, Hoo RC, Mak WW, Cooper GJ, Xu A (2006) Post-translational modifications of the four conserved lysine residues within the collagenous domain of adiponectin are required for the formation of its high molecular weight oligomeric complex. J Biol Chem 281(24):16391–16400PubMedCrossRef

21.

Liu Y, Retnakaran R, Hanley A, Tungtrongchitr R, Shaw C, Sweeney G (2007) Total and high molecular weight but not trimeric or hexameric forms of adiponectin correlate with markers of the metabolic syndrome and liver injury in Thai subjects. J Clin Endocrinol Metab 92(11):4313–4318PubMedCrossRef

22.

Hui X, Lam KS, Vanhoutte PM, Xu A (2012) Adiponectin and cardiovascular health: an update. Br J Pharmacol 165(3):574–590. doi:10.1111/j.1476-5381.2011.01395.x PubMedCrossRef

23.

Shetty S, Kusminski CM, Scherer PE (2009) Adiponectin in health and disease: evaluation of adiponectin-targeted drug development strategies. Trends Pharmacol Sci 30(5):234–239PubMedCrossRef

24.

Matsuzawa Y (2010) Adiponectin: a key player in obesity related disorders. Curr Pharm Des 16(17):1896–1901PubMedCrossRef

25.

Ouchi N, Shibata R, Walsh K (2006) Cardioprotection by adiponectin. Trends Cardiovasc Med 16(5):141–146PubMedCrossRef

26.

Ebert T, Fasshauer M (2011) Adiponectin: sometimes good, sometimes bad? Cardiology 118(4):236–237. doi:10.1159/000329647 PubMedCrossRef

27.

Fang X, Palanivel R, Cresser J, Schram K, Ganguly R, Thong FS, Tuinei J, Xu A, Abel ED, Sweeney G (2010) An APPL1-AMPK signaling axis mediates beneficial metabolic effects of adiponectin in the heart. Am J Physiol Endocrinol Metab 299(5):E721–E729. doi:10.1152/ajpendo.00086.2010 PubMedCrossRef

28.

Palanivel R, Fang X, Park M, Eguchi M, Pallan S, De Girolamo S, Liu Y, Wang Y, Xu A, Sweeney G (2007) Globular and full-length forms of adiponectin mediate specific changes in glucose and fatty acid uptake and metabolism in cardiomyocytes. Cardiovasc Res 75(1):148–157PubMedCrossRef

29.

Deepa SS, Dong LQ (2009) APPL1: role in adiponectin signaling and beyond. Am J Physiol Endocrinol Metab 296(1):E22–E36. doi:10.1152/ajpendo.90731.2008 PubMedCrossRef

30.

Leroith D (2012) Pathophysiology of the metabolic syndrome: implications for the cardiometabolic risks associated with type 2 diabetes. Am J Med Sci 343(1):13–16. doi:10.1097/MAJ.0b013e31823ea214 PubMedCrossRef

31.

Despres JP, Cartier A, Cote M, Arsenault BJ (2008) The concept of cardiometabolic risk: bridging the fields of diabetology and cardiology. Ann Med 40(7):514–523. doi:10.1080/07853890802004959 PubMedCrossRef

32.

Ding G, Qin Q, He N, Francis-David SC, Hou J, Liu J, Ricks E, Yang Q (2007) Adiponectin and its receptors are expressed in adult ventricular cardiomyocytes and upregulated by activation of peroxisome proliferator-activated receptor gamma. J Mol Cell Cardiol 43(1):73–84. doi:10.1016/j.yjmcc.2007.04.014 PubMedCrossRef

33.

Pineiro R, Iglesias MJ, Gallego R, Raghay K, Eiras S, Rubio J, Dieguez C, Gualillo O, Gonzalez-Juanatey JR, Lago F (2005) Adiponectin is synthesized and secreted by human and murine cardiomyocytes. FEBS Lett 579(23):5163–5169. doi:10.1016/j.febslet.2005.07.098 PubMedCrossRef

34.

Lopaschuk GD (2008) AMP-activated protein kinase control of energy metabolism in the ischemic heart. Int J Obes (Lond) 32(Suppl 4):S29–S35. doi:10.1038/ijo.2008.120 CrossRef

35.

Onay-Besikci A, Altarejos JY, Lopaschuk GD (2004) gAd-globular head domain of adiponectin increases fatty acid oxidation in newborn rabbit hearts. J Biol Chem 279(43):44320–44326. doi:10.1074/jbc.M400347200 PubMedCrossRef

36.

Kim MS, Wang Y, Rodrigues B (2012) Lipoprotein lipase mediated fatty acid delivery and its impact in diabetic cardiomyopathy. Biochim Biophys Acta 1821(5):800–808. doi:10.1016/j.bbalip.2011.10.001 PubMedCrossRef

37.

Ganguly R, Schram K, Fang X, Kim M, Rodrigues B, Thong FS, Sweeney G (2011) Adiponectin increases LPL activity via RhoA/ROCK-mediated actin remodelling in adult rat cardiomyocytes. Endocrinology 152(1):247–254. doi:10.1210/en.2010-0530 PubMedCrossRef

38.

Peterson LR, Herrero P, Schechtman KB, Racette SB, Waggoner AD, Kisrieva-Ware Z, Dence C, Klein S, Marsala J, Meyer T, Gropler RJ (2004) Effect of obesity and insulin resistance on myocardial substrate metabolism and efficiency in young women. Circulation 109(18):2191–2196. doi:10.1161/01.CIR.0000127959.28627.F8 PubMedCrossRef

39.

Liao Y, Takashima S, Maeda N, Ouchi N, Komamura K, Shimomura I, Hori M, Matsuzawa Y, Funahashi T, Kitakaze M (2005) Exacerbation of heart failure in adiponectin-deficient mice due to impaired regulation of AMPK and glucose metabolism. Cardiovasc Res 67(4):705–713PubMedCrossRef

40.

O’Shea KM, Chess DJ, Khairallah RJ, Rastogi S, Hecker PA, Sabbah HN, Walsh K, Stanley WC (2010) Effects of adiponectin deficiency on structural and metabolic remodeling in mice subjected to pressure overload. Am J Physiol Heart Circ Physiol 298(6):H1639–H1645. doi:10.1152/ajpheart.00957.2009 PubMedCrossRef

41.

Aerts JM, Ottenhoff R, Powlson AS, Grefhorst A, van Eijk M, Dubbelhuis PF, Aten J, Kuipers F, Serlie MJ, Wennekes T, Sethi JK, O’Rahilly S, Overkleeft HS (2007) Pharmacological inhibition of glucosylceramide synthase enhances insulin sensitivity. Diabetes 56(5):1341–1349PubMedCrossRef

42.

Holland WL, Brozinick JT, Wang LP, Hawkins ED, Sargent KM, Liu Y, Narra K, Hoehn KL, Knotts TA, Siesky A, Nelson DH, Karathanasis SK, Fontenot GK, Birnbaum MJ, Summers SA (2007) Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. Cell Metab 5(3):167–179PubMedCrossRef

43.

Cheng KK, Lam KS, Wu D, Wang Y, Sweeney G, Hoo RL, Zhang J, Xu A (2012) APPL1 potentiates insulin secretion in pancreatic beta cells by enhancing protein kinase Akt-dependent expression of SNARE proteins in mice. Proc Natl Acad Sci USA 109(23):8919–24. doi:10.1073/pnas.1202435109

44.

Wang Y, Cheng KK, Lam KS, Wu D, Wang Y, Huang Y, Vanhoutte PM, Sweeney G, Li Y, Xu A (2011) APPL1 counteracts obesity-induced vascular insulin resistance and endothelial dysfunction by modulating the endothelial production of nitric oxide and endothelin-1 in mice. Diabetes 60(11):3044–3054. doi:10.2337/db11-0666 PubMedCrossRef

45.

Bernardo BC, Weeks KL, Pretorius L, McMullen JR (2010) Molecular distinction between physiological and pathological cardiac hypertrophy: experimental findings and therapeutic strategies. Pharmacol Ther 128(1):191–227. doi:10.1016/j.pharmthera.2010.04.005 PubMedCrossRef

46.

Wang C, Li L, Zhang ZG, Fan D, Zhu Y, Wu LL (2010) Globular adiponectin inhibits angiotensin II-induced nuclear factor kappaB activation through AMP-activated protein kinase in cardiac hypertrophy. J Cell Physiol 222(1):149–155. doi:10.1002/jcp.21931 PubMedCrossRef

47.

Amin RH, Mathews ST, Alli A, Leff T (2010) Endogenously produced adiponectin protects cardiomyocytes from hypertrophy by a PPARgamma-dependent autocrine mechanism. Am J Physiol Heart Circ Physiol 299(3):H690–H698. doi:10.1152/ajpheart.01032.2009 PubMedCrossRef

48.

Essick EE, Ouchi N, Wilson RM, Ohashi K, Ghobrial J, Shibata R, Pimentel DR, Sam F (2011) Adiponectin mediates cardioprotection in oxidative stress-induced cardiac myocyte remodeling. Am J Physiol Heart Circ Physiol 301(3):H984–H993. doi:10.1152/ajpheart.00428.2011 PubMedCrossRef

49.

Shimano M, Ouchi N, Shibata R, Ohashi K, Pimentel DR, Murohara T, Walsh K (2010) Adiponectin deficiency exacerbates cardiac dysfunction following pressure overload through disruption of an AMPK-dependent angiogenic response. J Mol Cell Cardiol 49(2):210–220. doi:10.1016/j.yjmcc.2010.02.021 PubMedCrossRef

50.

Shibata R, Izumiya Y, Sato K, Papanicolaou K, Kihara S, Colucci WS, Sam F, Ouchi N, Walsh K (2007) Adiponectin protects against the development of systolic dysfunction following myocardial infarction. J Mol Cell Cardiol 42(6):1065–1074PubMedCrossRef

51.

Shibata R, Ouchi N, Ito M, Kihara S, Shiojima I, Pimentel DR, Kumada M, Sato K, Schiekofer S, Ohashi K, Funahashi T, Colucci WS, Walsh K (2004) Adiponectin-mediated modulation of hypertrophic signals in the heart. Nat Med 10(12):1384–1389PubMedCrossRef

52.

Hecker PA, O’Shea KM, Galvao TF, Brown BH, Stanley WC (2011) Role of adiponectin in the development of high fat diet-induced metabolic abnormalities in mice. Horm Metab Res 43(2):100–105. doi:10.1055/s-0030-1269898 PubMedCrossRef

53.

Denzel MS, Scimia MC, Zumstein PM, Walsh K, Ruiz-Lozano P, Ranscht B (2010) T-cadherin is critical for adiponectin-mediated cardioprotection in mice. J Clin Invest 120(12):4342–4352. doi:10.1172/JCI43464 PubMedCrossRef

54.

Fujita K, Maeda N, Sonoda M, Ohashi K, Hibuse T, Nishizawa H, Nishida M, Hiuge A, Kurata A, Kihara S, Shimomura I, Funahashi T (2008) Adiponectin protects against angiotensin II-induced cardiac fibrosis through activation of PPAR-alpha. Arterioscler Thromb Vasc Biol 28(5):863–870PubMedCrossRef

55.

Kassiotis C, Ballal K, Wellnitz K, Vela D, Gong M, Salazar R, Frazier OH, Taegtmeyer H (2009) Markers of autophagy are downregulated in failing human heart after mechanical unloading. Circulation 120(11 Suppl):S191–S197. doi:10.1161/CIRCULATIONAHA.108.842252 PubMedCrossRef

56.

Chandrashekhar Y (2005) Role of apoptosis in ventricular remodeling. Curr Heart Fail Rep 2(1):18–22PubMedCrossRef

57.

Chiong M, Wang ZV, Pedrozo Z, Cao DJ, Troncoso R, Ibacache M, Criollo A, Nemchenko A, Hill JA, Lavandero S (2011) Cardiomyocyte death: mechanisms and translational implications. Cell Death Dis 2:e244. doi:10.1038/cddis.2011.130 PubMedCrossRef

58.

Baines CP (2011) How and when do myocytes die during ischemia and reperfusion: the late phase. J Cardiovasc Pharmacol Ther 16(3–4):239–243. doi:10.1177/1074248411407769 PubMedCrossRef

59.

Trivedi PS, Barouch LA (2008) Cardiomyocyte apoptosis in animal models of obesity. Curr Hypertens Rep 10(6):454–460PubMedCrossRef

60.

Yarbrough WM, Mukherjee R, Escobar GP, Sample JA, McLean JE, Dowdy KB, Hendrick JW, Gibson WC, Hardin AE, Mingoia JT, White PC, Stiko A, Armstrong RC, Crawford FA, Spinale FG (2003) Pharmacologic inhibition of intracellular caspases after myocardial infarction attenuates left ventricular remodeling: a potentially novel pathway. J Thorac Cardiovasc Surg 126(6):1892–1899PubMedCrossRef

61.

Neviere R, Hassoun SM, Decoster B, Bouazza Y, Montaigne D, Marechal X, Marciniak C, Marchetti P, Lancel S (2010) Caspase-dependent protein phosphatase 2A activation contributes to endotoxin-induced cardiomyocyte contractile dysfunction. Crit Care Med 38(10):2031–2036. doi:10.1097/CCM.0b013e3181eedafb PubMed

62.

Zitvogel L, Kepp O, Galluzzi L, Kroemer G (2012) Inflammasomes in carcinogenesis and anticancer immune responses. Nat Immunol 13(4):343–351. doi:10.1038/ni.2224 PubMedCrossRef

63.

Park M, Youn B, Zheng XL, Wu D, Xu A, Sweeney G (2011) Globular adiponectin, acting via AdipoR1/APPL1, protects H9c2 cells from hypoxia/reoxygenation-induced apoptosis. PLoS ONE 6(4):e19143. doi:10.1371/journal.pone.0019143 PubMedCrossRef

64.

Tao L, Gao E, Jiao X, Yuan Y, Li S, Christopher TA, Lopez BL, Koch W, Chan L, Goldstein BJ, Ma XL (2007) Adiponectin cardioprotection after myocardial ischemia/reperfusion involves the reduction of oxidative/nitrative stress. Circulation 115(11):1408–1416PubMedCrossRef

65.

Yi W, Sun Y, Gao E, Wei X, Lau WB, Zheng Q, Wang Y, Yuan Y, Wang X, Tao L, Li R, Koch W, Ma XL (2011) Reduced cardioprotective action of adiponectin in high-fat diet-induced type II diabetic mice and its underlying mechanisms. Antioxid Redox Signal 15(7):1779–1788. doi:10.1089/ars.2010.3722 PubMedCrossRef

66.

Holland WL, Miller RA, Wang ZV, Sun K, Barth BM, Bui HH, Davis KE, Bikman BT, Halberg N, Rutkowski JM, Wade MR, Tenorio VM, Kuo MS, Brozinick JT, Zhang BB, Birnbaum MJ, Summers SA, Scherer PE (2011) Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin. Nat Med 17(1):55–63. doi:10.1038/nm.2277 PubMedCrossRef

67.

Konishi M, Haraguchi G, Ohigashi H, Ishihara T, Saito K, Nakano Y, Isobe M (2011) Adiponectin protects against doxorubicin-induced cardiomyopathy by anti-apoptotic effects through AMPK up-regulation. Cardiovasc Res 89(2):309–319. doi:10.1093/cvr/cvq335 PubMedCrossRef

68.

Shibata R, Sato K, Pimentel DR, Takemura Y, Kihara S, Ohashi K, Funahashi T, Ouchi N, Walsh K (2005) Adiponectin protects against myocardial ischemia-reperfusion injury through AMPK- and COX-2-dependent mechanisms. Nat Med 11(10):1096–1103PubMedCrossRef

69.

Kondo K, Shibata R, Unno K, Shimano M, Ishii M, Kito T, Shintani S, Walsh K, Ouchi N, Murohara T (2010) Impact of a single intracoronary administration of adiponectin on myocardial ischemia/reperfusion injury in a pig model. Circ Cardiovasc Interv 3(2):166–173. doi:10.1161/CIRCINTERVENTIONS.109.872044 PubMedCrossRef

70.

Yang Z, Klionsky DJ (2010) Eaten alive: a history of macroautophagy. Nat Cell Biol 12(9):814–822. doi:10.1038/ncb0910-814 PubMedCrossRef

71.

Chen Y, Klionsky DJ (2011) The regulation of autophagy—unanswered questions. J Cell Sci 124(Pt 2):161–170. doi:10.1242/jcs.064576 PubMedCrossRef

72.

Dutta D, Calvani R, Bernabei R, Leeuwenburgh C, Marzetti E (2012) Contribution of impaired mitochondrial autophagy to cardiac aging: mechanisms and therapeutic opportunities. Circ Res 110(8):1125–1138. doi:10.1161/CIRCRESAHA.111.246108 PubMedCrossRef

73.

Xie M, Morales CR, Lavandero S, Hill JA (2011) Tuning flux: autophagy as a target of heart disease therapy. Curr Opin Cardiol 26(3):216–222. doi:10.1097/HCO.0b013e328345980a PubMedCrossRef

74.

Mellor KM, Reichelt ME, Delbridge LM (2011) Autophagy anomalies in the diabetic myocardium. Autophagy 7(10):1263–1267. doi:10.4161/auto.7.10.17148 PubMedCrossRef

75.

Dong Y, Undyala VV, Gottlieb RA, Mentzer RM Jr, Przyklenk K (2010) Autophagy: definition, molecular machinery, and potential role in myocardial ischemia-reperfusion injury. J Cardiovasc Pharmacol Ther 15(3):220–230. doi:10.1177/1074248410370327 PubMedCrossRef

76.

Cao DJ, Gillette TG, Hill JA (2009) Cardiomyocyte autophagy: remodeling, repairing, and reconstructing the heart. Curr Hypertens Rep 11(6):406–411PubMedCrossRef

77.

Zhu H, Tannous P, Johnstone JL, Kong Y, Shelton JM, Richardson JA, Le V, Levine B, Rothermel BA, Hill JA (2007) Cardiac autophagy is a maladaptive response to hemodynamic stress. J Clin Invest 117(7):1782–1793. doi:10.1172/JCI27523 PubMedCrossRef

78.

Troncoso R, Vicencio JM, Parra V, Nemchenko A, Kawashima Y, Del Campo A, Toro B, Battiprolu PK, Aranguiz P, Chiong M, Yakar S, Gillette TG, Hill JA, Abel ED, Leroith D, Lavandero S (2012) Energy-preserving effects of IGF-1 antagonize starvation-induced cardiac autophagy. Cardiovasc Res 93(2):320–329. doi:10.1093/cvr/cvr321 PubMedCrossRef

79.

Sugimoto S, Shiomi K, Yamamoto A, Nishino I, Nonaka I, Ohi T (2007) LAMP-2 positive vacuolar myopathy with dilated cardiomyopathy. Intern Med 46(11):757–760PubMedCrossRef

80.

Mihaylova MM, Shaw RJ (2011) The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat Cell Biol 13(9):1016–1023. doi:10.1038/ncb2329 PubMedCrossRef

81.

Habeeb BS, Kitayama J, Nagawa H (2011) Adiponectin supports cell survival in glucose deprivation through enhancement of autophagic response in colorectal cancer cells. Cancer Sci 102(5):999–1006. doi:10.1111/j.1349-7006.2011.01902.x PubMedCrossRef

82.

He C, Bassik MC, Moresi V, Sun K, Wei Y, Zou Z, An Z, Loh J, Fisher J, Sun Q, Korsmeyer S, Packer M, May HI, Hill JA, Virgin HW, Gilpin C, Xiao G, Bassel-Duby R, Scherer PE, Levine B (2012) Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. Nature 481(7382):511–515. doi:10.1038/nature10758 PubMedCrossRef

83.

Aviv Y, Shaw J, Gang H, Kirshenbaum LA (2011) Regulation of autophagy in the heart: “you only live twice”. Antioxid Redox Signal 14(11):2245–2250. doi:10.1089/ars.2010.3479 PubMedCrossRef

84.

Gurusamy N, Das DK (2009) Is autophagy a double-edged sword for the heart? Acta Physiol Hung 96(3):267–276. doi:10.1556/APhysiol.96.2009.3.2 PubMedCrossRef

85.

Fomovsky GM, Thomopoulos S, Holmes JW (2010) Contribution of extracellular matrix to the mechanical properties of the heart. J Mol Cell Cardiol 48(3):490–496. doi:10.1016/j.yjmcc.2009.08.003 PubMedCrossRef

86.

Hutchinson KR, Stewart JA Jr, Lucchesi PA (2010) Extracellular matrix remodeling during the progression of volume overload-induced heart failure. J Mol Cell Cardiol 48(3):564–569. doi:10.1016/j.yjmcc.2009.06.001 PubMedCrossRef

87.

Schram K, Sweeney G (2008) Implications of myocardial matrix remodeling by adipokines in obesity-related heart failure. Trends Cardiovasc Med 18(6):199–205. doi:10.1016/j.tcm.2008.10.001 PubMedCrossRef

88.

Pischon T, Girman CJ, Hotamisligil GS, Rifai N, Hu FB, Rimm EB (2004) Plasma adiponectin levels and risk of myocardial infarction in men. JAMA 291(14):1730–1737PubMedCrossRef

89.

Frystyk J, Berne C, Berglund L, Jensevik K, Flyvbjerg A, Zethelius B (2007) Serum adiponectin is a predictor of coronary heart disease: a population-based 10-year follow-up study in elderly men. J Clin Endocrinol Metab 92(2):571–576PubMedCrossRef

90.

Koenig W, Khuseyinova N, Baumert J, Meisinger C, Lowel H (2006) Serum concentrations of adiponectin and risk of type 2 diabetes mellitus and coronary heart disease in apparently healthy middle-aged men: results from the 18-year follow-up of a large cohort from southern Germany. J Am Coll Cardiol 48(7):1369–1377PubMedCrossRef

91.

Schulze MB, Shai I, Rimm EB, Li T, Rifai N, Hu FB (2005) Adiponectin and future coronary heart disease events among men with type 2 diabetes. Diabetes 54(2):534–539PubMedCrossRef

92.

Laughlin GA, Barrett-Connor E, May S, Langenberg C (2007) Association of adiponectin with coronary heart disease and mortality: the Rancho Bernardo study. Am J Epidemiol 165(2):164–174PubMedCrossRef

93.

Kawano T, Saito T, Yasu T, Nakamura T, Namai K, Tamemoto H, Kawakami M, Saito M, Ishikawa SE (2005) Close association of hypoadiponectinemia with arteriosclerosis obliterans and ischemic heart disease. Metabolism 54(5):653–656PubMedCrossRef

94.

Hong SJ, Park CG, Seo HS, Oh DJ, Ro YM (2004) Associations among plasma adiponectin, hypertension, left ventricular diastolic function and left ventricular mass index. Blood Press 13(4):236–242PubMedCrossRef

95.

Chen WJ, Rijzewijk LJ, van der Meer RW, Heymans MW, van Duinkerken E, Lubberink M, Lammertsma AA, Lamb HJ, de Roos A, Romijn JA, Smit JW, Bax JJ, Bjerre M, Frystyk J, Flyvbjerg A, Diamant M (2011) Association of plasma osteoprotegerin and adiponectin with arterial function, cardiac function and metabolism in asymptomatic type 2 diabetic men. Cardiovasc Diabetol 10:67. doi:10.1186/1475-2840-10-67 PubMedCrossRef

96.

Bidulescu A, Liu J, Musani SK, Fox ER, Samdarshi TE, Sarpong DF, Vaccarino V, Wilson PW, Arnett DK, Din-Dzietham R, Taylor HA, Gibbons GH (2011) Association of adiponectin with left ventricular mass in blacks: the Jackson Heart Study. Circ Heart Fail 4(6):747–753. doi:10.1161/CIRCHEARTFAILURE.110.959742 PubMedCrossRef

97.

Unno K, Shibata R, Izawa H, Hirashiki A, Murase Y, Yamada T, Kobayashi M, Noda A, Nagata K, Ouchi N, Murohara T (2010) Adiponectin acts as a positive indicator of left ventricular diastolic dysfunction in patients with hypertrophic cardiomyopathy. Heart 96(5):357–361. doi:10.1136/hrt.2009.172320 PubMedCrossRef

98.

Kanaya AM, Wassel Fyr C, Vittinghoff E, Havel PJ, Cesari M, Nicklas B, Harris T, Newman AB, Satterfield S, Cummings SR (2006) Serum adiponectin and coronary heart disease risk in older Black and White Americans. J Clin Endocrinol Metab 91(12):5044–5050PubMedCrossRef

99.

George J, Patal S, Wexler D, Sharabi Y, Peleg E, Kamari Y, Grossman E, Sheps D, Keren G, Roth A (2006) Circulating adiponectin concentrations in patients with congestive heart failure. Heart 92(10):1420–1424PubMedCrossRef

100.

Cavusoglu E, Chopra V, Battala V, Ruwende C, Yanamadala S, Eng C, Pinsky DJ, Marmur JD (2008) Baseline plasma adiponectin levels as a predictor of left ventricular systolic dysfunction in patients referred for coronary angiography. Am J Cardiol 101(8):1073–1078. doi:10.1016/j.amjcard.2007.12.008 PubMedCrossRef

101.

McEntegart MB, Awede B, Petrie MC, Sattar N, Dunn FG, MacFarlane NG, McMurray JJ (2007) Increase in serum adiponectin concentration in patients with heart failure and cachexia: relationship with leptin, other cytokines, and B-type natriuretic peptide. Eur Heart J 28(7):829–835. doi:10.1093/eurheartj/ehm033 PubMedCrossRef

102.

Kistorp C, Faber J, Galatius S, Gustafsson F, Frystyk J, Flyvbjerg A, Hildebrandt P (2005) Plasma adiponectin, body mass index, and mortality in patients with chronic heart failure. Circulation 112(12):1756–1762. doi:10.1161/CIRCULATIONAHA.104.530972 PubMedCrossRef

103.

Nakamura T, Funayama H, Kubo N, Yasu T, Kawakami M, Saito M, Momomura S, Ishikawa SE (2006) Association of hyperadiponectinemia with severity of ventricular dysfunction in congestive heart failure. Circulation 70(12):1557–1562CrossRef

104.

Beatty AL, Zhang MH, Ku IA, Na B, Schiller NB, Whooley MA (2012) Adiponectin is associated with increased mortality and heart failure in patients with stable ischemic heart disease: Data from the Heart and Soul Study. Atherosclerosis 220(2):587–92. doi:10.1016/j.atherosclerosis.2011.11.038

105.

Kozakova M, Muscelli E, Flyvbjerg A, Frystyk J, Morizzo C, Palombo C, Ferrannini E (2008) Adiponectin and left ventricular structure and function in healthy adults. J Clin Endocrinol Metab 93(7):2811–2818. doi:10.1210/jc.2007-2580 PubMedCrossRef

106.

Gustafsson S, Lind L, Zethelius B, Venge P, Flyvbjerg A, Soderberg S, Ingelsson E (2010) Adiponectin and cardiac geometry and function in elderly: results from two community-based cohort studies. Eur J Endocrinol 162(3):543–550. doi:10.1530/EJE-09-1006 PubMedCrossRef

107.

Xu A, Chan KW, Hoo RL, Wang Y, Tan KC, Zhang J, Chen B, Lam MC, Tse C, Cooper GJ, Lam KS (2005) Testosterone selectively reduces the high molecular weight form of adiponectin by inhibiting its secretion from adipocytes. J Biol Chem 280(18):18073–18080. doi:10.1074/jbc.M414231200 PubMedCrossRef

108.

Arai Y, Takayama M, Abe Y, Hirose N (2011) Adipokines and aging. J Atheroscler Thromb 18(7):545–550PubMedCrossRef

109.

Kadowaki T, Yamauchi T, Kubota N (2008) The physiological and pathophysiological role of adiponectin and adiponectin receptors in the peripheral tissues and CNS. FEBS Lett 582(1):74–80. doi:10.1016/j.febslet.2007.11.070 PubMedCrossRef

110.

Dadson K, Liu Y, Sweeney G (2011) Adiponectin action: a combination of endocrine and autocrine/paracrine effects. Front Cell Endocrinol 2(62):1–14

111.

Palanivel R, Vu V, Park M, Fang X, Sweeney G (2008) Differential impact of adipokines derived from primary adipocytes of wild-type versus streptozotocin-induced diabetic rats on glucose and fatty acid metabolism in cardiomyocytes. J Endocrinol 199(3):389–397. doi:10.1677/JOE-08-0336 PubMedCrossRef

112.

Fang X, Fetros J, Dadson KE, Xu A, Sweeney G (2009) Leptin prevents the metabolic effects of adiponectin in L6 myotubes. Diabetologia 52(10):2190–2200. doi:10.1007/s00125-009-1462-0 PubMedCrossRef

113.

Yoon JH, Park JK, Oh SS, Lee KH, Kim SK, Cho IJ, Kim JK, Kang HT, Ahn SG, Lee JW, Lee SH, Eom A, Kim JY, Ahn SV, Koh SB (2011) The ratio of serum leptin to adiponectin provides adjunctive information to the risk of metabolic syndrome beyond the homeostasis model assessment insulin resistance: the Korean Genomic Rural Cohort Study. Clin Chim Acta Int J Clin Chem 412(23–24):2199–2205. doi:10.1016/j.cca.2011.08.003 CrossRef

114.

Ebinuma H, Miida T, Yamauchi T, Hada Y, Hara K, Kubota N, Kadowaki T (2007) Improved ELISA for selective measurement of adiponectin multimers and identification of adiponectin in human cerebrospinal fluid. Clin Chem 53(8):1541–1544. doi:10.1373/clinchem.2007.085654 PubMedCrossRef

115.

Lopez L (2009) Advances in echocardiography. Curr Opin Pediatr 21(5):579–584. doi:10.1097/MOP.0b013e32832ff38e PubMedCrossRef

116.

Ohara T, Hashimura K, Asakura M, Ogai A, Amaki M, Hasegawa T, Kanzaki H, Sonoda M, Nishizawa H, Funahashi T, Kitakaze M (2011) Dynamic changes in plasma total and high molecular weight adiponectin levels in acute heart failure. J Cardiol 58(2):181–190. doi:10.1016/j.jjcc.2011.06.010 PubMedCrossRef

117.

Masson S, Gori F, Latini R, Milani V, Flyvbjerg A, Frystyk J, Crociati L, Pietri S, Vago T, Barlera S, Maggioni AP, Tognoni G, Tavazzi L, Omland T, Franzosi MG (2011) Adiponectin in chronic heart failure: influence of diabetes and genetic variants. Eur J Clin Invest 41(12):1330–1338. doi:10.1111/j.1365-2362.2011.02548.x PubMedCrossRef

118.

Pedersen BK, Febbraio MA (2008) Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Phys Rev 88(4):1379–1406. doi:10.1152/physrev.90100.2007 CrossRef

119.

Skurk C, Wittchen F, Suckau L, Witt H, Noutsias M, Fechner H, Schultheiss HP, Poller W (2008) Description of a local cardiac adiponectin system and its deregulation in dilated cardiomyopathy. Eur Heart J 29(9):1168–1180. doi:10.1093/eurheartj/ehn136 PubMedCrossRef

120.

Liao Y, Xuan W, Zhao J, Bin J, Zhao H, Asakura M, Funahashi T, Takashima S, Kitakaze M (2010) Antihypertrophic effects of adiponectin on cardiomyocytes are associated with the inhibition of heparin-binding epidermal growth factor signaling. Biochem Biophys Res Commun 393(3):519–525. doi:10.1016/j.bbrc.2010.02.039 PubMedCrossRef

121.

Haugen E, Furukawa Y, Isic A, Fu M (2008) Increased adiponectin level in parallel with increased NT-pro BNP in patients with severe heart failure in the elderly: a hospital cohort study. Int J Cardiol 125(2):216–219. doi:10.1016/j.ijcard.2007.12.002 PubMedCrossRef

122.

Tsukamoto O, Fujita M, Kato M, Yamazaki S, Asano Y, Ogai A, Okazaki H, Asai M, Nagamachi Y, Maeda N, Shintani Y, Minamino T, Asakura M, Kishimoto I, Funahashi T, Tomoike H, Kitakaze M (2009) Natriuretic peptides enhance the production of adiponectin in human adipocytes and in patients with chronic heart failure. J Am Coll Cardiol 53(22):2070–2077. doi:10.1016/j.jacc.2009.02.038 PubMedCrossRef

123.

Kintscher U (2007) Does adiponectin resistance exist in chronic heart failure? Eur Heart J 28(14):1676–1677. doi:10.1093/eurheartj/ehm233 PubMedCrossRef

124.

Khan RS, Kato TS, Chokshi A, Chew M, Yu S, Wu C, Singh P, Cheema FH, Takayama H, Harris C, Reyes-Soffer G, Knoll R, Milting H, Naka Y, Mancini D, Schulze PC (2012) Adipose tissue inflammation and adiponectin resistance in patients with advanced heart failure: correction after ventricular assist device implantation. Circ Heart Fail 5(3):340–348. doi:10.1161/CIRCHEARTFAILURE.111.964031 PubMedCrossRef

125.

Li R, Lau WB, Ma XL (2010) Adiponectin resistance and vascular dysfunction in the hyperlipidemic state. Acta Pharmacol Sin 31(10):1258–1266. doi:10.1038/aps.2010.95 PubMedCrossRef

126.

Van Berendoncks AM, Garnier A, Beckers P, Hoymans VY, Possemiers N, Fortin D, Van Hoof V, Dewilde S, Vrints CJ, Ventura-Clapier R, Conraads VM (2011) Exercise training reverses adiponectin resistance in skeletal muscle of patients with chronic heart failure. Heart 97(17):1403–1409. doi:10.1136/hrt.2011.226373 PubMedCrossRef

127.

Springer J, Anker SD, Doehner W (2010) Adiponectin resistance in heart failure and the emerging pattern of metabolic failure in chronic heart failure. Circ Heart Fail 3(2):181–182. doi:10.1161/CIRCHEARTFAILURE.110.945063 PubMedCrossRef

128.

Van Berendoncks AM, Garnier A, Beckers P, Hoymans VY, Possemiers N, Fortin D, Martinet W, Van Hoof V, Vrints CJ, Ventura-Clapier R, Conraads VM (2010) Functional adiponectin resistance at the level of the skeletal muscle in mild to moderate chronic heart failure. Circ Heart Fail 3(2):185–194. doi:10.1161/CIRCHEARTFAILURE.109.885525 PubMedCrossRef

129.

Lin HV, Kim JY, Pocai A, Rossetti L, Shapiro L, Scherer PE, Accili D (2007) Adiponectin resistance exacerbates insulin resistance in insulin receptor transgenic/knockout mice. Diabetes 56(8):1969–1976. doi:10.2337/db07-0127 PubMedCrossRef

130.

Mullen KL, Smith AC, Junkin KA, Dyck DJ (2007) Globular adiponectin resistance develops independently of impaired insulin-stimulated glucose transport in soleus muscle from high-fat-fed rats. Am J Physiol Endocrinol Metab 293(1):E83–E90. doi:10.1152/ajpendo.00545.2006 PubMedCrossRef

131.

Fang X, Palanivel R, Zhou X, Liu Y, Xu A, Wang Y, Sweeney G (2005) Hyperglycemia- and hyperinsulinemia-induced alteration of adiponectin receptor expression and adiponectin effects in L6 myoblasts. J Mol Endocrinol 35(3):465–476. doi:10.1677/jme.1.01877 PubMedCrossRef

132.

Van Berendoncks AM, Conraads VM (2011) Functional adiponectin resistance and exercise intolerance in heart failure. Curr Heart Fail Rep 8(2):113–122. doi:10.1007/s11897-011-0056-6 PubMedCrossRef

133.

Wang T, Qiao S, Lei S, Liu Y, Ng KF, Xu A, Lam KS, Irwin MG, Xia Z (2011) N-acetylcysteine and allopurinol synergistically enhance cardiac adiponectin content and reduce myocardial reperfusion injury in diabetic rats. PLoS ONE 6(8):e23967. doi:10.1371/journal.pone.0023967 PubMedCrossRef

134.

Jang Y, Lee JH, Wang Y, Sweeney G (2012) Emerging clinical and experimental evidence for the role of lipocalin-2 in metabolic syndrome. Clin Exp Pharmacol Physiol 39(2):194–199. doi:10.1111/j.1440-1681.2011.05557.x PubMedCrossRef

135.

Wang Y, Lam KS, Kraegen EW, Sweeney G, Zhang J, Tso AW, Chow WS, Wat NM, Xu JY, Hoo RL, Xu A (2007) Lipocalin-2 is an inflammatory marker closely associated with obesity, insulin resistance, and hyperglycemia in humans. Clin Chem 53(1):34–41. doi:10.1373/clinchem.2006.075614 PubMedCrossRef

136.

Law IK, Xu A, Lam KS, Berger T, Mak TW, Vanhoutte PM, Liu JT, Sweeney G, Zhou M, Yang B, Wang Y (2010) Lipocalin-2 deficiency attenuates insulin resistance associated with aging and obesity. Diabetes 59(4):872–882. doi:10.2337/db09-1541 PubMedCrossRef

137.

Latouche C, El Moghrabi S, Messaoudi S, Nguyen Dinh Cat A, Hernandez-Diaz I, Alvarez de la Rosa D, Perret C, Lopez Andres N, Rossignol P, Zannad F, Farman N, Jaisser F (2012) Neutrophil gelatinase-associated lipocalin is a novel mineralocorticoid target in the cardiovascular system. Hypertension 59(5):966–972. doi:10.1161/HYPERTENSIONAHA.111.187872 PubMedCrossRef

138.

Ding L, Hanawa H, Ota Y, Hasegawa G, Hao K, Asami F, Watanabe R, Yoshida T, Toba K, Yoshida K, Ogura M, Kodama M, Aizawa Y (2010) Lipocalin-2/neutrophil gelatinase-B associated lipocalin is strongly induced in hearts of rats with autoimmune myocarditis and in human myocarditis. Circulation 74(3):523–530CrossRef

139.

Choi KM, Lee JS, Kim EJ, Baik SH, Seo HS, Choi DS, Oh DJ, Park CG (2008) Implication of lipocalin-2 and visfatin levels in patients with coronary heart disease. Eur J Endocrinol 158(2):203–207. doi:10.1530/EJE-07-0633 PubMedCrossRef

140.

Aigner F, Maier HT, Schwelberger HG, Wallnofer EA, Amberger A, Obrist P, Berger T, Mak TW, Maglione M, Margreiter R, Schneeberger S, Troppmair J (2007) Lipocalin-2 regulates the inflammatory response during ischemia and reperfusion of the transplanted heart. Am J Transplant 7(4):779–788. doi:10.1111/j.1600-6143.2006.01723.x PubMedCrossRef

141.

Yang B, Fan P, Xu A, Lam KS, Berger T, Mak TW, Tse HF, Yue JW, Song E, Vanhoutte PM, Sweeney G, Wang Y (2012) Improved functional recovery to I/R injury in hearts from lipocalin-2 deficiency mice: restoration of mitochondrial function and phospholipids remodeling. Am J Transl Res 4(1):60–71PubMed

142.

Xu G, Ahn J, Chang S, Eguchi M, Ogier A, Han S, Park Y, Shim C, Jang Y, Yang B, Xu A, Wang Y, Sweeney G (2012) Lipocalin-2 induces cardiomyocyte apoptosis by increasing intracellular iron accumulation. J Biol Chem 287(7):4808–4817. doi:10.1074/jbc.M111.275719 PubMedCrossRef

143.

Murphy CJ, Oudit GY (2010) Iron-overload cardiomyopathy: pathophysiology, diagnosis, and treatment. J Card Fail 16(11):888–900. doi:10.1016/j.cardfail.2010.05.009 PubMedCrossRef

144.

Gujja P, Rosing DR, Tripodi DJ, Shizukuda Y (2010) Iron overload cardiomyopathy: better understanding of an increasing disorder. J Am Coll Cardiol 56(13):1001–1012. doi:10.1016/j.jacc.2010.03.083 PubMedCrossRef

145.

Sommer P, Sweeney G (2010) Functional and mechanistic integration of infection and the metabolic syndrome. Korean Diabetes J 34(2):71–76. doi:10.4093/kdj.2010.34.2.71 PubMedCrossRef

146.

Yndestad A, Landro L, Ueland T, Dahl CP, Flo TH, Vinge LE, Espevik T, Froland SS, Husberg C, Christensen G, Dickstein K, Kjekshus J, Oie E, Gullestad L, Aukrust P (2009) Increased systemic and myocardial expression of neutrophil gelatinase-associated lipocalin in clinical and experimental heart failure. Eur Heart J 30(10):1229–1236. doi:10.1093/eurheartj/ehp088 PubMedCrossRef

147.

Mann DL (2011) The emerging role of innate immunity in the heart and vascular system: for whom the cell tolls. Circ Res 108(9):1133–1145. doi:10.1161/CIRCRESAHA.110.226936 PubMedCrossRef

Title: Direct effects of adipokines on the heart: focus on adiponectin
Authors: Min Park
Gary Sweeney
Publication date: 01-09-2013
Publisher: Springer US
Published in: Heart Failure Reviews / Issue 5/2013
Print ISSN: 1382-4147
Electronic ISSN: 1573-7322
DOI: https://doi.org/10.1007/s10741-012-9337-8

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Direct effects of adipokines on the heart: focus on adiponectin

Abstract

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 5/2013

Metabolic and structural impairment of skeletal muscle in heart failure

Tragic heart, magic art

Introduction to special issue on cardiac metabolism in hypertrophy and failure

1H-MR spectroscopy for analysis of cardiac lipid and creatine metabolism

Autophagy: an affair of the heart

Mitochondrial dysfunction in heart failure

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page