Diabetes Metab J.  2013 Dec;37(6):404-414. 10.4093/dmj.2013.37.6.404.

Resistin in Rodents and Humans

• Park HK
• Ahima RS

• KMID: 2174221
• DOI: http://doi.org/10.4093/dmj.2013.37.6.404

Abstract

Obesity is characterized by excess accumulation of lipids in adipose tissue and other organs, and chronic inflammation associated with insulin resistance and an increased risk of type 2 diabetes. Obesity, type 2 diabetes, and cardiovascular diseases are major health concerns. Resistin was first discovered as an adipose-secreted hormone (adipokine) linked to obesity and insulin resistance in rodents. Adipocyte-derived resistin is increased in obese rodents and strongly related to insulin resistance. However, in contrast to rodents, resistin is expressed and secreted from macrophages in humans and is increased in inflammatory conditions. Some studies have also suggested an association between increased resistin levels and insulin resistance, diabetes and cardiovascular disease. Genetic studies have provided additional evidence for a role of resistin in insulin resistance and inflammation. Resistin appears to mediate the pathogenesis of atherosclerosis by promoting endothelial dysfunction, vascular smooth muscle cell proliferation, arterial inflammation, and formation of foam cells. Indeed, resistin is predictive of atherosclerosis and poor clinical outcomes in patients with coronary artery disease and ischemic stroke. There is also growing evidence that elevated resistin is associated with the development of heart failure. This review will focus on the biology of resistin in rodents and humans, and evidence linking resistin with type 2 diabetes, atherosclerosis, and cardiovascular disease.

Keyword

Adipocytes; Atherosclerosis; Cardiovascular diseases; Diabetes mellitus, type 2; Inflammation; Insulin resistance; Macrophages; Obesity; Polymorphism, genetic; Resistin

MeSH Terms

Adipocytes
Adipose Tissue
Arteritis
Atherosclerosis
Biology
Cardiovascular Diseases
Cell Proliferation
Coronary Artery Disease
Diabetes Mellitus, Type 2
Foam Cells
Heart Failure
Humans*
Inflammation
Insulin Resistance
Macrophages
Muscle, Smooth, Vascular
Obesity
Polymorphism, Genetic
Resistin*
Rodentia*
Stroke
Resistin

Figure

• 

  Fig. 1 Roles of resistin in inflammation, glucose homeostasis, and cardiovascular diseases. Resistin is induced in response to various stimuli, including proinflammatory cytokines, lipopolysaccharide (LPS), and genetically determined factors. Resistin targets several types of cells, promoting inflammation, insulin resistance, and atherosclerosis. Resistin is up-regulated and secreted from PBMC and macrophages, and in turn, acts on these cells, leading to the development of insulin resistance and enhancing inflammatory processes through activation of nuclear factor (NF)-κB. Resistin contributes to the pathogenesis of atherosclerosis by disrupting vascular endothelial cellular function, and increasing proliferation of smooth muscle cells, and foam cell transformation. Resistin directly affects the function of cardiomyocytes predisposing to myocardial injury. Adapted from Schwartz et al. Trends Endocrinol Metab 2011;22:259-65, with permission from Elsevier [55]. HSC, hepatic stellate cell; MCP, monocyte chemoattractant protein; IL, interleukin; TNF, tumor necrosis factor; PBMC, peripheral blood mononuclear cell; ICAM, intercellular adhesion molecule; VCAM, vascular cell adhesion molecule; ET, endothelin; VSMC, vascular smooth muscle cell; ERK, extracellular signal-regulated kinase; PI3K, phosphatidylinositol-3-kinase; MAPK, mitogen-activated protein kinase; TZD, thiazolidinedione.

Reference

1. Kahn SE, Hull RL, Utzschneider KM. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature. 2006; 444:840–846.

2. Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA. The hormone resistin links obesity to diabetes. Nature. 2001; 409:307–312.

3. Patel L, Buckels AC, Kinghorn IJ, Murdock PR, Holbrook JD, Plumpton C, Macphee CH, Smith SA. Resistin is expressed in human macrophages and directly regulated by PPAR gamma activators. Biochem Biophys Res Commun. 2003; 300:472–476.

4. Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006; 444:860–867.

5. Shojima N, Sakoda H, Ogihara T, Fujishiro M, Katagiri H, Anai M, Onishi Y, Ono H, Inukai K, Abe M, Fukushima Y, Kikuchi M, Oka Y, Asano T. Humoral regulation of resistin expression in 3T3-L1 and mouse adipose cells. Diabetes. 2002; 51:1737–1744.

6. Hartman HB, Hu X, Tyler KX, Dalal CK, Lazar MA. Mechanisms regulating adipocyte expression of resistin. J Biol Chem. 2002; 277:19754–19761.

7. Haugen F, Jorgensen A, Drevon CA, Trayhurn P. Inhibition by insulin of resistin gene expression in 3T3-L1 adipocytes. FEBS Lett. 2001; 507:105–108.

8. Rajala MW, Lin Y, Ranalletta M, Yang XM, Qian H, Gingerich R, Barzilai N, Scherer PE. Cell type-specific expression and coregulation of murine resistin and resistin-like molecule-alpha in adipose tissue. Mol Endocrinol. 2002; 16:1920–1930.

9. Zhong Q, Lin CY, Clarke KJ, Kemppainen RJ, Schwartz DD, Judd RL. Endothelin-1 inhibits resistin secretion in 3T3-L1 adipocytes. Biochem Biophys Res Commun. 2002; 296:383–387.

10. Wolfing B, Neumeier M, Buechler C, Aslanidis C, Scholmerich J, Schaffler A. Interfering effects of insulin, growth hormone and glucose on adipokine secretion. Exp Clin Endocrinol Diabetes. 2008; 116:47–52.

11. Pang SS, Le YY. Role of resistin in inflammation and inflammation-related diseases. Cell Mol Immunol. 2006; 3:29–34.

12. Fasshauer M, Klein J, Neumann S, Eszlinger M, Paschke R. Tumor necrosis factor alpha is a negative regulator of resistin gene expression and secretion in 3T3-L1 adipocytes. Biochem Biophys Res Commun. 2001; 288:1027–1031.

13. Kaser S, Kaser A, Sandhofer A, Ebenbichler CF, Tilg H, Patsch JR. Resistin messenger-RNA expression is increased by proinflammatory cytokines in vitro. Biochem Biophys Res Commun. 2003; 309:286–290.

14. Lehrke M, Reilly MP, Millington SC, Iqbal N, Rader DJ, Lazar MA. An inflammatory cascade leading to hyperresistinemia in humans. PLoS Med. 2004; 1:e45.

15. Tomaru T, Steger DJ, Lefterova MI, Schupp M, Lazar MA. Adipocyte-specific expression of murine resistin is mediated by synergism between peroxisome proliferator-activated receptor gamma and CCAAT/enhancer-binding proteins. J Biol Chem. 2009; 284:6116–6125.

16. Rajala MW, Qi Y, Patel HR, Takahashi N, Banerjee R, Pajvani UB, Sinha MK, Gingerich RL, Scherer PE, Ahima RS. Regulation of resistin expression and circulating levels in obesity, diabetes, and fasting. Diabetes. 2004; 53:1671–1679.

17. Barnes KM, Miner JL. Role of resistin in insulin sensitivity in rodents and humans. Curr Protein Pept Sci. 2009; 10:96–107.

18. Patel SD, Rajala MW, Rossetti L, Scherer PE, Shapiro L. Disulfide-dependent multimeric assembly of resistin family hormones. Science. 2004; 304:1154–1158.

19. Graveleau C, Zaha VG, Mohajer A, Banerjee RR, Dudley-Rucker N, Steppan CM, Rajala MW, Scherer PE, Ahima RS, Lazar MA, Abel ED. Mouse and human resistins impair glucose transport in primary mouse cardiomyocytes, and oligomerization is required for this biological action. J Biol Chem. 2005; 280:31679–31685.

20. Gerber M, Boettner A, Seidel B, Lammert A, Bar J, Schuster E, Thiery J, Kiess W, Kratzsch J. Serum resistin levels of obese and lean children and adolescents: biochemical analysis and clinical relevance. J Clin Endocrinol Metab. 2005; 90:4503–4509.

21. Aruna B, Islam A, Ghosh S, Singh AK, Vijayalakshmi M, Ahmad F, Ehtesham NZ. Biophysical analyses of human resistin: oligomer formation suggests novel biological function. Biochemistry. 2008; 47:12457–12466.

22. Filkova M, Haluzik M, Gay S, Senolt L. The role of resistin as a regulator of inflammation: implications for various human pathologies. Clin Immunol. 2009; 133:157–170.

23. Rajala MW, Obici S, Scherer PE, Rossetti L. Adipose-derived resistin and gut-derived resistin-like molecule-beta selectively impair insulin action on glucose production. J Clin Invest. 2003; 111:225–230.

24. Muse ED, Obici S, Bhanot S, Monia BP, McKay RA, Rajala MW, Scherer PE, Rossetti L. Role of resistin in diet-induced hepatic insulin resistance. J Clin Invest. 2004; 114:232–239.

25. Li FP, He J, Li ZZ, Luo ZF, Yan L, Li Y. Effects of resistin expression on glucose metabolism and hepatic insulin resistance. Endocrine. 2009; 35:243–251.

26. Banerjee RR, Rangwala SM, Shapiro JS, Rich AS, Rhoades B, Qi Y, Wang J, Rajala MW, Pocai A, Scherer PE, Steppan CM, Ahima RS, Obici S, Rossetti L, Lazar MA. Regulation of fasted blood glucose by resistin. Science. 2004; 303:1195–1198.

27. Qi Y, Nie Z, Lee YS, Singhal NS, Scherer PE, Lazar MA, Ahima RS. Loss of resistin improves glucose homeostasis in leptin deficiency. Diabetes. 2006; 55:3083–3090.

28. Palanivel R, Maida A, Liu Y, Sweeney G. Regulation of insulin signalling, glucose uptake and metabolism in rat skeletal muscle cells upon prolonged exposure to resistin. Diabetologia. 2006; 49:183–190.

29. Fan HQ, Gu N, Liu F, Fei L, Pan XQ, Guo M, Chen RH, Guo XR. Prolonged exposure to resistin inhibits glucose uptake in rat skeletal muscles. Acta Pharmacol Sin. 2007; 28:410–416.

30. Daquinag AC, Zhang Y, Amaya-Manzanares F, Simmons PJ, Kolonin MG. An isoform of decorin is a resistin receptor on the surface of adipose progenitor cells. Cell Stem Cell. 2011; 9:74–86.

31. Sanchez-Solana B, Laborda J, Baladron V. Mouse resistin modulates adipogenesis and glucose uptake in 3T3-L1 preadipocytes through the ROR1 receptor. Mol Endocrinol. 2012; 26:110–127.

32. Satoh H, Nguyen MT, Miles PD, Imamura T, Usui I, Olefsky JM. Adenovirus-mediated chronic "hyper-resistinemia" leads to in vivo insulin resistance in normal rats. J Clin Invest. 2004; 114:224–231.

33. Steppan CM, Wang J, Whiteman EL, Birnbaum MJ, Lazar MA. Activation of SOCS-3 by resistin. Mol Cell Biol. 2005; 25:1569–1575.

34. Muse ED, Lam TK, Scherer PE, Rossetti L. Hypothalamic resistin induces hepatic insulin resistance. J Clin Invest. 2007; 117:1670–1678.

35. Lazar MA. Resistin- and Obesity-associated metabolic diseases. Horm Metab Res. 2007; 39:710–716.

36. Savage DB, Sewter CP, Klenk ES, Segal DG, Vidal-Puig A, Considine RV, O'Rahilly S. Resistin / Fizz3 expression in relation to obesity and peroxisome proliferator-activated receptor-gamma action in humans. Diabetes. 2001; 50:2199–2202.

37. Samaha FF, Szapary PO, Iqbal N, Williams MM, Bloedon LT, Kochar A, Wolfe ML, Rader DJ. Effects of rosiglitazone on lipids, adipokines, and inflammatory markers in nondiabetic patients with low high-density lipoprotein cholesterol and metabolic syndrome. Arterioscler Thromb Vasc Biol. 2006; 26:624–630.

38. Fain JN, Cheema PS, Bahouth SW, Lloyd Hiler M. Resistin release by human adipose tissue explants in primary culture. Biochem Biophys Res Commun. 2003; 300:674–678.

39. Bertolani C, Sancho-Bru P, Failli P, Bataller R, Aleffi S, DeFranco R, Mazzinghi B, Romagnani P, Milani S, Gines P, Colmenero J, Parola M, Gelmini S, Tarquini R, Laffi G, Pinzani M, Marra F. Resistin as an intrahepatic cytokine: overexpression during chronic injury and induction of proinflammatory actions in hepatic stellate cells. Am J Pathol. 2006; 169:2042–2053.

40. Burnett MS, Lee CW, Kinnaird TD, Stabile E, Durrani S, Dullum MK, Devaney JM, Fishman C, Stamou S, Canos D, Zbinden S, Clavijo LC, Jang GJ, Andrews JA, Zhu J, Epstein SE. The potential role of resistin in atherogenesis. Atherosclerosis. 2005; 182:241–248.

41. Jung HS, Park KH, Cho YM, Chung SS, Cho HJ, Cho SY, Kim SJ, Kim SY, Lee HK, Park KS. Resistin is secreted from macrophages in atheromas and promotes atherosclerosis. Cardiovasc Res. 2006; 69:76–85.

42. Pagano C, Marin O, Calcagno A, Schiappelli P, Pilon C, Milan G, Bertelli M, Fanin E, Andrighetto G, Federspil G, Vettor R. Increased serum resistin in adults with prader-willi syndrome is related to obesity and not to insulin resistance. J Clin Endocrinol Metab. 2005; 90:4335–4340.

43. Azuma K, Katsukawa F, Oguchi S, Murata M, Yamazaki H, Shimada A, Saruta T. Correlation between serum resistin level and adiposity in obese individuals. Obes Res. 2003; 11:997–1001.

44. Moschen AR, Molnar C, Wolf AM, Weiss H, Graziadei I, Kaser S, Ebenbichler CF, Stadlmann S, Moser PL, Tilg H. Effects of weight loss induced by bariatric surgery on hepatic adipocytokine expression. J Hepatol. 2009; 51:765–777.

45. de Luis DA, Terroba MC, Cuellar L, Conde R, Primo D, Aller R, Sagrado MG, Izaola O. Resistin levels in morbid obese patients following the biliopancreatic diversion surgery. Horm Metab Res. 2011; 43:205–208.

46. McTernan PG, Fisher FM, Valsamakis G, Chetty R, Harte A, McTernan CL, Clark PM, Smith SA, Barnett AH, Kumar S. Resistin and type 2 diabetes: regulation of resistin expression by insulin and rosiglitazone and the effects of recombinant resistin on lipid and glucose metabolism in human differentiated adipocytes. J Clin Endocrinol Metab. 2003; 88:6098–6106.

47. Lee JH, Chan JL, Yiannakouris N, Kontogianni M, Estrada E, Seip R, Orlova C, Mantzoros CS. Circulating resistin levels are not associated with obesity or insulin resistance in humans and are not regulated by fasting or leptin administration: cross-sectional and interventional studies in normal, insulin-resistant, and diabetic subjects. J Clin Endocrinol Metab. 2003; 88:4848–4856.

48. Reilly MP, Lehrke M, Wolfe ML, Rohatgi A, Lazar MA, Rader DJ. Resistin is an inflammatory marker of atherosclerosis in humans. Circulation. 2005; 111:932–939.

49. Jain SH, Massaro JM, Hoffmann U, Rosito GA, Vasan RS, Raji A, O'Donnell CJ, Meigs JB, Fox CS. Cross-sectional associations between abdominal and thoracic adipose tissue compartments and adiponectin and resistin in the Framingham Heart Study. Diabetes Care. 2009; 32:903–908.

50. Youn BS, Yu KY, Park HJ, Lee NS, Min SS, Youn MY, Cho YM, Park YJ, Kim SY, Lee HK, Park KS. Plasma resistin concentrations measured by enzyme-linked immunosorbent assay using a newly developed monoclonal antibody are elevated in individuals with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2004; 89:150–156.

51. Hivert MF, Sullivan LM, Fox CS, Nathan DM, D'Agostino RB Sr, Wilson PW, Meigs JB. Associations of adiponectin, resistin, and tumor necrosis factor-alpha with insulin resistance. J Clin Endocrinol Metab. 2008; 93:3165–3172.

52. Tsiotra PC, Tsigos C, Anastasiou E, Yfanti E, Boutati E, Souvatzoglou E, Kyrou I, Raptis SA. Peripheral mononuclear cell resistin mRNA expression is increased in type 2 diabetic women. Mediators Inflamm. 2008; 2008:892864.

53. Qatanani M, Szwergold NR, Greaves DR, Ahima RS, Lazar MA. Macrophage-derived human resistin exacerbates adipose tissue inflammation and insulin resistance in mice. J Clin Invest. 2009.

54. Chen BH, Song Y, Ding EL, Roberts CK, Manson JE, Rifai N, Buring JE, Gaziano JM, Liu S. Circulating levels of resistin and risk of type 2 diabetes in men and women: results from two prospective cohorts. Diabetes Care. 2009; 32:329–334.

55. Schwartz DR, Lazar MA. Human resistin: found in translation from mouse to man. Trends Endocrinol Metab. 2011; 22:259–265.

56. Menzaghi C, Coco A, Salvemini L, Thompson R, De Cosmo S, Doria A, Trischitta V. Heritability of serum resistin and its genetic correlation with insulin resistance-related features in nondiabetic Caucasians. J Clin Endocrinol Metab. 2006; 91:2792–2795.

57. Azuma K, Oguchi S, Matsubara Y, Mamizuka T, Murata M, Kikuchi H, Watanabe K, Katsukawa F, Yamazaki H, Shimada A, Saruta T. Novel resistin promoter polymorphisms: association with serum resistin level in Japanese obese individuals. Horm Metab Res. 2004; 36:564–570.

58. Osawa H, Onuma H, Ochi M, Murakami A, Yamauchi J, Takasuka T, Tanabe F, Shimizu I, Kato K, Nishida W, Yamada K, Tabara Y, Yasukawa M, Fujii Y, Ohashi J, Miki T, Makino H. Resistin SNP-420 determines its monocyte mRNA and serum levels inducing type 2 diabetes. Biochem Biophys Res Commun. 2005; 335:596–602.

59. Osawa H, Yamada K, Onuma H, Murakami A, Ochi M, Kawata H, Nishimiya T, Niiya T, Shimizu I, Nishida W, Hashiramoto M, Kanatsuka A, Fujii Y, Ohashi J, Makino H. The G/G genotype of a resistin single-nucleotide polymorphism at -420 increases type 2 diabetes mellitus susceptibility by inducing promoter activity through specific binding of Sp1/3. Am J Hum Genet. 2004; 75:678–686.

60. Osawa H, Tabara Y, Kawamoto R, Ohashi J, Ochi M, Onuma H, Nishida W, Yamada K, Nakura J, Kohara K, Miki T, Makino H. Plasma resistin, associated with single nucleotide polymorphism -420, is correlated with insulin resistance, lower HDL cholesterol, and high-sensitivity C-reactive protein in the Japanese general population. Diabetes Care. 2007; 30:1501–1506.

61. Cho YM, Youn BS, Chung SS, Kim KW, Lee HK, Yu KY, Park HJ, Shin HD, Park KS. Common genetic polymorphisms in the promoter of resistin gene are major determinants of plasma resistin concentrations in humans. Diabetologia. 2004; 47:559–565.

62. Xu JY, Sham PC, Xu A, Tso AW, Wat NM, Cheng KY, Fong CH, Janus ED, Lam KS. Resistin gene polymorphisms and progression of glycaemia in southern Chinese: a 5-year prospective study. Clin Endocrinol (Oxf). 2007; 66:211–217.

63. Norata GD, Ongari M, Garlaschelli K, Tibolla G, Grigore L, Raselli S, Vettoretti S, Baragetti I, Noto D, Cefalu AB, Buccianti G, Averna M, Catapano AL. Effect of the -420C/G variant of the resistin gene promoter on metabolic syndrome, obesity, myocardial infarction and kidney dysfunction. J Intern Med. 2007; 262:104–112.

64. Qasim AN, Metkus TS, Tadesse M, Lehrke M, Restine S, Wolfe ML, Hannenhalli S, Cappola T, Rader DJ, Reilly MP. Resistin gene variation is associated with systemic inflammation but not plasma adipokine levels, metabolic syndrome or coronary atherosclerosis in nondiabetic Caucasians. Clin Endocrinol (Oxf). 2009; 70:698–705.

65. Hivert MF, Manning AK, McAteer JB, Dupuis J, Fox CS, Cupples LA, Meigs JB, Florez JC. Association of variants in RETN with plasma resistin levels and diabetes-related traits in the Framingham Offspring Study. Diabetes. 2009; 58:750–756.

66. El-Shal AS, Pasha HF, Rashad NM. Association of resistin gene polymorphisms with insulin resistance in Egyptian obese patients. Gene. 2013; 515:233–238.

67. Tang NP, Wang LS, Yang L, Zhou B, Gu HJ, Sun QM, Cong RH, Zhu HJ, Wang B. A polymorphism in the resistin gene promoter and the risk of coronary artery disease in a Chinese population. Clin Endocrinol (Oxf). 2008; 68:82–87.

68. Bokarewa M, Nagaev I, Dahlberg L, Smith U, Tarkowski A. Resistin, an adipokine with potent proinflammatory properties. J Immunol. 2005; 174:5789–5795.

69. Silswal N, Singh AK, Aruna B, Mukhopadhyay S, Ghosh S, Ehtesham NZ. Human resistin stimulates the pro-inflammatory cytokines TNF-alpha and IL-12 in macrophages by NF-kappaB-dependent pathway. Biochem Biophys Res Commun. 2005; 334:1092–1101.

70. Shetty GK, Economides PA, Horton ES, Mantzoros CS, Veves A. Circulating adiponectin and resistin levels in relation to metabolic factors, inflammatory markers, and vascular reactivity in diabetic patients and subjects at risk for diabetes. Diabetes Care. 2004; 27:2450–2457.

71. Axelsson J, Bergsten A, Qureshi AR, Heimburger O, Barany P, Lonnqvist F, Lindholm B, Nordfors L, Alvestrand A, Stenvinkel P. Elevated resistin levels in chronic kidney disease are associated with decreased glomerular filtration rate and inflammation, but not with insulin resistance. Kidney Int. 2006; 69:596–604.

72. Senolt L, Housa D, Vernerova Z, Jirasek T, Svobodova R, Veigl D, Anderlova K, Muller-Ladner U, Pavelka K, Haluzik M. Resistin in rheumatoid arthritis synovial tissue, synovial fluid and serum. Ann Rheum Dis. 2007; 66:458–463.

73. Sunden-Cullberg J, Nystrom T, Lee ML, Mullins GE, Tokics L, Andersson J, Norrby-Teglund A, Treutiger CJ. Pronounced elevation of resistin correlates with severity of disease in severe sepsis and septic shock. Crit Care Med. 2007; 35:1536–1542.

74. Bo S, Gambino R, Pagani A, Guidi S, Gentile L, Cassader M, Pagano GF. Relationships between human serum resistin, inflammatory markers and insulin resistance. Int J Obes (Lond). 2005; 29:1315–1320.

75. Kunnari A, Ukkola O, Paivansalo M, Kesaniemi YA. High plasma resistin level is associated with enhanced highly sensitive C-reactive protein and leukocytes. J Clin Endocrinol Metab. 2006; 91:2755–2760.

76. Qi Q, Wang J, Li H, Yu Z, Ye X, Hu FB, Franco OH, Pan A, Liu Y, Lin X. Associations of resistin with inflammatory and fibrinolytic markers, insulin resistance, and metabolic syndrome in middle-aged and older Chinese. Eur J Endocrinol. 2008; 159:585–593.

77. Fargnoli JL, Sun Q, Olenczuk D, Qi L, Zhu Y, Hu FB, Mantzoros CS. Resistin is associated with biomarkers of inflammation while total and high-molecular weight adiponectin are associated with biomarkers of inflammation, insulin resistance, and endothelial function. Eur J Endocrinol. 2010; 162:281–288.

78. Konrad A, Lehrke M, Schachinger V, Seibold F, Stark R, Ochsenkuhn T, Parhofer KG, Goke B, Broedl UC. Resistin is an inflammatory marker of inflammatory bowel disease in humans. Eur J Gastroenterol Hepatol. 2007; 19:1070–1074.

79. Schaffler A, Hamer O, Dickopf J, Goetz A, Landfried K, Voelk M, Herfarth H, Kopp A, Buchler C, Scholmerich J, Brunnler T. Admission resistin levels predict peripancreatic necrosis and clinical severity in acute pancreatitis. Am J Gastroenterol. 2010; 105:2474–2484.

80. Koch A, Gressner OA, Sanson E, Tacke F, Trautwein C. Serum resistin levels in critically ill patients are associated with inflammation, organ dysfunction and metabolism and may predict survival of non-septic patients. Crit Care. 2009; 13:R95.

81. Park HK, Qatanani M, Briggs ER, Ahima RS, Lazar MA. Inflammatory induction of human resistin causes insulin resistance in endotoxemic mice. Diabetes. 2011; 60:775–783.

82. Tarkowski A, Bjersing J, Shestakov A, Bokarewa MI. Resistin competes with lipopolysaccharide for binding to toll-like receptor 4. J Cell Mol Med. 2010; 14:1419–1431.

83. Verma S, Li SH, Wang CH, Fedak PW, Li RK, Weisel RD, Mickle DA. Resistin promotes endothelial cell activation: further evidence of adipokine-endothelial interaction. Circulation. 2003; 108:736–740.

84. Mu H, Ohashi R, Yan S, Chai H, Yang H, Lin P, Yao Q, Chen C. Adipokine resistin promotes in vitro angiogenesis of human endothelial cells. Cardiovasc Res. 2006; 70:146–157.

85. Calabro P, Samudio I, Willerson JT, Yeh ET. Resistin promotes smooth muscle cell proliferation through activation of extracellular signal-regulated kinase 1/2 and phosphatidylinositol 3-kinase pathways. Circulation. 2004; 110:3335–3340.

86. Shen YH, Zhang L, Gan Y, Wang X, Wang J, LeMaire SA, Coselli JS, Wang XL. Up-regulation of PTEN (phosphatase and tensin homolog deleted on chromosome ten) mediates p38 MAPK stress signal-induced inhibition of insulin signaling. A cross-talk between stress signaling and insulin signaling in resistin-treated human endothelial cells. J Biol Chem. 2006; 281:7727–7736.

87. Chen C, Jiang J, Lu JM, Chai H, Wang X, Lin PH, Yao Q. Resistin decreases expression of endothelial nitric oxide synthase through oxidative stress in human coronary artery endothelial cells. Am J Physiol Heart Circ Physiol. 2010; 299:H193–H201.

88. Hsu WY, Chao YW, Tsai YL, Lien CC, Chang CF, Deng MC, Ho LT, Kwok CF, Juan CC. Resistin induces monocyte-endothelial cell adhesion by increasing ICAM-1 and VCAM-1 expression in endothelial cells via p38MAPK-dependent pathway. J Cell Physiol. 2011; 226:2181–2188.

89. Manduteanu I, Pirvulescu M, Gan AM, Stan D, Simion V, Dragomir E, Calin M, Manea A, Simionescu M. Similar effects of resistin and high glucose on P-selectin and fractalkine expression and monocyte adhesion in human endothelial cells. Biochem Biophys Res Commun. 2010; 391:1443–1448.

90. Xu W, Yu L, Zhou W, Luo M. Resistin increases lipid accumulation and CD36 expression in human macrophages. Biochem Biophys Res Commun. 2006; 351:376–382.

91. Rae C, Robertson SA, Taylor JM, Graham A. Resistin induces lipolysis and re-esterification of triacylglycerol stores, and increases cholesteryl ester deposition, in human macrophages. FEBS Lett. 2007; 581:4877–4883.

92. Calabro P, Cirillo P, Limongelli G, Maddaloni V, Riegler L, Palmieri R, Pacileo G, De Rosa S, Pacileo M, De Palma R, Golino P, Calabro R. Tissue factor is induced by resistin in human coronary artery endothelial cells by the NF-kB-dependent pathway. J Vasc Res. 2011; 48:59–66.

93. Jamaluddin MS, Weakley SM, Yao Q, Chen C. Resistin: functional roles and therapeutic considerations for cardiovascular disease. Br J Pharmacol. 2012; 165:622–632.

94. Ohmori R, Momiyama Y, Kato R, Taniguchi H, Ogura M, Ayaori M, Nakamura H, Ohsuzu F. Associations between serum resistin levels and insulin resistance, inflammation, and coronary artery disease. J Am Coll Cardiol. 2005; 46:379–380.

95. Wang H, Chen DY, Cao J, He ZY, Zhu BP, Long M. High serum resistin level may be an indicator of the severity of coronary disease in acute coronary syndrome. Chin Med Sci J. 2009; 24:161–166.

96. On YK, Park HK, Hyon MS, Jeon ES. Serum resistin as a biological marker for coronary artery disease and restenosis in type 2 diabetic patients. Circ J. 2007; 71:868–873.

97. Krecki R, Krzeminska-Pakula M, Peruga JZ, Szczesniak P, Lipiec P, Wierzbowska-Drabik K, Orszulak-Michalak D, Kasprzak JD. Elevated resistin opposed to adiponectin or angiogenin plasma levels as a strong, independent predictive factor for the occurrence of major adverse cardiac and cerebrovascular events in patients with stable multivessel coronary artery disease over 1-year follow-up. Med Sci Monit. 2011; 17:CR26–CR32.

98. Momiyama Y, Ohmori R, Uto-Kondo H, Tanaka N, Kato R, Taniguchi H, Arakawa K, Nakamura H, Ohsuzu F. Serum resistin levels and cardiovascular events in patients undergoing percutaneous coronary intervention. J Atheroscler Thromb. 2011; 18:108–114.

99. Li L, Han JL, Mao JM, Guo LJ, Gao W. Association between serum resistin level and cardiovascular events in postmenopausal women with acute coronary syndrome undergoing percutaneous coronary intervention. Chin Med J (Engl). 2013; 126:1058–1062.

100. Lee SH, Ha JW, Kim JS, Choi EY, Park S, Kang SM, Choi D, Jang Y, Chung N. Plasma adiponectin and resistin levels as predictors of mortality in patients with acute myocardial infarction: data from infarction prognosis study registry. Coron Artery Dis. 2009; 20:33–39.

101. Weikert C, Westphal S, Berger K, Dierkes J, Mohlig M, Spranger J, Rimm EB, Willich SN, Boeing H, Pischon T. Plasma resistin levels and risk of myocardial infarction and ischemic stroke. J Clin Endocrinol Metab. 2008; 93:2647–2653.

102. Osawa H, Doi Y, Makino H, Ninomiya T, Yonemoto K, Kawamura R, Hata J, Tanizaki Y, Iida M, Kiyohara Y. Diabetes and hypertension markedly increased the risk of ischemic stroke associated with high serum resistin concentration in a general Japanese population: the Hisayama Study. Cardiovasc Diabetol. 2009; 8:60.

103. Rajpathak SN, Kaplan RC, Wassertheil-Smoller S, Cushman M, Rohan TE, McGinn AP, Wang T, Strickler HD, Scherer PE, Mackey R, Curb D, Ho GY. Resistin, but not adiponectin and leptin, is associated with the risk of ischemic stroke among postmenopausal women: results from the Women's Health Initiative. Stroke. 2011; 42:1813–1820.

104. Prugger C, Luc G, Haas B, Morange PE, Ferrieres J, Amouyel P, Kee F, Ducimetiere P, Empana JP. PRIME Study Group. Multiple biomarkers for the prediction of ischemic stroke: the PRIME study. Arterioscler Thromb Vasc Biol. 2013; 33:659–666.

105. Lubos E, Messow CM, Schnabel R, Rupprecht HJ, Espinola-Klein C, Bickel C, Peetz D, Post F, Lackner KJ, Tiret L, Munzel T, Blankenberg S. Resistin, acute coronary syndrome and prognosis results from the AtheroGene study. Atherosclerosis. 2007; 193:121–128.

106. Efstathiou SP, Tsiakou AG, Tsioulos DI, Panagiotou TN, Pefanis AV, Achimastos AD, Mountokalakis TD. Prognostic significance of plasma resistin levels in patients with atherothrombotic ischemic stroke. Clin Chim Acta. 2007; 378:78–85.

107. Lee SE, Kim HS. Human resistin in cardiovascular disease. J Smooth Muscle Res. 2012; 48:27–35.

108. Menzaghi C, Bacci S, Salvemini L, Mendonca C, Palladino G, Fontana A, De Bonis C, Marucci A, Goheen E, Prudente S, Morini E, Rizza S, Kanagaki A, Fini G, Mangiacotti D, Federici M, De Cosmo S, Pellegrini F, Doria A, Trischitta V. Serum resistin, cardiovascular disease and all-cause mortality in patients with type 2 diabetes. PLoS One. 2013; 8:e64729.

109. Choi HY, Kim S, Yang SJ, Yoo HJ, Seo JA, Kim SG, Kim NH, Baik SH, Choi DS, Choi KM. Association of adiponectin, resistin, and vascular inflammation: analysis with 18F-fluorodeoxyglucose positron emission tomography. Arterioscler Thromb Vasc Biol. 2011; 31:944–949.

110. Hoefle G, Saely CH, Risch L, Koch L, Schmid F, Rein P, Aczel S, Berchtold S, Drexel H. Relationship between the adipose-tissue hormone resistin and coronary artery disease. Clin Chim Acta. 2007; 386:1–6.

111. Pilz S, Weihrauch G, Seelhorst U, Wellnitz B, Winkelmann BR, Boehm BO, Marz W. Implications of resistin plasma levels in subjects undergoing coronary angiography. Clin Endocrinol (Oxf). 2007; 66:380–386.

112. Ding Q, White SP, Ling C, Zhou W. Resistin and cardiovascular disease. Trends Cardiovasc Med. 2011; 21:20–27.

113. Kim M, Oh JK, Sakata S, Liang I, Park W, Hajjar RJ, Lebeche D. Role of resistin in cardiac contractility and hypertrophy. J Mol Cell Cardiol. 2008; 45:270–280.

114. Wang BW, Hung HF, Chang H, Kuan P, Shyu KG. Mechanical stretch enhances the expression of resistin gene in cultured cardiomyocytes via tumor necrosis factor-alpha. Am J Physiol Heart Circ Physiol. 2007; 293:H2305–H2312.

115. Rothwell SE, Richards AM, Pemberton CJ. Resistin worsens cardiac ischaemia-reperfusion injury. Biochem Biophys Res Commun. 2006; 349:400–407.

116. Takeishi Y, Niizeki T, Arimoto T, Nozaki N, Hirono O, Nitobe J, Watanabe T, Takabatake N, Kubota I. Serum resistin is associated with high risk in patients with congestive heart failure: a novel link between metabolic signals and heart failure. Circ J. 2007; 71:460–464.

117. Frankel DS, Vasan RS, D'Agostino RB Sr, Benjamin EJ, Levy D, Wang TJ, Meigs JB. Resistin, adiponectin, and risk of heart failure the Framingham offspring study. J Am Coll Cardiol. 2009; 53:754–762.

118. Butler J, Kalogeropoulos A, Georgiopoulou V, de Rekeneire N, Rodondi N, Smith AL, Hoffmann U, Kanaya A, Newman AB, Kritchevsky SB, Vasan RS, Wilson PW, Harris TB. Health ABC Study. Serum resistin concentrations and risk of new onset heart failure in older persons: the health, aging, and body composition (Health ABC) study. Arterioscler Thromb Vasc Biol. 2009; 29:1144–1149.

119. Bhalla V, Kalogeropoulos A, Georgiopoulou V, Butler J. Serum resistin: physiology, pathophysiology and implications for heart failure. Biomark Med. 2010; 4:445–452.