Endocrinol Metab.  2018 Mar;33(1):33-43. 10.3803/EnM.2018.33.1.33.

Association of Adipokines with Development and Progression of Nonalcoholic Fatty Liver Disease

• Boutari C
• Perakakis
• Mantzoros

• KMID: 2407118
• DOI: http://doi.org/10.3803/EnM.2018.33.1.33

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease affecting 30% of the general population and 40% to 70% of obese individuals. Adipose tissue plays a crucial role in its pathogenesis, as it produces and secretes pro- and anti-inflammatory cytokines called adipokines. Adiponectin and leptin have well-determined actions in terms of NAFLD pathophysiology. Adiponectin deficiency is associated with a pro-inflammatory condition, as it is observed in obesity and other metabolic disorders. On the other hand, increased leptin levels, above the normal levels, act as a pro-inflammatory stimulus. Regarding other adipokines (resistin, visfatin, chemerin, retinol-binding protein 4, irisin), data about their contribution to NAFLD pathogenesis and progression are inconclusive. In addition, pharmacological agents like thiazolidinediones (pioglitazone and rosiglitazone), that are used in the management of NAFLD exert favourable effects on adipokine levels, which in turn may contribute to the improvement of liver function. This review summarizes the current knowledge and developments in the association between adipokines and NAFLD and discusses possible therapeutic implications targeting the modulation of adipokine levels as a potential tool for the treatment of NAFLD.

Keyword

Non-alcoholic fatty liver disease; Adipokines; Adiponectin; Leptin; Resistin; Nicotinamide phosphoribosyltra; Chemerin; Retinol-binding protein 4

MeSH Terms

Adipokines*
Adiponectin
Adipose Tissue
Cytokines
Hand
Leptin
Liver
Liver Diseases
Nicotinamide Phosphoribosyltransferase
Non-alcoholic Fatty Liver Disease*
Obesity
Resistin
Thiazolidinediones
Adipokines
Adiponectin
Cytokines
Leptin
Nicotinamide Phosphoribosyltransferase
Resistin
Thiazolidinediones

Reference

1. Fazel Y, Koenig AB, Sayiner M, Goodman ZD, Younossi ZM. Epidemiology and natural history of non-alcoholic fatty liver disease. Metabolism. 2016; 65:1017–1025.

2. Reccia I, Kumar J, Akladios C, Virdis F, Pai M, Habib N, et al. Non-alcoholic fatty liver disease: a sign of systemic disease. Metabolism. 2017; 72:94–108.

3. Katsiki N, Mikhailidis DP, Mantzoros CS. Non-alcoholic fatty liver disease and dyslipidemia: an update. Metabolism. 2016; 65:1109–1123.

4. Polyzos SA, Bugianesi E, Kountouras J, Mantzoros CS. Nonalcoholic fatty liver disease: updates on associations with the metabolic syndrome and lipid profile and effects of treatment with PPAR-γ agonists. Metabolism. 2017; 66:64–68.

5. Huh JH, Kim KJ, Kim SU, Han SH, Han KH, Cha BS, et al. Obesity is more closely related with hepatic steatosis and fibrosis measured by transient elastography than metabolic health status. Metabolism. 2017; 66:23–31.

6. Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther. 2011; 34:274–285.

7. Polyzos SA, Mantzoros CS. Nonalcoholic fatty future disease. Metabolism. 2016; 65:1007–1016.

8. Karajamaki AJ, Bloigu R, Kauma H, Kesaniemi YA, Koivurova OP, Perkiomaki J, et al. Non-alcoholic fatty liver disease with and without metabolic syndrome: different long-term outcomes. Metabolism. 2017; 66:55–63.

9. Hazlehurst JM, Woods C, Marjot T, Cobbold JF, Tomlinson JW. Non-alcoholic fatty liver disease and diabetes. Metabolism. 2016; 65:1096–1108.

10. Polyzos SA, Kountouras J, Zavos C. Nonalcoholic fatty liver disease: the pathogenetic roles of insulin resistance and adipocytokines. Curr Mol Med. 2009; 9:299–314.

11. Buzzetti E, Pinzani M, Tsochatzis EA. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism. 2016; 65:1038–1048.

12. Zoller H, Tilg H. Nonalcoholic fatty liver disease and hepatocellular carcinoma. Metabolism. 2016; 65:1151–1160.

13. Bhala N, Angulo P, van der Poorten D, Lee E, Hui JM, Saracco G, et al. The natural history of nonalcoholic fatty liver disease with advanced fibrosis or cirrhosis: an international collaborative study. Hepatology. 2011; 54:1208–1216.

14. Chung M, Ma J, Patel K, Berger S, Lau J, Lichtenstein AH. Fructose, high-fructose corn syrup, sucrose, and nonalcoholic fatty liver disease or indexes of liver health: a systematic review and meta-analysis. Am J Clin Nutr. 2014; 100:833–849.

15. Mota M, Banini BA, Cazanave SC, Sanyal AJ. Molecular mechanisms of lipotoxicity and glucotoxicity in nonalcoholic fatty liver disease. Metabolism. 2016; 65:1049–1061.

16. Tilg H. Adipocytokines in nonalcoholic fatty liver disease: key players regulating steatosis, inflammation and fibrosis. Curr Pharm Des. 2010; 16:1893–1895.

17. Polyzos SA, Kountouras J, Zavos Ch. The multi-hit process and the antagonistic roles of tumor necrosis factor-alpha and adiponectin in non alcoholic fatty liver disease. Hippokratia. 2009; 13:127.

18. Scheja L, Heeren J. Metabolic interplay between white, beige, brown adipocytes and the liver. J Hepatol. 2016; 64:1176–1186.

19. Polyzos SA, Mantzoros CS. Leptin in health and disease: facts and expectations at its twentieth anniversary. Metabolism. 2015; 64:5–12.

20. Polyzos SA, Kountouras J, Zavos C, Tsiaousi E. The role of adiponectin in the pathogenesis and treatment of non-alcoholic fatty liver disease. Diabetes Obes Metab. 2010; 12:365–383.

21. Heiker JT, Kosel D, Beck-Sickinger AG. Molecular mechanisms of signal transduction via adiponectin and adiponectin receptors. Biol Chem. 2010; 391:1005–1018.

22. Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S, et al. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature. 2003; 423:762–769.

23. Yamauchi T, Nio Y, Maki T, Kobayashi M, Takazawa T, Iwabu M, et al. Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. Nat Med. 2007; 13:332–339.

24. Maeda N, Takahashi M, Funahashi T, Kihara S, Nishizawa H, Kishida K, et al. PPARgamma ligands increase expression and plasma concentrations of adiponectin, an adiposederived protein. Diabetes. 2001; 50:2094–2099.

25. Moschen AR, Molnar C, Geiger S, Graziadei I, Ebenbichler CF, Weiss H, et al. Anti-inflammatory effects of excessive weight loss: potent suppression of adipose interleukin 6 and tumour necrosis factor alpha expression. Gut. 2010; 59:1259–1264.

26. Kim JY, van de Wall E, Laplante M, Azzara A, Trujillo ME, Hofmann SM, et al. Obesity-associated improvements in metabolic profile through expansion of adipose tissue. J Clin Invest. 2007; 117:2621–2637.

27. Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med. 2001; 7:941–946.

28. Liu X, Perakakis N, Gong H, Chamberland JP, Brinkoetter MT, Hamnvik OR, et al. Adiponectin administration prevents weight gain and glycemic profile changes in diet-induced obese immune deficient Rag1−/− mice lacking mature lymphocytes. Metabolism. 2016; 65:1720–1730.

29. Hui JM, Hodge A, Farrell GC, Kench JG, Kriketos A, George J. Beyond insulin resistance in NASH: TNF-alpha or adiponectin? Hepatology. 2004; 40:46–54.

30. Polyzos SA, Toulis KA, Goulis DG, Zavos C, Kountouras J. Serum total adiponectin in nonalcoholic fatty liver disease: a systematic review and meta-analysis. Metabolism. 2011; 60:313–326.

31. Polyzos SA, Kountouras J, Zavos C. Nonlinear distribution of adiponectin in patients with nonalcoholic fatty liver disease limits its use in linear regression analysis. J Clin Gastroenterol. 2010; 44:229–230.

32. Polyzos SA, Kountouras J, Zavos C, Stergiopoulos C. Adipocytokines in insulin resistance and non-alcoholic fatty liver disease: the two sides of the same coin. Med Hypotheses. 2010; 74:1089–1090.

33. van der Poorten D, Samer CF, Ramezani-Moghadam M, Coulter S, Kacevska M, Schrijnders D, et al. Hepatic fat loss in advanced nonalcoholic steatohepatitis: are alterations in serum adiponectin the cause? Hepatology. 2013; 57:2180–2188.

34. Engl J, Sturm W, Sandhofer A, Kaser S, Tschoner A, Tatarczyk T, et al. Effect of pronounced weight loss on visceral fat, liver steatosis and adiponectin isoforms. Eur J Clin Invest. 2008; 38:238–244.

35. Wong VW, Wong GL, Choi PC, Chan AW, Li MK, Chan HY, et al. Disease progression of non-alcoholic fatty liver disease: a prospective study with paired liver biopsies at 3 years. Gut. 2010; 59:969–974.

36. Zelber-Sagi S, Lotan R, Shlomai A, Webb M, Harrari G, Buch A, et al. Predictors for incidence and remission of NAFLD in the general population during a seven-year prospective follow-up. J Hepatol. 2012; 56:1145–1151.

37. Zhou YJ, Zhang ZS, Nie YQ, Cao J, Cao CY, Li YY. Association of adiponectin gene variation with progression of nonalcoholic fatty liver disease: a 4-year follow-up survey. J Dig Dis. 2015; 16:601–609.

38. Ayonrinde OT, Olynyk JK, Beilin LJ, Mori TA, Pennell CE, de Klerk N, et al. Gender-specific differences in adipose distribution and adipocytokines influence adolescent nonalcoholic fatty liver disease. Hepatology. 2011; 53:800–809.

39. Feldman A, Eder SK, Felder TK, Kedenko L, Paulweber B, Stadlmayr A, et al. Clinical and metabolic characterization of lean Caucasian subjects with non-alcoholic fatty liver. Am J Gastroenterol. 2017; 112:102–110.

40. Borel AL, Nazare JA, Baillot A, Almeras N, Tremblay A, Bergeron J, et al. Cardiometabolic risk improvement in response to a 3-yr lifestyle modification program in men: contribution of improved cardiorespiratory fitness vs. weight loss. Am J Physiol Endocrinol Metab. 2017; 312:E273–E281.

41. Triantafyllou GA, Paschou SA, Mantzoros CS. Leptin and hormones: energy homeostasis. Endocrinol Metab Clin North Am. 2016; 45:633–645.

42. Abd El-Kader SM, Al-Shreef FM, Al-Jiffri OH. Biochemical parameters response to weight loss in patients with non-alcoholic steatohepatitis. Afr Health Sci. 2016; 16:242–249.

43. Polyzos SA, Mantzoros CS. Adiponectin as a target for the treatment of nonalcoholic steatohepatitis with thiazolidinediones: a systematic review. Metabolism. 2016; 65:1297–1306.

44. Punthakee Z, Almeras N, Despres JP, Dagenais GR, Anand SS, Hunt DL, et al. Impact of rosiglitazone on body composition, hepatic fat, fatty acids, adipokines and glucose in persons with impaired fasting glucose or impaired glucose tolerance: a sub-study of the DREAM trial. Diabet Med. 2014; 31:1086–1092.

45. Shargorodsky M, Omelchenko E, Matas Z, Boaz M, Gavish D. Relation between augmentation index and adiponectin during one-year metformin treatment for nonalcoholic steatohepatosis: effects beyond glucose lowering? Cardiovasc Diabetol. 2012; 11:61.

46. Matarese G, Procaccini C, De Rosa V, Horvath TL, La Cava A. Regulatory T cells in obesity: the leptin connection. Trends Mol Med. 2010; 16:247–256.

47. Meek TH, Morton GJ. The role of leptin in diabetes: metabolic effects. Diabetologia. 2016; 59:928–932.

48. Kakuma T, Lee Y, Higa M, Wang Zw, Pan W, Shimomura I, et al. Leptin, troglitazone, and the expression of sterol regulatory element binding proteins in liver and pancreatic islets. Proc Natl Acad Sci U S A. 2000; 97:8536–8541.

49. Ferre P, Foufelle F. Hepatic steatosis: a role for de novo lipogenesis and the transcription factor SREBP-1c. Diabetes Obes Metab. 2010; 12:Suppl 2. 83–92.

50. Ikejima K, Honda H, Yoshikawa M, Hirose M, Kitamura T, Takei Y, et al. Leptin augments inflammatory and profibrogenic responses in the murine liver induced by hepatotoxic chemicals. Hepatology. 2001; 34:288–297.

51. Polyzos SA, Aronis KN, Kountouras J, Raptis DD, Vasiloglou MF, Mantzoros CS. Circulating leptin in non-alcoholic fatty liver disease: a systematic review and meta-analysis. Diabetologia. 2016; 59:30–43.

52. An BQ, Lu LL, Yuan C, Xin YN, Xuan SY. Leptin receptor gene polymorphisms and the risk of non-alcoholic fatty liver disease and coronary atherosclerosis in the Chinese Han population. Hepat Mon. 2016; 16:e35055.

53. Polyzos SA, Kountouras J, Mantzoros CS, Polymerou V, Katsinelos P. Effects of combined low-dose spironolactone plus vitamin E vs vitamin E monotherapy on insulin resistance, non-invasive indices of steatosis and fibrosis, and adipokine levels in non-alcoholic fatty liver disease: a randomized controlled trial. Diabetes Obes Metab. 2017; 19:1805–1809.

54. Saryusz-Wolska M, Szymanska-Garbacz E, Jablkowski M, Bialkowska J, Pawlowski M, Kwiecinska E, et al. Rosiglitazone treatment in nondiabetic subjects with nonalcoholic fatty liver disease. Pol Arch Med Wewn. 2011; 121:61–66.

55. Bertolani C, Sancho-Bru P, Failli P, Bataller R, Aleffi S, DeFranco R, et al. 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.

56. Rangwala SM, Rich AS, Rhoades B, Shapiro JS, Obici S, Rossetti L, et al. Abnormal glucose homeostasis due to chronic hyperresistinemia. Diabetes. 2004; 53:1937–1941.

57. Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, et al. The hormone resistin links obesity to diabetes. Nature. 2001; 409:307–312.

58. Nobili V, Carpino G, Alisi A, Franchitto A, Alpini G, De Vito R, et al. Hepatic progenitor cells activation, fibrosis, and adipokines production in pediatric nonalcoholic fatty liver disease. Hepatology. 2012; 56:2142–2153.

59. Banerjee RR, Rangwala SM, Shapiro JS, Rich AS, Rhoades B, Qi Y, et al. Regulation of fasted blood glucose by resistin. Science. 2004; 303:1195–1198.

60. Lee JH, Chan JL, Yiannakouris N, Kontogianni M, Estrada E, Seip R, et al. 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.

61. Fargnoli JL, Sun Q, Olenczuk D, Qi L, Zhu Y, Hu FB, et al. 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.

62. 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.

63. Senates E, Colak Y, Yesil A, Coskunpinar E, Sahin O, Kahraman OT, et al. Circulating resistin is elevated in patients with non-alcoholic fatty liver disease and is associated with steatosis, portal inflammation, insulin resistance and nonalcoholic steatohepatitis scores. Minerva Med. 2012; 103:369–376.

64. Argentou M, Tiniakos DG, Karanikolas M, Melachrinou M, Makri MG, Kittas C, et al. Adipokine serum levels are related to liver histology in severely obese patients undergoing bariatric surgery. Obes Surg. 2009; 19:1313–1323.

65. Pagano C, Soardo G, Pilon C, Milocco C, Basan L, Milan G, et al. Increased serum resistin in nonalcoholic fatty liver disease is related to liver disease severity and not to insulin resistance. J Clin Endocrinol Metab. 2006; 91:1081–1086.

66. Shen C, Zhao CY, Wang W, Wang YD, Sun H, Cao W, et al. The relationship between hepatic resistin overexpression and inflammation in patients with nonalcoholic steatohepatitis. BMC Gastroenterol. 2014; 14:39.

67. Musso G, Bo S, Cassader M, De Michieli F, Gambino R. Impact of sterol regulatory element-binding factor-1c polymorphism on incidence of nonalcoholic fatty liver disease and on the severity of liver disease and of glucose and lipid dysmetabolism. Am J Clin Nutr. 2013; 98:895–906.

68. Bekaert M, Verhelst X, Geerts A, Lapauw B, Calders P. Association of recently described adipokines with liver histology in biopsy-proven non-alcoholic fatty liver disease: a systematic review. Obes Rev. 2016; 17:68–80.

69. Ajmera V, Perito ER, Bass NM, Terrault NA, Yates KP, Gill R, et al. Novel plasma biomarkers associated with liver disease severity in adults with nonalcoholic fatty liver disease. Hepatology. 2017; 65:65–77.

70. Jamali R, Razavizade M, Arj A, Aarabi MH. Serum adipokines might predict liver histology findings in non-alcoholic fatty liver disease. World J Gastroenterol. 2016; 22:5096–5103.

71. Moschen AR, Kaser A, Enrich B, Mosheimer B, Theurl M, Niederegger H, et al. Visfatin, an adipocytokine with proinflammatory and immunomodulating properties. J Immunol. 2007; 178:1748–1758.

72. Saxena NK, Anania FA. Adipocytokines and hepatic fibrosis. Trends Endocrinol Metab. 2015; 26:153–161.

73. Polyzos SA, Kountouras J, Papatheodorou A, Katsiki E, Patsiaoura K, Zafeiriadou E, et al. Adipocytokines and cytokeratin-18 in patients with nonalcoholic fatty liver disease: introduction of CHA index. Ann Hepatol. 2013; 12:749–757.

74. Genc H, Dogru T, Kara M, Tapan S, Ercin CN, Acikel C, et al. Association of plasma visfatin with hepatic and systemic inflammation in nonalcoholic fatty liver disease. Ann Hepatol. 2013; 12:548–555.

75. Auguet T, Terra X, Porras JA, Orellana-Gavalda JM, Martinez S, Aguilar C, et al. Plasma visfatin levels and gene expression in morbidly obese women with associated fatty liver disease. Clin Biochem. 2013; 46:202–208.

76. Jamali R, Arj A, Razavizade M, Aarabi MH. Prediction of nonalcoholic fatty liver disease via a novel panel of serum adipokines. Medicine (Baltimore). 2016; 95:e2630.

77. Kukla M, Ciupinska-Kajor M, Kajor M, Wylezol M, Zwirska-Korczala K, Hartleb M, et al. Liver visfatin expression in morbidly obese patients with nonalcoholic fatty liver disease undergoing bariatric surgery. Pol J Pathol. 2010; 61:147–153.

78. Aller R, de Luis DA, Izaola O, Sagrado MG, Conde R, Velasco MC, et al. Influence of visfatin on histopathological changes of non-alcoholic fatty liver disease. Dig Dis Sci. 2009; 54:1772–1777.

79. Bozaoglu K, Bolton K, McMillan J, Zimmet P, Jowett J, Collier G, et al. Chemerin is a novel adipokine associated with obesity and metabolic syndrome. Endocrinology. 2007; 148:4687–4694.

80. Ress C, Tschoner A, Engl J, Klaus A, Tilg H, Ebenbichler CF, et al. Effect of bariatric surgery on circulating chemerin levels. Eur J Clin Invest. 2010; 40:277–280.

81. Zabel BA, Silverio AM, Butcher EC. Chemokine-like receptor 1 expression and chemerin-directed chemotaxis distinguish plasmacytoid from myeloid dendritic cells in human blood. J Immunol. 2005; 174:244–251.

82. Krautbauer S, Wanninger J, Eisinger K, Hader Y, Beck M, Kopp A, et al. Chemerin is highly expressed in hepatocytes and is induced in non-alcoholic steatohepatitis liver. Exp Mol Pathol. 2013; 95:199–205.

83. Sell H, Divoux A, Poitou C, Basdevant A, Bouillot JL, Bedossa P, et al. Chemerin correlates with markers for fatty liver in morbidly obese patients and strongly decreases after weight loss induced by bariatric surgery. J Clin Endocrinol Metab. 2010; 95:2892–2896.

84. Docke S, Lock JF, Birkenfeld AL, Hoppe S, Lieske S, Rieger A, et al. Elevated hepatic chemerin mRNA expression in human non-alcoholic fatty liver disease. Eur J Endocrinol. 2013; 169:547–557.

85. Kukla M, Zwirska-Korczala K, Hartleb M, Waluga M, Chwist A, Kajor M, et al. Serum chemerin and vaspin in non-alcoholic fatty liver disease. Scand J Gastroenterol. 2010; 45:235–242.

86. Wolfs MG, Gruben N, Rensen SS, Verdam FJ, Greve JW, Driessen A, et al. Determining the association between adipokine expression in multiple tissues and phenotypic features of non-alcoholic fatty liver disease in obesity. Nutr Diabetes. 2015; 5:e146.

87. Blaner WS. Retinol-binding protein: the serum transport protein for vitamin A. Endocr Rev. 1989; 10:308–316.

88. Kloting N, Graham TE, Berndt J, Kralisch S, Kovacs P, Wason CJ, et al. Serum retinol-binding protein is more highly expressed in visceral than in subcutaneous adipose tissue and is a marker of intra-abdominal fat mass. Cell Metab. 2007; 6:79–87.

89. Graham TE, Yang Q, Bluher M, Hammarstedt A, Ciaraldi TP, Henry RR, et al. Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects. N Engl J Med. 2006; 354:2552–2563.

90. Yang Q, Graham TE, Mody N, Preitner F, Peroni OD, Zabolotny JM, et al. Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature. 2005; 436:356–362.

91. Stefan N, Hennige AM, Staiger H, Machann J, Schick F, Schleicher E, et al. High circulating retinol-binding protein 4 is associated with elevated liver fat but not with total, subcutaneous, visceral, or intramyocellular fat in humans. Diabetes Care. 2007; 30:1173–1178.

92. Seo JA, Kim NH, Park SY, Kim HY, Ryu OH, Lee KW, et al. Serum retinol-binding protein 4 levels are elevated in non-alcoholic fatty liver disease. Clin Endocrinol (Oxf). 2008; 68:555–560.

93. Terra X, Auguet T, Broch M, Sabench F, Hernandez M, Pastor RM, et al. Retinol binding protein-4 circulating levels were higher in nonalcoholic fatty liver disease vs. histologically normal liver from morbidly obese women. Obesity (Silver Spring). 2013; 21:170–177.

94. Alkhouri N, Lopez R, Berk M, Feldstein AE. Serum retinol-binding protein 4 levels in patients with nonalcoholic fatty liver disease. J Clin Gastroenterol. 2009; 43:985–989.

95. Polyzos SA, Kountouras J, Anastasilakis AD, Geladari EV, Mantzoros CS. Irisin in patients with nonalcoholic fatty liver disease. Metabolism. 2014; 63:207–217.

96. Perakakis N, Triantafyllou GA, Fernandez-Real JM, Huh JY, Park KH, Seufert J, et al. Physiology and role of irisin in glucose homeostasis. Nat Rev Endocrinol. 2017; 13:324–337.

97. Polyzos SA, Anastasilakis AD, Efstathiadou ZA, Makras P, Perakakis N, Kountouras J, et al. Irisin in metabolic diseases. Endocrine. 2018; 59:260–274.

98. Aldiss P, Betts J, Sale C, Pope M, Symonds ME. Exercise-induced ‘browning’ of adipose tissues. Metabolism. 2018; 81:63–70.

99. Sahin-Efe A, Upadhyay J, Ko BJ, Dincer F, Park KH, Migdal A, et al. Irisin and leptin concentrations in relation to obesity, and developing type 2 diabetes: a cross sectional and a prospective case-control study nested in the Normative Aging Study. Metabolism. 2018; 79:24–32.

100. Qiu S, Cai X, Yin H, Zugel M, Sun Z, Steinacker JM, et al. Association between circulating irisin and insulin resistance in non-diabetic adults: a meta-analysis. Metabolism. 2016; 65:825–834.

101. Anastasilakis AD, Koulaxis D, Kefala N, Polyzos SA, Upadhyay J, Pagkalidou E, et al. Circulating irisin levels are lower in patients with either stable coronary artery disease (CAD) or myocardial infarction (MI) versus healthy controls, whereas follistatin and activin A levels are higher and can discriminate MI from CAD with similar to CK-MB accuracy. Metabolism. 2017; 73:1–8.

102. Huh JY, Mantzoros CS. Irisin physiology, oxidative stress, and thyroid dysfunction: what next? Metabolism. 2015; 64:765–767.

103. Jang HB, Kim HJ, Kang JH, Park SI, Park KH, Lee HJ. Association of circulating irisin levels with metabolic and metabolite profiles of Korean adolescents. Metabolism. 2017; 73:100–108.

104. Shanaki M, Moradi N, Emamgholipour S, Fadaei R, Poustchi H. Lower circulating irisin is associated with nonalcoholic fatty liver disease and type 2 diabetes. Diabetes Metab Syndr. 2017; 11:Suppl 1. S467–S472.

105. Petta S, Valenti L, Svegliati-Baroni G, Ruscica M, Pipitone RM, Dongiovanni P, et al. Fibronectin type III domain-containing protein 5 rs3480 A>G polymorphism, irisin, and liver fibrosis in patients with nonalcoholic fatty liver disease. J Clin Endocrinol Metab. 2017; 102:2660–2669.

106. Zhang HJ, Zhang XF, Ma ZM, Pan LL, Chen Z, Han HW, et al. Irisin is inversely associated with intrahepatic triglyceride contents in obese adults. J Hepatol. 2013; 59:557–562.

107. Viitasalo A, Atalay M, Pihlajamaki J, Jaaskelainen J, Korkmaz A, Kaminska D, et al. The 148 M allele of the PNPLA3 is associated with plasma irisin levels in a population sample of Caucasian children: the PANIC Study. Metabolism. 2015; 64:793–796.

108. Polyzos SA, Mantzoros CS. An update on the validity of irisin assays and the link between irisin and hepatic metabolism. Metabolism. 2015; 64:937–942.

109. Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006; 355:2297–2307.

110. Chrusciel P, Sahebkar A, Rembek-Wieliczko M, Serban MC, Ursoniu S, Mikhailidis DP, et al. Impact of statin therapy on plasma adiponectin concentrations: a systematic review and meta-analysis of 43 randomized controlled trial arms. Atherosclerosis. 2016; 253:194–208.

111. Su JR, Lu ZH, Su Y, Zhao N, Dong CL, Sun L, et al. Relationship of serum adiponectin levels and metformin therapy in patients with type 2 diabetes. Horm Metab Res. 2016; 48:92–98.

112. Zhuang X, Sun F, Li L, Jiang D, Li X, Sun A, et al. Therapeutic effect of metformin on chemerin in non-obese patients with non-alcoholic fatty liver disease (NAFLD). Clin Lab. 2015; 61:1409–1414.

113. Tsoukas MA, Farr OM, Mantzoros CS. Leptin in congenital and HIV-associated lipodystrophy. Metabolism. 2015; 64:47–59.