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Adipokines in Nonalcoholic Fatty Liver Disease

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Adipose Tissue and Adipokines in Health and Disease

Part of the book series: Nutrition and Health ((NH))

Abstract

The pathogenesis of NAFLD and NASH is hastened by a disturbance of adipose secretion, including decreased production of adiponectin and increased production of TNF-α, characteristic of obesity. NASH suppressive effects of the leptin are diminished by its pro-oxidant and fibrogenic properties. Resistin’s involvement in NASH is documented in rodent models, which may not accurately reflect NAFLD in humans. Vaspin, visfatin, apelin, nesfatin, omentin and chemerin require further study in patients with NAFLD and NASH.

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References

  1. Falck-Ytter Y, Younossi ZM, Marchesini G, McCullough AJ. Clinical features and natural history of nonalcoholic steatosis syndromes. Semin Liver Dis. 2001;21(1):17–26. Review.

    CAS  PubMed  Google Scholar 

  2. Younossi ZM, Diehl AM, Ong JP. Nonalcoholic fatty liver disease: an agenda for clinical research. Hepatology. 2002;35(4):746–52.

    PubMed  Google Scholar 

  3. Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology. 1999;116(6):1413–9.

    CAS  PubMed  Google Scholar 

  4. Younossi ZM, Stepanova M, Afendy M, Fang Y, Younossi Y, Mir H, Srishord M. Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008. Clin Gastroenterol Hepatol. 2011;9(6):524–30.e1. quiz e60. Epub 2011 Mar 25.

    PubMed  Google Scholar 

  5. 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(3):274–85.

    CAS  PubMed  Google Scholar 

  6. Suzuki A, Angulo P, Lymp J, St Sauver J, Muto A, Okada T, Lindor K. Chronological development of elevated aminotransferases in a nonalcoholic population. Hepatology. 2005;41(1):64–71.

    CAS  PubMed  Google Scholar 

  7. Benedetti A. Attraction and growing interest for the fatty liver by the scientific associations. Eur Rev Med Pharmacol Sci. 2005;9(5):251–2.

    CAS  PubMed  Google Scholar 

  8. Lam B, Younossi ZM. Treatment options for nonalcoholic fatty liver disease. Therap Adv Gastroenterol. 2010;3(2):121–37.

    CAS  PubMed Central  PubMed  Google Scholar 

  9. Ong JP, Younossi ZM. Approach to the diagnosis and treatment of nonalcoholic fatty liver disease. Clin Liver Dis. 2005;9(4):617–34. vi. Review.

    PubMed  Google Scholar 

  10. Caldwell SH, Oelsner DH, Iezzoni JC, Hespenheide EE, Battle EH, Driscoll CJ. Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease. Hepatology. 1999;29(3):664–9.

    CAS  PubMed  Google Scholar 

  11. Yasui K, Hashimoto E, Tokushige K, Koike K, Shima T, Kanbara Y, Saibara T, Uto H, Takami S, Kawanaka M, Komorizono Y, Okanoue T, The Japan NASH Study Group. Clinical and pathological progression of non-alcoholic steatohepatitis to hepatocellular carcinoma. Hepatol Res. 2012;42(8):767–73.

    CAS  PubMed  Google Scholar 

  12. Bugianesi E, Leone N, Vanni E, Marchesini G, Brunello F, Carucci P, Musso A, De Paolis P, Capussotti L, Salizzoni M, Rizzetto M. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology. 2002;123(1):134–40.

    PubMed  Google Scholar 

  13. Bhatia LS, Curzen NP, Calder PC, Byrne CD. Non-alcoholic fatty liver disease: a new and important cardiovascular risk factor? Eur Heart J. 2012;33(10):1190–200.

    CAS  PubMed  Google Scholar 

  14. Younossi ZM, Page S, Rafiq N, Birerdinc A, Stepanova M, Hossain N, Afendy A, Younoszai Z, Goodman Z, Baranova A. A biomarker panel for non-alcoholic steatohepatitis (NASH) and NASH-related fibrosis. Obes Surg. 2011;21(4):431–9.

    PubMed  Google Scholar 

  15. Younossi ZM, Jarrar M, Nugent C, Randhawa M, Afendy M, Stepanova M, Rafiq N, Goodman Z, Chandhoke V, Baranova A. A novel diagnostic biomarker panel for obesity-related nonalcoholic steatohepatitis (NASH). Obes Surg. 2008;18(11):1430–7.

    PubMed  Google Scholar 

  16. Shen J, Chan HL, Wong GL, Choi PC, Chan AW, Chan HY, Chim AM, Yeung DK, Chan FK, Woo J, Yu J, Chu WC, Wong VW. Non-invasive diagnosis of non-alcoholic steatohepatitis by combined serum biomarkers. J Hepatol. 2012;56(6):1363–70.

    CAS  PubMed  Google Scholar 

  17. Friedrich-Rust M, Romen D, Vermehren J, Kriener S, Sadet D, Herrmann E, Zeuzem S, Bojunga J. Acoustic radiation force impulse-imaging and transient elastography for non-invasive assessment of liver fibrosis and steatosis in NAFLD. Eur J Radiol. 2012;81(3):e325–31.

    PubMed  Google Scholar 

  18. Ratziu V, Charlotte F, Heurtier A, Gombert S, Giral P, Bruckert E, Grimaldi A, Capron F, Poynard T, LIDO Study Group. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology. 2005;128(7):1898–906.

    PubMed  Google Scholar 

  19. Arun J, Jhala N, Lazenby AJ, Clements R, Abrams GA. Influence of liver biopsy heterogeneity and diagnosis of nonalcoholic steatohepatitis in subjects undergoing gastric bypass. Obes Surg. 2007;17:155–61.

    PubMed  Google Scholar 

  20. Torres DM, Williams CD, Harrison SA. Features, diagnosis, and treatment of nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2012;10(8):837–58.

    PubMed  Google Scholar 

  21. de Oliveira CP, Stefano JT, de Siqueira ER, Silva LS, de Campos Mazo DF, Lima VM, Furuya CK, Mello ES, Souza FG, Rabello F, Santos TE, Nogueira MA, Caldwell SH, Alves VA, Carrilho FJ. Combination of N-acetylcysteine and metformin improves histological steatosis and fibrosis in patients with non-alcoholic steatohepatitis. Hepatol Res. 2008;38(2):159–65.

    PubMed  Google Scholar 

  22. Stephen S, Baranova A, Younossi ZM. Nonalcoholic fatty liver disease and bariatric surgery. Expert Rev Gastroenterol Hepatol. 2012;6(2):163–71.

    PubMed  Google Scholar 

  23. Martel C, Esposti DD, Bouchet A, Brenner C, Lemoine A. Non-alcoholic steatohepatitis: new insights from OMICS studies. Curr Pharm Biotechnol. 2012;13(5):726–35.

    CAS  PubMed  Google Scholar 

  24. Chitturi S, Farrell GC. Etiopathogenesis of nonalcoholic steatohepatitis. Semin Liver Dis. 2001;21(1):27–41.

    CAS  PubMed  Google Scholar 

  25. Koteish A, Diehl AM. Animal models of steatosis. Semin Liver Dis. 2001;21(1):89–104.

    CAS  PubMed  Google Scholar 

  26. Baranova A, Tran TP, Birerdinc A, Younossi ZM. Systematic review: association of polycystic ovary syndrome with metabolic syndrome and non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2011;33(7):801–14.

    CAS  PubMed  Google Scholar 

  27. Ortiz-Lopez C, Lomonaco R, Orsak B, Finch J, Chang Z, Kochunov VG, Hardies J, Cusi K. Prevalence of prediabetes and diabetes and metabolic profile of patients with nonalcoholic fatty liver disease (NAFLD). Diabetes Care. 2012;35(4):873–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  28. Sakaguchi S, Takahashi S, Sasaki T, Kumagai T, Nagata K. Progression of alcoholic and non-alcoholic steatohepatitis: common metabolic aspects of innate immune system and oxidative stress. Drug Metab Pharmacokinet. 2011;26(1):30–46.

    CAS  PubMed  Google Scholar 

  29. Serviddio G, Bellanti F, Vendemiale G, Altomare E. Mitochondrial dysfunction in nonalcoholic steatohepatitis. Expert Rev Gastroenterol Hepatol. 2011;5(2):233–44.

    CAS  PubMed  Google Scholar 

  30. Diehl AM. Tumor necrosis factor and its potential role in insulin resistance and nonalcoholic fatty liver disease. Clin Liver Dis. 2004;8(3):619–38.

    PubMed  Google Scholar 

  31. Jarrar MH, Baranova A, Collantes R, Ranard B, Stepanova M, Bennett C, Fang Y, Elariny H, Goodman Z, Chandhoke V, Younossi ZM. Adipokines and cytokines in non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2008;27(5):412–21.

    CAS  PubMed  Google Scholar 

  32. Fantuzzi G. Adipose tissue, adipokines, and inflammation. J Allergy Clin Immunol. 2005;115(5):911–9. quiz 920.

    CAS  PubMed  Google Scholar 

  33. Lee YH, Pratley RE. The evolving role of inflammation in obesity and the metabolic syndrome. Curr Diab Rep. 2005;5(1):70–5.

    CAS  PubMed  Google Scholar 

  34. Fain JN, Tichansky DS, Madan AK. Most of the interleukin 1 receptor antagonist, cathepsin S, macrophage migration inhibitory factor, nerve growth factor, and interleukin 18 release by explants of human adipose tissue is by the non-fat cells, not by the adipocytes. Metabolism. 2006;55(8):1113–21.

    CAS  PubMed  Google Scholar 

  35. Wilkinson M, Brown R, Imran SA, Ur E. Adipokine gene expression in brain and pituitary gland. Neuroendocrinology. 2007;86(3):191–209.

    CAS  PubMed  Google Scholar 

  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(10):2199–202.

    CAS  PubMed  Google Scholar 

  37. Nanji AA. Animal models of nonalcoholic fatty liver disease and steatohepatitis. Clin Liver Dis. 2004;8(3):559–74. ix.

    PubMed  Google Scholar 

  38. Li Z, Yang S, Lin H, Huang J, Watkins PA, Moser AB, Desimone C, Song XY, Diehl AM. Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease. Hepatology. 2003;37(2):343–50.

    CAS  PubMed  Google Scholar 

  39. Raso GM, Esposito E, Iacono A, Pacilio M, Cuzzocrea S, Canani RB, Calignano A, Meli R. Comparative therapeutic effects of metformin and vitamin E in a model of non-alcoholic steatohepatitis in the young rat. Eur J Pharmacol. 2009;604(1–3):125–31.

    CAS  PubMed  Google Scholar 

  40. Berg AH, Combs TP, Du X, Brownlee M, Scherer PE. The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med. 2001;7(8):947–53.

    CAS  PubMed  Google Scholar 

  41. Yamauchi T, Kamon J, Waki H, Imai Y, Shimozawa N, Hioki K, Uchida S, Ito Y, Takakuwa K, Matsui J, Takata M, Eto K, Terauchi Y, Komeda K, Tsunoda M, Murakami K, Ohnishi Y, Naitoh T, Yamamura K, Ueyama Y, Froguel P, Kimura S, Nagai R, Kadowaki T. Globular adiponectin protected ob/ob mice from diabetes and ApoE-deficient mice from atherosclerosis. J Biol Chem. 2003;278(4):2461–8.

    CAS  PubMed  Google Scholar 

  42. Xu A, Wang Y, Keshaw H, Xu LY, Lam KS, Cooper GJ. The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J Clin Invest. 2003;112(1):91–100.

    CAS  PubMed Central  PubMed  Google Scholar 

  43. Kamada Y, Tamura S, Kiso S, Matsumoto H, Saji Y, Yoshida Y, Fukui K, Maeda N, Nishizawa H, Nagaretani H, Okamoto Y, Kihara S, Miyagawa J, Shinomura Y, Funahashi T, Matsuzawa Y. Enhanced carbon tetrachloride-induced liver fibrosis in mice lacking adiponectin. Gastroenterology. 2003;125(6):1796–807.

    CAS  PubMed  Google Scholar 

  44. Masaki T, Chiba S, Tatsukawa H, Yasuda T, Noguchi H, Seike M, Yoshimatsu H. Adiponectin protects LPS-induced liver injury through modulation of TNF-alpha in KK-Ay obese mice. Hepatology. 2004;40(1):177–84.

    CAS  PubMed  Google Scholar 

  45. Yang RZ, Huang Q, Xu A, McLenithan JC, Eisen JA, Shuldiner AR, Alkan S, Gong DW. Comparative studies of resistin expression and phylogenomics in human and mouse. Biochem Biophys Res Commun. 2003;310(3):927–35. Erratum in: Biochem Biophys Res Commun. 2003 Dec 19;312(3):866. Eison Jonathan A [corrected to Eisen Jonathan A].

    CAS  PubMed  Google Scholar 

  46. López-Bermejo A, Botas P, Funahashi T, Delgado E, Kihara S, Ricart W, Fernández-Real JM. Adiponectin, hepatocellular dysfunction and insulin sensitivity. Clin Endocrinol (Oxf). 2004;60(2):256–63.

    Google Scholar 

  47. Pagano C, Soardo G, Esposito W, Fallo F, Basan L, Donnini D, Federspil G, Sechi LA, Vettor R. Plasma adiponectin is decreased in nonalcoholic fatty liver disease. Eur J Endocrinol. 2005;152(1):113–8.

    CAS  PubMed  Google Scholar 

  48. Mendez-Sanchez N, Chavez-Tapia NC, Villa AR, Sanchez-Lara K, Zamora-Valdes D, Ramos MH, Uribe M. Adiponectin as a protective factor in hepatic steatosis. World J Gastroenterol. 2005;11(12):1737–41.

    CAS  PubMed  Google Scholar 

  49. Zou CC, Liang L, Hong F, Fu JF, Zhao ZY. Serum adiponectin, resistin levels and non-alcoholic fatty liver disease in obese children. Endocr J. 2005;52(5):519–24.

    CAS  PubMed  Google Scholar 

  50. Bugianesi E, Pagotto U, Manini R, Vanni E, Gastaldelli A, de Iasio R, Gentilcore E, Natale S, Cassader M, Rizzetto M, Pasquali R, Marchesini G. Plasma adiponectin in nonalcoholic fatty liver is related to hepatic insulin resistance and hepatic fat content, not to liver disease severity. J Clin Endocrinol Metab. 2005;90(6):3498–504.

    CAS  PubMed  Google Scholar 

  51. Hui JM, Hodge A, Farrell GC, Kench JG, Kriketos A, George J. Beyond insulin resistance in NASH: TNF-alpha or adiponectin? Hepatology. 2004;40(1):46–54.

    CAS  PubMed  Google Scholar 

  52. Musso G, Gambino R, Biroli G, Carello M, Fagà E, Pacini G, De Michieli F, Cassader M, Durazzo M, Rizzetto M, Pagano G. Hypoadiponectinemia predicts the severity of hepatic fibrosis and pancreatic Beta-cell dysfunction in nondiabetic nonobese patients with nonalcoholic steatohepatitis. Am J Gastroenterol. 2005;100(11):2438–46.

    CAS  PubMed  Google Scholar 

  53. Musso G, Gambino R, Durazzo M, Biroli G, Carello M, Fagà E, Pacini G, De Michieli F, Rabbione L, Premoli A, Cassader M, Pagano G. Adipokines in NASH: postprandial lipid metabolism as a link between adiponectin and liver disease. Hepatology. 2005;42(5):1175–83.

    CAS  PubMed  Google Scholar 

  54. Comuzzie AG, Funahashi T, Sonnenberg G, Martin LJ, Jacob HJ, Black AE, Maas D, Takahashi M, Kihara S, Tanaka S, Matsuzawa Y, Blangero J, Cohen D, Kissebah A. The genetic basis of plasma variation in adiponectin, a global endophenotype for obesity and the metabolic syndrome. J Clin Endocrinol Metab. 2001;86(9):4321–5.

    CAS  PubMed  Google Scholar 

  55. Lindsay RS, Funahashi T, Krakoff J, Matsuzawa Y, Tanaka S, Kobes S, Bennett PH, Tataranni PA, Knowler WC, Hanson RL. Genome-wide linkage analysis of serum adiponectin in the Pima Indian population. Diabetes. 2003;52(9):2419–25.

    CAS  PubMed  Google Scholar 

  56. Menzaghi C, Ercolino T, Salvemini L, Coco A, Kim SH, Fini G, Doria A, Trischitta V. Multigenic control of serum adiponectin levels: evidence for a role of the APM1 gene and a locus on 14q13. Physiol Genomics. 2004;19(2):170–4. Epub 2004 Jul 13.

    CAS  PubMed  Google Scholar 

  57. Menzaghi C, Ercolino T, Di Paola R, Berg AH, Warram JH, Scherer PE, Trischitta V, Doria A. A haplotype at the adiponectin locus is associated with obesity and other features of the insulin resistance syndrome. Diabetes. 2002;51(7):2306–12.

    CAS  PubMed  Google Scholar 

  58. Gupta AC, Misra R, Sakhuja P, Singh Y, Basir SF, Sarin SK. Association of adiponectin gene functional polymorphisms (−11377C/G and +45T/G) with nonalcoholic fatty liver disease. Gene. 2012;496(1):63–7.

    CAS  PubMed  Google Scholar 

  59. Pajvani UB, Hawkins M, Combs TP, Rajala MW, Doebber T, Berger JP, et al. Complex distribution, not absolute amount of adiponectin, correlates with thiazolidinedione-mediated improvement in insulin sensitivity. J Biol Chem. 2004;279:12152–62.

    CAS  PubMed  Google Scholar 

  60. Kantartzis K, Staiger H, Machann J, Schick F, Claussen CD, Machicao F, Fritsche A, Häring HU, Stefan N. Adiponectin oligomers and ectopic fat in liver and skeletal muscle in humans. Obesity (Silver Spring). 2009;17(2):390–2.

    CAS  Google Scholar 

  61. Pettinelli P, Videla LA. Up-regulation of PPAR-gamma mRNA expression in the liver of obese patients: an additional reinforcing lipogenic mechanism to SREBP-1c induction. J Clin Endocrinol Metab. 2011;96(5):1424–30.

    CAS  PubMed  Google Scholar 

  62. Kaser S, Moschen A, Cayon A, Kaser A, Crespo J, Pons-Romero F, Ebenbichler CF, Patsch JR, Tilg H. Adiponectin and its receptors in non-alcoholic steatohepatitis. Gut. 2005;54(1):117–21.

    CAS  PubMed Central  PubMed  Google Scholar 

  63. Shimizu A, Takamura T, Matsuzawa N, Nakamura S, Nabemoto S, Takeshita Y, Misu H, Kurita S, Sakurai M, Yokoyama M, Zen Y, Sasaki M, Nakanuma Y, Kaneko S. Regulation of adiponectin receptor expression in human liver and a hepatocyte cell line. Metabolism. 2007;56(11):1478–85.

    CAS  PubMed  Google Scholar 

  64. Vuppalanchi R, Marri S, Kolwankar D, Considine RV, Chalasani N. Is adiponectin involved in the pathogenesis of nonalcoholic steatohepatitis? A preliminary human study. J Clin Gastroenterol. 2005;39(3):237–42.

    PubMed  Google Scholar 

  65. Carazo A, León J, Casado J, Gila A, Delgado S, Martín A, Sanjuan L, Caballero T, Muñoz JA, Quiles R, Ruiz-Extremera A, Alcázar LM, Salmerón J. Hepatic expression of adiponectin receptors increases with non-alcoholic fatty liver disease progression in morbid obesity in correlation with glutathione peroxidase. Obes Surg. 2011;21(4):492–500.

    PubMed  Google Scholar 

  66. Ma H, Gomez V, Lu L, Yang X, Wu X, Xiao SY. Expression of adiponectin and its receptors in livers of morbidly obese patients with non-alcoholic fatty liver disease. J Gastroenterol Hepatol. 2009;24(2):233–7.

    CAS  PubMed  Google Scholar 

  67. Uribe M, Zamora-Valdés D, Moreno-Portillo M, Bermejo-Martínez L, Pichardo-Bahena R, Baptista-González HA, Ponciano-Rodríguez G, Uribe MH, Medina-Santillán R, Méndez-Sánchez N. Hepatic expression of ghrelin and adiponectin and their receptors in patients with nonalcoholic fatty liver disease. Ann Hepatol. 2008;7(1):67–71.

    CAS  PubMed  Google Scholar 

  68. Stefan N, Machicao F, Staiger H, Machann J, Schick F, Tschritter O, Spieth C, Weigert C, Fritsche A, Stumvoll M, Häring HU. Polymorphisms in the gene encoding adiponectin receptor 1 are associated with insulin resistance and high liver fat. Diabetologia. 2005;48(11):2282–91.

    CAS  PubMed  Google Scholar 

  69. Kotronen A, Yki-Järvinen H, Aminoff A, Bergholm R, Pietiläinen KH, Westerbacka J, Talmud PJ, Humphries SE, Hamsten A, Isomaa B, Groop L, Orho-Melander M, Ehrenborg E, Fisher RM. Genetic variation in the ADIPOR2 gene is associated with liver fat content and its surrogate markers in three independent cohorts. Eur J Endocrinol. 2009;160(4):593–602.

    CAS  PubMed  Google Scholar 

  70. López-Bermejo A, Botas-Cervero P, Ortega-Delgado F, Delgado E, García-Gil MM, Funahashi T, Ricart W, Fernández-Real JM. Association of ADIPOR2 with liver function tests in type 2 diabetic subjects. Obesity (Silver Spring). 2008;16(10):2308–13.

    Google Scholar 

  71. 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(4):1092–101.

    CAS  PubMed  Google Scholar 

  72. Bajaj M, Suraamornkul S, Hardies LJ, Pratipanawatr T, DeFronzo RA. Plasma resistin concentration, hepatic fat content, and hepatic and peripheral insulin resistance in pioglitazone-treated type II diabetic patients. Int J Obes Relat Metab Disord. 2004;28(6):783–9.

    CAS  PubMed  Google Scholar 

  73. Nobili V, Carpino G, Alisi A, Franchitto A, Alpini G, De Vito R, Onori P, Alvaro D, Gaudio E. Hepatic progenitor cells activation, fibrosis and adipokines production in pediatric nonalcoholic fatty liver disease. Hepatology. 2012;56(6):2142–53.

    CAS  PubMed  Google Scholar 

  74. Lebensztejn DM, Wojtkowska M, Skiba E, Werpachowska I, Tobolczyk J, Kaczmarski M. Serum concentration of adiponectin, leptin and resistin in obese children with non-alcoholic fatty liver disease. Adv Med Sci. 2009;54(2):177–82.

    CAS  PubMed  Google Scholar 

  75. Le D, Marks D, Lyle E, Corless CL, Diggs BS, Jobe BA, Kay T, Deveney CW, Wolfe BM, Roberts Jr CT, O’Rourke RW. Serum leptin levels, hepatic leptin receptor transcription, and clinical predictors of non-alcoholic steatohepatitis in obese bariatric surgery patients. Surg Endosc. 2007;21(9):1593–9.

    CAS  PubMed  Google Scholar 

  76. Schaab M, Kausch H, Klammt J, Nowicki M, Anderegg U, Gebhardt R, Rose-John S, Scheller J, Thiery J, Kratzsch J. Novel regulatory mechanisms for generation of the soluble leptin receptor: implications for leptin action. PLoS One. 2012;7(4):e34787.

    CAS  PubMed Central  PubMed  Google Scholar 

  77. Huang XD, Fan Y, Zhang H, Wang P, Yuan JP, Li MJ, Zhan XY. Serum leptin and soluble leptin receptor in non-alcoholic fatty liver disease. World J Gastroenterol. 2008;14(18):2888–93.

    CAS  PubMed Central  PubMed  Google Scholar 

  78. Medici V, Ali MR, Seo S, Aoki CA, Rossaro L, Kim K, Fuller WD, Vidovszky TJ, Smith W, Jiang JX, Maganti K, Havel PJ, Kamboj A, Ramsamooj R, Török NJ. Increased soluble leptin receptor levels in morbidly obese patients with insulin resistance and nonalcoholic fatty liver disease. Obesity (Silver Spring). 2010;18(12):2268–73.

    CAS  Google Scholar 

  79. Ge F, Zhou S, Hu C, Lobdell IV H, Berk PD. Insulin- and leptin-regulated fatty acid uptake plays a key causal role in hepatic steatosis in mice with intact leptin signaling but not in ob/ob or db/db mice. Am J Physiol Gastrointest Liver Physiol. 2010;299(4):G855–66.

    CAS  PubMed Central  PubMed  Google Scholar 

  80. Shamsuzzaman AS, Winnicki M, Wolk R, Svatikova A, Phillips BG, Davison DE, Berger PB, Somers VK. Independent association between plasma leptin and C-reactive protein in healthy humans. Circulation. 2004;109(18):2181–5.

    CAS  PubMed  Google Scholar 

  81. Wang J, Leclercq I, Brymora JM, Xu N, Ramezani-Moghadam M, London RM, Brigstock D, George J. Kupffer cells mediate leptin-induced liver fibrosis. Gastroenterology. 2009;137(2):713–23.

    CAS  PubMed Central  PubMed  Google Scholar 

  82. Petersen KF, Oral EA, Dufour S, Befroy D, Ariyan C, Yu C, Cline GW, DePaoli AM, Taylor SI, Gorden P, Shulman GI. Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J Clin Invest. 2002;109(10):1345–50.

    CAS  PubMed Central  PubMed  Google Scholar 

  83. Javor ED, Cochran EK, Musso C, Young JR, Depaoli AM, Gorden P. Long-term efficacy of leptin replacement in patients with generalized lipodystrophy. Diabetes. 2005;54(7):1994–2002.

    CAS  PubMed  Google Scholar 

  84. Chan JL, Lutz K, Cochran E, Huang W, Peters Y, Weyer C, Gorden P. Clinical effects of long-term metreleptin treatment in patients with lipodystrophy. Endocr Pract. 2011;17(6):922–32.

    PubMed Central  PubMed  Google Scholar 

  85. Swellam M, Hamdy N. Association of nonalcoholic fatty liver disease with a single nucleotide polymorphism on the gene encoding leptin receptor. IUBMB Life. 2012;64(2):180–6.

    CAS  PubMed  Google Scholar 

  86. Lu H, Sun J, Sun L, Shu X, Xu Y, Xie D. Polymorphism of human leptin receptor gene is associated with type 2 diabetic patients complicated with non-alcoholic fatty liver disease in China. J Gastroenterol Hepatol. 2009;24(2):228–32.

    CAS  PubMed  Google Scholar 

  87. Aller R, De Luis DA, Izaola O, González Sagrado M, Conde R, Pacheco D, Velasco MC, Ovalle HF. Lys656Asn polymorphism of leptin receptor, leptin levels and insulin resistance in patients with non alcoholic fatty liver disease. Eur Rev Med Pharmacol Sci. 2012;16(3):335–41.

    CAS  PubMed  Google Scholar 

  88. Fain JN. Release of interleukins and other inflammatory cytokines by human adipose tissue is enhanced in obesity and primarily due to the nonfat cells. Vitam Horm. 2006;74:443–77.

    CAS  PubMed  Google Scholar 

  89. Crespo J, Cayón A, Fernández-Gil P, Hernández-Guerra M, Mayorga M, Domínguez-Díez A, Fernández-Escalante JC, Pons-Romero F. Gene expression of tumor necrosis factor alpha and TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients. Hepatology. 2001;34(6):1158–63.

    CAS  PubMed  Google Scholar 

  90. Wang JK, Feng ZW, Li YC, Li QY, Tao XY. Association of tumor necrosis factor-α gene promoter polymorphism at sites −308 and −238 with non-alcoholic fatty liver disease: a meta-analysis. J Gastroenterol Hepatol. 2012;27(4):670–6.

    CAS  PubMed  Google Scholar 

  91. Adams LA, Zein CO, Angulo P, Lindor KD. A pilot trial of pentoxifylline in nonalcoholic steatohepatitis. Am J Gastroenterol. 2004;99(12):2365–8.

    CAS  PubMed  Google Scholar 

  92. Satapathy SK, Garg S, Chauhan R, Sakhuja P, Malhotra V, Sharma BC, Sarin SK. Beneficial effects of tumor necrosis factor-alpha inhibition by pentoxifylline on clinical, biochemical, and metabolic parameters of patients with nonalcoholic steatohepatitis. Am J Gastroenterol. 2004;99(10):1946–52.

    CAS  PubMed  Google Scholar 

  93. Zein CO, Yerian LM, Gogate P, Lopez R, Kirwan JP, Feldstein AE, McCullough AJ. Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial. Hepatology. 2011;54(5):1610–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  94. Li W, Zheng L, Sheng C, Cheng X, Qing L, Qu S. Systematic review on the treatment of pentoxifylline in patients with non-alcoholic fatty liver disease. Lipids Health Dis. 2011;10:49.

    CAS  PubMed Central  PubMed  Google Scholar 

  95. Estep M, Armistead D, Hossain N, Elarainy H, Goodman Z, Baranova A, Chandhoke V, Younossi ZM. Differential expression of miRNAs in the visceral adipose tissue of patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2010;32(3):487–97.

    CAS  PubMed  Google Scholar 

  96. Fain JN. Release of inflammatory mediators by human adipose tissue is enhanced in obesity and primarily by the nonfat cells: a review. Mediators Inflamm. 2010;2010:513948.

    PubMed Central  PubMed  Google Scholar 

  97. Fain JN, Madan AK, Hiler ML, Cheema P, Bahouth SW. Comparison of the release of adipokines by adipose tissue, adipose tissue matrix, and adipocytes from visceral and subcutaneous abdominal adipose tissues of obese humans. Endocrinology. 2004;145(5):2273–82.

    CAS  PubMed  Google Scholar 

  98. Fain JN, Bahouth SW, Madan AK. Involvement of multiple signaling pathways in the post-bariatric induction of IL-6 and IL-8 mRNA and release in human visceral adipose tissue. Biochem Pharmacol. 2005;69(9):1315–24.

    CAS  PubMed  Google Scholar 

  99. Bahcecioglu IH, Yalniz M, Ataseven H, Ilhan N, Ozercan IH, Seckin D, Sahin K. Levels of serum hyaluronic acid, TNF-alpha and IL-8 in patients with nonalcoholic steatohepatitis. Hepatogastroenterology. 2005;52(65):1549–53.

    CAS  PubMed  Google Scholar 

  100. Coulon S, Francque S, Colle I, Verrijken A, Blomme B, Heindryckx F, De Munter S, Prawitt J, Caron S, Staels B, Van Vlierberghe H, Van Gaal L, Geerts A. Evaluation of inflammatory and angiogenic factors in patients with non-alcoholic fatty liver disease. Cytokine. 2012;59(2):442–9.

    CAS  PubMed  Google Scholar 

  101. Teoh N, Field J, Farrell G. Interleukin-6 is a key mediator of the hepatoprotective and pro-proliferative effects of ischaemic preconditioning in mice. J Hepatol. 2006;45(1):20–7.

    CAS  PubMed  Google Scholar 

  102. Gao B. Therapeutic potential of interleukin-6 in preventing obesity- and alcohol-associated fatty liver transplant failure. Alcohol. 2004;34(1):59–65.

    CAS  PubMed  Google Scholar 

  103. Sartipy P, Loskutoff DJ. Monocyte chemoattractant protein 1 in obesity and insulin resistance. Proc Natl Acad Sci U S A. 2003;100:7265–70.

    CAS  PubMed Central  PubMed  Google Scholar 

  104. Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, Kitazawa S, Miyachi H, Maeda S, Egashira K, et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest. 2006;116:1494–505.

    CAS  PubMed Central  PubMed  Google Scholar 

  105. Baeck C, Wehr A, Karlmark KR, Heymann F, Vucur M, Gassler N, Huss S, Klussmann S, Eulberg D, Luedde T, Trautwein C, Tacke F. Pharmacological inhibition of the chemokine CCL2 (MCP-1) diminishes liver macrophage infiltration and steatohepatitis in chronic hepatic injury. Gut. 2012;61(3):416–26.

    CAS  PubMed  Google Scholar 

  106. Kirovski G, Dorn C, Huber H, Moleda L, Niessen C, Wobser H, Schacherer D, Buechler C, Wiest R, Hellerbrand C. Elevated systemic monocyte chemoattractrant protein-1 in hepatic steatosis without significant hepatic inflammation. Exp Mol Pathol. 2011;91(3):780–3.

    CAS  PubMed  Google Scholar 

  107. Bertola A, Ciucci T, Rousseau D, Bourlier V, Duffaut C, Bonnafous S, Blin-Wakkach C, Anty R, Iannelli A, Gugenheim J, Tran A, Bouloumié A, Gual P, Wakkach A. Identification of adipose tissue dendritic cells correlated with obesity-associated insulin-resistance and inducing Th17 responses in mice and patients. Diabetes. 2012;61(9):2238–47.

    CAS  PubMed Central  PubMed  Google Scholar 

  108. Tang Y, Bian Z, Zhao L, Liu Y, Liang S, Wang Q, Han X, Peng Y, Chen X, Shen L, Qiu D, Li Z, Ma X. Interleukin-17 exacerbates hepatic steatosis and inflammation in non-alcoholic fatty liver disease. Clin Exp Immunol. 2011;166(2):281–90.

    CAS  PubMed Central  PubMed  Google Scholar 

  109. Charlton M, Sreekumar R, Rasmussen D, Lindor K, Nair KS. Apolipoprotein synthesis in nonalcoholic steatohepatitis. Hepatology. 2002;35(4):898–904.

    CAS  PubMed  Google Scholar 

  110. Chan DC, Watts GF, Ooi EM, Chan DT, Wong AT, Barrett PH. Apolipoprotein A-II and adiponectin as determinants of very low-density lipoprotein apolipoprotein B-100 metabolism in nonobese men. Metabolism. 2011;60(10):1482–7.

    CAS  PubMed  Google Scholar 

  111. Ng TW, Watts GF, Farvid MS, Chan DC, Barrett PH. Adipocytokines and VLDL metabolism: independent regulatory effects of adiponectin, insulin resistance, and fat compartments on VLDL apolipoprotein B-100 kinetics? Diabetes. 2005;54(3):795–802.

    CAS  PubMed  Google Scholar 

  112. Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S, Yamashita S, Noda M, Kita S, Ueki K, Eto K, Akanuma Y, Froguel P, Foufelle F, Ferre P, Carling D, Kimura S, Nagai R, Kahn BB, Kadowaki T. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med. 2002;8(11):1288–95. Epub 2002 Oct 7.

    CAS  PubMed  Google Scholar 

  113. Ganguly R, Schram K, Fang X, Kim M, Rodrigues B, Thong FS, Sweeney G. Adiponectin increases LPL activity via RhoA/ROCK-mediated actin remodelling in adult rat cardiomyocytes. Endocrinology. 2011;152(1):247–54.

    CAS  PubMed  Google Scholar 

  114. von Eynatten M, Schneider JG, Humpert PM, Rudofsky G, Schmidt N, Barosch P, Hamann A, Morcos M, Kreuzer J, Bierhaus A, Nawroth PP, Dugi KA. Decreased plasma lipoprotein lipase in hypoadiponectinemia: an association independent of systemic inflammation and insulin resistance. Diabetes Care. 2004;27(12):2925–9.

    Google Scholar 

  115. De Vries R, Wolffenbuttel BH, Sluiter WJ, van Tol A, Dullaart RP. Post-heparin plasma lipoprotein lipase, but not hepatic lipase activity, is related to plasma adiponectin in type 2 diabetic patients and healthy subjects. Clin Lab. 2005;51(7–8):403–9.

    PubMed  Google Scholar 

  116. Loucif Y, Méthot J, Tremblay K, Brisson D, Gaudet D. Contribution of adiponectin to the cardiometabolic risk of postmenopausal women with loss-of-function lipoprotein lipase gene mutations. Menopause. 2011;18(5):558–62.

    PubMed  Google Scholar 

  117. Yoon MJ, Lee GY, Chung JJ, Ahn YH, Hong SH, Kim JB. Adiponectin increases fatty acid oxidation in skeletal muscle cells by sequential activation of AMP-activated protein kinase, p38 mitogen-activated protein kinase, and peroxisome proliferator-activated receptor alpha. Diabetes. 2006;55(9):2562–70.

    CAS  PubMed  Google Scholar 

  118. Shetty S, Ramos-Roman MA, Cho YR, Brown J, Plutzky J, Muise ES, Horton JD, Scherer PE, Parks EJ. Enhanced fatty acid flux triggered by adiponectin overexpression. Endocrinology. 2012;153(1):113–22.

    CAS  PubMed Central  PubMed  Google Scholar 

  119. Shimabukuro M, Koyama K, Chen G, Wang MY, Trieu F, Lee Y, Newgard CB, Unger RH. Direct antidiabetic effect of leptin through triglyceride depletion of tissues. Proc Natl Acad Sci U S A. 1997;94(9):4637–41.

    CAS  PubMed Central  PubMed  Google Scholar 

  120. Lee Y, Wang MY, Kakuma T, Wang ZW, Babcock E, McCorkle K, Higa M, Zhou YT, Unger RH. Liporegulation in diet-induced obesity. The antisteatotic role of hyperleptinemia. J Biol Chem. 2001;276(8):5629–35. Epub 2000 Nov 28.

    CAS  PubMed  Google Scholar 

  121. Wang Y, Kuropatwinski KK, White DW, Hawley TS, Hawley RG, Tartaglia LA, Baumann H. Leptin receptor action in hepatic cells. J Biol Chem. 1997;272(26):16216–23.

    CAS  PubMed  Google Scholar 

  122. Cohen P, Friedman JM. Leptin and the control of metabolism: role for stearoyl-CoA desaturase-1 (SCD-1). J Nutr. 2004;134(9):2455S–63. Review.

    CAS  PubMed  Google Scholar 

  123. Asilmaz E, Cohen P, Miyazaki M, Dobrzyn P, Ueki K, Fayzikhodjaeva G, Soukas AA, Kahn CR, Ntambi JM, Socci ND, Friedman JM. Site and mechanism of leptin action in a rodent form of congenital lipodystrophy. J Clin Invest. 2004;113(3):414–24.

    CAS  PubMed Central  PubMed  Google Scholar 

  124. Miyazaki M, Kim YC, Gray-Keller MP, Attie AD, Ntambi JM. The biosynthesis of hepatic cholesterol esters and triglycerides is impaired in mice with a disruption of the gene for stearoyl-CoA desaturase 1. J Biol Chem. 2000;275(39):30132–8.

    CAS  PubMed  Google Scholar 

  125. Lee Y, Yu X, Gonzales F, Mangelsdorf DJ, Wang MY, Richardson C, Witters LA, Unger RH. PPAR alpha is necessary for the lipopenic action of hyperleptinemia on white adipose and liver tissue. Proc Natl Acad Sci U S A. 2002;99(18):11848–53. Epub 2002 Aug 23.

    CAS  PubMed Central  PubMed  Google Scholar 

  126. Minokoshi Y, Kim YB, Peroni OD, Fryer LG, Müller C, Carling D, Kahn BB. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature. 2002;415(6869):339–43.

    CAS  PubMed  Google Scholar 

  127. VanPatten S, Ranginani N, Shefer S, Nguyen LB, Rossetti L, Cohen DE. Impaired biliary lipid secretion in obese Zucker rats: leptin promotes hepatic cholesterol clearance. Am J Physiol Gastrointest Liver Physiol. 2001;281(2):G393–404.

    CAS  PubMed  Google Scholar 

  128. Méndez-Sánchez N, Ponciano-Rodrigoez G, Chavez-Tapia N, Uribe M. Effects of leptin on biliary lipids: potential consequences for gallstone formation and therapy in obesity. Curr Drug Targets Immune Endocr Metabol Disord. 2005;5(2):203–8.

    PubMed  Google Scholar 

  129. Nobili V, Manco M, Ciampalini P, Diciommo V, Devito R, Piemonte F, Comparcola D, Guidi R, Marcellini M. Leptin, free leptin index, insulin resistance and liver fibrosis in children with non-alcoholic fatty liver disease. Eur J Endocrinol. 2006;155(5):735–43.

    CAS  PubMed  Google Scholar 

  130. 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(2):224–31.

    CAS  PubMed Central  PubMed  Google Scholar 

  131. Sato N, Kobayashi K, Inoguchi T, Sonoda N, Imamura M, Sekiguchi N, Nakashima N, Nawata H. Adenovirus-mediated high expression of resistin causes dyslipidemia in mice. Endocrinology. 2005;146(1):273–9. Epub 2004 Oct 7.

    CAS  PubMed  Google Scholar 

  132. Singhal NS, Patel RT, Qi Y, Lee YS, Ahima RS. Loss of resistin ameliorates hyperlipidemia and hepatic steatosis in leptin-deficient mice. Am J Physiol Endocrinol Metab. 2008;295(2):E331–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  133. Chen CC, Li TC, Li CI, Liu CS, Wang HJ, Lin CC. Serum resistin level among healthy subjects: relationship to anthropometric and metabolic parameters. Metabolism. 2005;54(4):471–5.

    CAS  PubMed  Google Scholar 

  134. Costandi J, Melone M, Zhao A, Rashid S. Human resistin stimulates hepatic overproduction of atherogenic ApoB-containing lipoprotein particles by enhancing ApoB stability and impairing intracellular insulin signaling. Circ Res. 2011;108(6):727–42.

    CAS  PubMed  Google Scholar 

  135. Fon Tacer K, Kuzman D, Seliskar M, Pompon D, Rozman D. TNF-alpha interferes with lipid homeostasis and activates acute and proatherogenic processes. Physiol Genomics. 2007;31(2):216–27.

    PubMed  Google Scholar 

  136. Qin B, Anderson RA, Adeli K. Tumor necrosis factor-alpha directly stimulates the overproduction of hepatic apolipoprotein B100-containing VLDL via impairment of hepatic insulin signaling. Am J Physiol Gastrointest Liver Physiol. 2008;294(5):G1120–9.

    CAS  PubMed  Google Scholar 

  137. Glosli H, Gudbrandsen OA, Mullen AJ, Halvorsen B, Røst TH, Wergedahl H, Prydz H, Aukrust P, Berge RK. Down-regulated expression of PPARalpha target genes, reduced fatty acid oxidation and altered fatty acid composition in the liver of mice transgenic for hTNFalpha. Biochim Biophys Acta. 2005;1734(3):235–46.

    CAS  PubMed  Google Scholar 

  138. Ruan H, Miles PD, Ladd CM, Ross K, Golub TR, Olefsky JM, Lodish HF. Profiling gene transcription in vivo reveals adipose tissue as an immediate target of tumor necrosis factor-alpha: implications for insulin resistance. Diabetes. 2002;51:3176–88.

    CAS  PubMed  Google Scholar 

  139. Bugianesi E, Moscatiello S, Ciaravella MF, Marchesini G. Insulin resistance in nonalcoholic fatty liver disease. Curr Pharm Des. 2010;16(17):1941–51.

    CAS  PubMed  Google Scholar 

  140. Yamauchi T, Kadowaki T. Physiological and pathophysiological roles of adiponectin and adiponectin receptors in the integrated regulation of metabolic and cardiovascular diseases. Int J Obes (Lond). 2008;32 Suppl 7:S13–8.

    CAS  Google Scholar 

  141. Foretz M, Ancellin N, Andreelli F, Saintillan Y, Grondin P, Kahn A, Thorens B, Vaulont S, Viollet B. Short-term overexpression of a constitutively active form of AMP-activated protein kinase in the liver leads to mild hypoglycemia and fatty liver. Diabetes. 2005;54(5):1331–9.

    CAS  PubMed  Google Scholar 

  142. Parulkar AA, Pendergrass ML, Granda-Ayala R, Lee TR, Fonseca VA. Nonhypoglycemic effects of thiazolidinediones. Ann Intern Med. 2001;134(1):61–71. Review. Erratum in: Ann Intern Med 2001 Aug 21;135(4):307.

    CAS  PubMed  Google Scholar 

  143. Watkins SM, Reifsnyder PR, Pan HJ, German JB, Leiter EH. Lipid metabolome-wide effects of the PPARgamma agonist rosiglitazone. J Lipid Res. 2002;43(11):1809–17.

    CAS  PubMed  Google Scholar 

  144. Miller RA, Chu Q, Le Lay J, Scherer PE, Ahima RS, Kaestner KH, Foretz M, Viollet B, Birnbaum MJ. Adiponectin suppresses gluconeogenic gene expression in mouse hepatocytes independent of LKB1-AMPK signaling. J Clin Invest. 2011;121(6):2518–28.

    CAS  PubMed Central  PubMed  Google Scholar 

  145. Cowherd RB, Asmar MM, Alderman JM, Alderman EA, Garland AL, Busby WH, Bodnar WM, Rusyn I, Medoff BD, Tisch R, Mayer-Davis E, Swenberg JA, Zeisel SH, Combs TP. Adiponectin lowers glucose production by increasing SOGA. Am J Pathol. 2010;177(4):1936–45.

    PubMed  Google Scholar 

  146. Tishinsky JM, Robinson LE, Dyck DJ. Insulin-sensitizing properties of adiponectin. Biochimie. 2012;94(10):2131–6.

    CAS  PubMed  Google Scholar 

  147. Anubhuti, Arora S. Leptin and its metabolic interactions: an update. Diabetes Obes Metab. 2008;10(11):973–93.

    CAS  PubMed  Google Scholar 

  148. Cummings BP, Bettaieb A, Graham JL, Stanhope KL, Dill R, Morton GJ, Haj FG, Havel PJ. Subcutaneous administration of leptin normalizes fasting plasma glucose in obese type 2 diabetic UCD-T2DM rats. Proc Natl Acad Sci U S A. 2011;108(35):14670–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  149. Bjorbak C, Lavery HJ, Bates SH, Olson RK, Davis SM, Flier JS, Myers Jr MG. SOCS3 mediates feedback inhibition of the leptin receptor via Tyr985. J Biol Chem. 2000;275(51):40649–57.

    CAS  PubMed  Google Scholar 

  150. Tom RZ, Sjögren RJ, Vieira E, Glund S, Iglesias-Gutiérrez E, Garcia-Roves PM, Myers Jr MG, Björnholm M. Increased hepatic insulin sensitivity in mice lacking inhibitory leptin receptor signals. Endocrinology. 2011;152(6):2237–46.

    CAS  PubMed  Google Scholar 

  151. Lam NT, Lewis JT, Cheung AT, Luk CT, Tse J, Wang J, Bryer-Ash M, Kolls JK, Kieffer TJ. Leptin increases hepatic insulin sensitivity and protein tyrosine phosphatase 1B expression. Mol Endocrinol. 2004;18(6):1333–45.

    CAS  PubMed  Google Scholar 

  152. Brabant G, Müller G, Horn R, Anderwald C, Roden M, Nave H. Hepatic leptin signaling in obesity. FASEB J. 2005;19(8):1048–50.

    CAS  PubMed  Google Scholar 

  153. 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(5661):1195–8.

    CAS  PubMed  Google Scholar 

  154. Gerber M, Boettner A, Seidel B, Lammert A, Bär 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(8):4503–9. Epub 2005 May 31.

    CAS  PubMed  Google Scholar 

  155. Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS. Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature. 1997;389(6651):610–4.

    CAS  PubMed  Google Scholar 

  156. Gupta D, Khandelwal RL. Modulation of insulin effects on phosphorylation of protein kinase B and glycogen synthesis by tumor necrosis factor-alpha in HepG2 cells. Biochim Biophys Acta. 2004;1671(1–3):51–8.

    CAS  PubMed  Google Scholar 

  157. Gao Z, Hwang D, Bataille F, Lefevre M, York D, Quon MJ, Ye J. Serine phosphorylation of insulin receptor substrate 1 by inhibitor kappa B kinase complex. J Biol Chem. 2002;277(50):48115–21. Epub 2002 Sep 25.

    CAS  PubMed  Google Scholar 

  158. Hotamisligil GS. Inflammatory pathways and insulin action. Int J Obes Relat Metab Disord. 2003;27 Suppl 3:S53–5. Review.

    CAS  PubMed  Google Scholar 

  159. Nohara A, Okada S, Ohshima K, Pessin JE, Mori M. Cyclin-dependent kinase-5 is a key molecule in tumor necrosis factor-α-induced insulin resistance. J Biol Chem. 2011;286(38):33457–65.

    CAS  PubMed Central  PubMed  Google Scholar 

  160. Brown JE, Onyango DJ, Ramanjaneya M, Conner AC, Patel ST, Dunmore SJ, Randeva HS. Visfatin regulates insulin secretion, insulin receptor signalling and mRNA expression of diabetes-related genes in mouse pancreatic beta-cells. J Mol Endocrinol. 2010;44(3):171–8.

    CAS  PubMed  Google Scholar 

  161. Skop V, Kontrová K, Zídek V, Pravenec M, Kazdová L, Mikulík K, Sajdok J, Zídková J. Autocrine effects of visfatin on hepatocyte sensitivity to insulin action. Physiol Res. 2010;59(4):615–8.

    CAS  PubMed  Google Scholar 

  162. Hida K, Wada J, Eguchi J, Zhang H, Baba M, Seida A, Hashimoto I, Okada T, Yasuhara A, Nakatsuka A, Shikata K, Hourai S, Futami J, Watanabe E, Matsuki Y, Hiramatsu R, Akagi S, Makino H, Kanwar YS. Visceral adipose tissue-derived serine protease inhibitor: a unique insulin-sensitizing adipocytokine in obesity. Proc Natl Acad Sci U S A. 2005;102(30):10610–5. Epub 2005 Jul 19.

    CAS  PubMed Central  PubMed  Google Scholar 

  163. Jeong E, Youn BS, Kim DW, Kim EH, Park JW, Namkoong C, Jeong JY, Yoon SY, Park JY, Lee KU, Kim MS. Circadian rhythm of serum vaspin in healthy male volunteers: relation to meals. J Clin Endocrinol Metab. 2010;95(4):1869–75.

    CAS  PubMed  Google Scholar 

  164. Teshigawara S, Wada J, Hida K, Nakatsuka A, Eguchi J, Murakami K, Kanzaki M, Inoue K, Terami T, Katayama A, Iseda I, Matsushita Y, Miyatake N, McDonald JF, Hotta K, Makino H. Serum vaspin concentrations are closely related to insulin resistance, and rs77060950 at SERPINA12 genetically defines distinct group with higher serum levels in Japanese population. J Clin Endocrinol Metab. 2012;97(7):E1202–7.

    CAS  PubMed  Google Scholar 

  165. Klöting N, Berndt J, Kralisch S, Kovacs P, Fasshauer M, Schön MR, Stumvoll M, Blüher M. Vaspin gene expression in human adipose tissue: association with obesity and type 2 diabetes. Biochem Biophys Res Commun. 2006;339(1):430–6.

    PubMed  Google Scholar 

  166. Sörhede Winzell M, Magnusson C, Ahrén B. The apj receptor is expressed in pancreatic islets and its ligand, apelin, inhibits insulin secretion in mice. Regul Pept. 2005;131(1–3):12–7.

    PubMed  Google Scholar 

  167. Boucher J, Masri B, Daviaud D, Gesta S, Guigné C, Mazzucotelli A, Castan-Laurell I, Tack I, Knibiehler B, Carpéné C, Audigier Y, Saulnier-Blache JS, Valet P. Apelin, a newly identified adipokine up-regulated by insulin and obesity. Endocrinology. 2005;146(4):1764–71. Epub 2005 Jan 27.

    CAS  PubMed  Google Scholar 

  168. Ercin CN, Dogru T, Tapan S, Kara M, Haymana C, Karadurmus N, Karslioglu Y, Acikel C. Plasma apelin levels in subjects with nonalcoholic fatty liver disease. Metabolism. 2010;59(7):977–81.

    CAS  PubMed  Google Scholar 

  169. Ernst MC, Issa M, Goralski KB, Sinal CJ. Chemerin exacerbates glucose intolerance in mouse models of obesity and diabetes. Endocrinology. 2010;151(5):1998–2007.

    CAS  PubMed  Google Scholar 

  170. Ernst MC, Haidl ID, Zúñiga LA, Dranse HJ, Rourke JL, Zabel BA, Butcher EC, Sinal CJ. Disruption of the chemokine-like receptor-1 (CMKLR1) gene is associated with reduced adiposity and glucose intolerance. Endocrinology. 2012;153(2):672–82.

    CAS  PubMed Central  PubMed  Google Scholar 

  171. Takahashi M, Okimura Y, Iguchi G, Nishizawa H, Yamamoto M, Suda K, Kitazawa R, Fujimoto W, Takahashi K, Zolotaryov FN, Hong KS, Kiyonari H, Abe T, Kaji H, Kitazawa S, Kasuga M, Chihara K, Takahashi Y. Chemerin regulates β-cell function in mice. Sci Rep. 2011;1:123.

    PubMed Central  PubMed  Google Scholar 

  172. Takahashi M, Takahashi Y, Takahashi K, Zolotaryov FN, Hong KS, Kitazawa R, Iida K, Okimura Y, Kaji H, Kitazawa S, Kasuga M, Chihara K. Chemerin enhances insulin signaling and potentiates insulin-stimulated glucose uptake in 3T3-L1 adipocytes. FEBS Lett. 2008;582(5):573–8.

    CAS  PubMed  Google Scholar 

  173. Suzuki Y, Song SH, Sato K, So KH, Ardiyanti A, Kitayama S, Hong YH, Lee SD, Choi KC, Hagino A, Katoh K, Roh SG. Chemerin analog regulates energy metabolism in sheep. Anim Sci J. 2012;83(3):263–7.

    CAS  PubMed  Google Scholar 

  174. Wanninger J, Bauer S, Eisinger K, Weiss TS, Walter R, Hellerbrand C, Schäffler A, Higuchi A, Walsh K, Buechler C. Adiponectin upregulates hepatocyte CMKLR1 which is reduced in human fatty liver. Mol Cell Endocrinol. 2012;349(2):248–54.

    CAS  PubMed Central  PubMed  Google Scholar 

  175. Yang M, Zhang Z, Wang C, Li K, Li S, Boden G, Li L, Yang G. Nesfatin-1 action in the brain increases insulin sensitivity through Akt/AMPK/TORC2 pathway in diet-induced insulin resistance. Diabetes. 2012;61(8):1959–68.

    CAS  PubMed Central  PubMed  Google Scholar 

  176. Gonzalez R, Reingold BK, Gao X, Gaidhu MP, Tsushima RG, Unniappan S. Nesfatin-1 exerts a direct, glucose-dependent insulinotropic action on mouse islet β- and MIN6 cells. J Endocrinol. 2011;208(3):R9–16.

    CAS  PubMed  Google Scholar 

  177. Nakata M, Manaka K, Yamamoto S, Mori M, Yada T. Nesfatin-1 enhances glucose-induced insulin secretion by promoting Ca(2+) influx through L-type channels in mouse islet β-cells. Endocr J. 2011;58(4):305–13.

    CAS  PubMed  Google Scholar 

  178. Zhang Z, Li L, Yang M, Liu H, Boden G, Yang G. Increased plasma levels of nesfatin-1 in patients with newly diagnosed type 2 diabetes mellitus. Exp Clin Endocrinol Diabetes. 2012;120(2):91–5.

    CAS  PubMed  Google Scholar 

  179. Deniz R, Gurates B, Aydin S, Celik H, Sahin I, Baykus Y, Catak Z, Aksoy A, Citil C, Gungor S. Nesfatin-1 and other hormone alterations in polycystic ovary syndrome. Endocrine. 2012;42(3):694–9.

    CAS  PubMed  Google Scholar 

  180. Tan BK, Hallschmid M, Kern W, Lehnert H, Randeva HS. Decreased cerebrospinal fluid/plasma ratio of the novel satiety molecule, nesfatin-1/NUCB-2, in obese humans: evidence of nesfatin-1/NUCB-2 resistance and implications for obesity treatment. J Clin Endocrinol Metab. 2011;96(4):E669–73.

    CAS  PubMed  Google Scholar 

  181. Yang RZ, Lee MJ, Hu H, Pray J, Wu HB, Hansen BC, Shuldiner AR, Fried SK, McLenithan JC, Gong DW. Identification of omentin as a novel depot-specific adipokine in human adipose tissue: possible role in modulating insulin action. Am J Physiol Endocrinol Metab. 2006;290(6):E1253–61.

    CAS  PubMed  Google Scholar 

  182. Tan BK, Adya R, Farhatullah S, Lewandowski KC, O’Hare P, Lehnert H, Randeva HS. Omentin-1, a novel adipokine, is decreased in overweight insulin-resistant women with polycystic ovary syndrome: ex vivo and in vivo regulation of omentin-1 by insulin and glucose. Diabetes. 2008;57(4):801–8.

    CAS  PubMed  Google Scholar 

  183. Yan P, Liu D, Long M, Ren Y, Pang J, Li R. Changes of serum omentin levels and relationship between omentin and adiponectin concentrations in type 2 diabetes mellitus. Exp Clin Endocrinol Diabetes. 2011;119(4):257–63.

    CAS  PubMed  Google Scholar 

  184. Nakanishi S, Yamane K, Kamei N, Nojima H, Okubo M, Kohno N. A protective effect of adiponectin against oxidative stress in Japanese Americans: the association between adiponectin or leptin and urinary isoprostane. Metabolism. 2005;54(2):194–9.

    CAS  PubMed  Google Scholar 

  185. Soares AF, Guichardant M, Cozzone D, Bernoud-Hubac N, Bouzaïdi-Tiali N, Lagarde M, Géloën A. Effects of oxidative stress on adiponectin secretion and lactate production in 3T3-L1 adipocytes. Free Radic Biol Med. 2005;38(7):882–9.

    CAS  PubMed  Google Scholar 

  186. Yuan F, Li YN, Liu YH, Yi B, Tian JW, Liu FY. Adiponectin inhibits the generation of reactive oxygen species induced by high glucose and promotes endothelial NO synthase formation in human mesangial cells. Mol Med Rep. 2012;6(2):449–53.

    CAS  PubMed  Google Scholar 

  187. Chedid P, Hurtado-Nedelec M, Marion-Gaber B, Bournier O, Hayem G, Gougerot-Pocidalo MA, Frystyk J, Flyvbjerg A, El Benna J, Marie JC. Adiponectin and its globular fragment differentially modulate the oxidative burst of primary human phagocytes. Am J Pathol. 2012;180(2):682–92.

    CAS  PubMed  Google Scholar 

  188. Zhou M, Xu A, Tam PK, Lam KS, Huang B, Liang Y, Lee IK, Wu D, Wang Y. Upregulation of UCP2 by adiponectin: the involvement of mitochondrial superoxide and hnRNP K. PLoS One. 2012;7(2):e32349.

    CAS  PubMed Central  PubMed  Google Scholar 

  189. Huang W, Dedousis N, Bandi A, Lopaschuk GD, O’Doherty RM. Liver triglyceride secretion and lipid oxidative metabolism are rapidly altered by leptin in vivo. Endocrinology. 2006;147(3):1480–7.

    CAS  PubMed  Google Scholar 

  190. Sailaja JB, Balasubramaniyan V, Nalini N. Effect of exogenous leptin administration on high fat diet induced oxidative stress. Pharmazie. 2004;59(6):475–9.

    PubMed  Google Scholar 

  191. Balasubramaniyan V, Kalaivani Sailaja J, Nalini N. Role of leptin on alcohol-induced oxidative stress in Swiss mice. Pharmacol Res. 2003;47(3):211–6.

    CAS  PubMed  Google Scholar 

  192. Oztay F, Kandil A, Gurel E, Ustunova S, Kapucu A, Balci H, Akgun-Dar K, Demirci C. The relationship between nitric oxide and leptin in the lung of rat with streptozotocin-induced diabetes. Cell Biochem Funct. 2008;26(2):162–71.

    CAS  PubMed  Google Scholar 

  193. Förstermann U, Li H. Therapeutic effect of enhancing endothelial nitric oxide synthase (eNOS) expression and preventing eNOS uncoupling. Br J Pharmacol. 2011;164(2):213–23.

    PubMed Central  PubMed  Google Scholar 

  194. Leclercq IA, Field J, Enriquez A, Farrell GC, Robertson GR. Constitutive and inducible expression of hepatic CYP2E1 in leptin-deficient ob/ob mice. Biochem Biophys Res Commun. 2000;268(2):337–44.

    CAS  PubMed  Google Scholar 

  195. Caro AA, Cederbaum AI. Oxidative stress, toxicology, and pharmacology of CYP2E1. Annu Rev Pharmacol Toxicol. 2004;44:27–42.

    CAS  PubMed  Google Scholar 

  196. Aubert J, Begriche K, Knockaert L, Robin MA, Fromenty B. Increased expression of cytochrome P450 2E1 in nonalcoholic fatty liver disease: mechanisms and pathophysiological role. Clin Res Hepatol Gastroenterol. 2011;35(10):630–7.

    CAS  PubMed  Google Scholar 

  197. Kougias P, Chai H, Lin PH, Lumsden AB, Yao Q, Chen C. Adipocyte-derived cytokine resistin causes endothelial dysfunction of porcine coronary arteries. J Vasc Surg. 2005;41(4):691–8.

    PubMed  Google Scholar 

  198. Chemaly ER, Hadri L, Zhang S, Kim M, Kohlbrenner E, Sheng J, Liang L, Chen J, K-Raman P, Hajjar RJ, Lebeche D. Long-term in vivo resistin overexpression induces myocardial dysfunction and remodeling in rats. J Mol Cell Cardiol. 2011;51(2):144–55.

    CAS  PubMed Central  PubMed  Google Scholar 

  199. Smith SR, Bai F, Charbonneau C, Janderová L, Argyropoulos G. A promoter genotype and oxidative stress potentially link resistin to human insulin resistance. Diabetes. 2003;52(7):1611–8.

    CAS  PubMed  Google Scholar 

  200. Szalowska E, Elferink MG, Hoek A, Groothuis GM, Vonk RJ. Resistin is more abundant in liver than adipose tissue and is not up-regulated by lipopolysaccharide. J Clin Endocrinol Metab. 2009;94(8):3051–7.

    CAS  PubMed  Google Scholar 

  201. Fernández-Checa JC. Alcohol-induced liver disease: when fat and oxidative stress meet. Ann Hepatol. 2003;2(2):69–75. Review.

    PubMed  Google Scholar 

  202. García-Ruiz C, Colell A, Marí M, Morales A, Fernández-Checa JC. Direct effect of ceramide on the mitochondrial electron transport chain leads to generation of reactive oxygen species. Role of mitochondrial glutathione. J Biol Chem. 1997;272(17):11369–77.

    PubMed  Google Scholar 

  203. Arora AS, Jones BJ, Patel TC, Bronk SF, Gores GJ. Ceramide induces hepatocyte cell death through disruption of mitochondrial function in the rat. Hepatology. 1997;25(4):958–63.

    CAS  PubMed  Google Scholar 

  204. Chen XH, Zhao YP, Xue M, Ji CB, Gao CL, Zhu JG, Qin DN, Kou CZ, Qin XH, Tong ML, Guo XR. TNF-alpha induces mitochondrial dysfunction in 3T3-L1 adipocytes. Mol Cell Endocrinol. 2010;328(1–2):63–9.

    CAS  PubMed  Google Scholar 

  205. Nagai H, Matsumaru K, Feng G, Kaplowitz N. Reduced glutathione depletion causes necrosis and sensitization to tumor necrosis factor-alpha-induced apoptosis in cultured mouse hepatocytes. Hepatology. 2002;36(1):55–64.

    CAS  PubMed  Google Scholar 

  206. Glosli H, Tronstad KJ, Wergedal H, Müller F, Svardal A, Aukrust P, Berge RK, Prydz H. Human TNF-alpha in transgenic mice induces differential changes in redox status and glutathione-regulating enzymes. FASEB J. 2002;16(11):1450–2. Epub 2002 Jul 18.

    CAS  PubMed  Google Scholar 

  207. Nobili V, Pastore A, Gaeta LM, Tozzi G, Comparcola D, Sartorelli MR, Marcellini M, Bertini E, Piemonte F. Glutathione metabolism and antioxidant enzymes in patients affected by nonalcoholic steatohepatitis. Clin Chim Acta. 2005;355(1–2):105–11.

    CAS  PubMed  Google Scholar 

  208. Cortez-Pinto H, Yang SQ, Lin HZ, Costa S, Hwang CS, Lane MD, Bagby G, Diehl AM. Bacterial lipopolysaccharide induces uncoupling protein-2 expression in hepatocytes by a tumor necrosis factor-alpha-dependent mechanism. Biochem Biophys Res Commun. 1998;251(1):313–9.

    CAS  PubMed  Google Scholar 

  209. Baffy G, Zhang CY, Glickman JN, Lowell BB. Obesity-related fatty liver is unchanged in mice deficient for mitochondrial uncoupling protein 2. Hepatology. 2002;35(4):753–61.

    CAS  PubMed  Google Scholar 

  210. Park JW, Jeong G, Kim SJ, Kim MK, Park SM. Predictors reflecting the pathological severity of non-alcoholic fatty liver disease: comprehensive study of clinical and immunohistochemical findings in younger Asian patients. J Gastroenterol Hepatol. 2007;22(4):491–7.

    CAS  PubMed  Google Scholar 

  211. Yoshino J, Mills KF, Yoon MJ, Imai S. Nicotinamide mononucleotide, a key NAD(+) intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab. 2011;14(4):528–36.

    CAS  PubMed Central  PubMed  Google Scholar 

  212. Zhang LQ, Adyshev DM, Singleton P, Li H, Cepeda J, Huang SY, Zou X, Verin AD, Tu J, Garcia JG, Ye SQ. Interactions between PBEF and oxidative stress proteins—a potential new mechanism underlying PBEF in the pathogenesis of acute lung injury. FEBS Lett. 2008;582(13):1802–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  213. Montecucco F, Bauer I, Braunersreuther V, Bruzzone S, Akhmedov A, Lüscher TF, Speer T, Poggi A, Mannino E, Pelli G, Galan K, Bertolotto M, Lenglet S, Garuti A, Montessuit C, Lerch R, Pellieux C, Vuilleumier N, Dallegri F, Mage J, Sebastian C, Mostoslavsky R, Gayet-Ageron A, Patrone F, Mach F, Nencioni A. Inhibition of nicotinamide phosphoribosyltransferase reduces neutrophil-mediated injury in myocardial infarction. Antioxid Redox Signal. 2013;18(6):630–41.

    CAS  PubMed Central  PubMed  Google Scholar 

  214. Boini KM, Zhang C, Xia M, Han WQ, Brimson C, Poklis JL, Li PL. Visfatin-induced lipid raft redox signaling platforms and dysfunction in glomerular endothelial cells. Biochim Biophys Acta. 2010;1801(12):1294–304.

    CAS  PubMed Central  PubMed  Google Scholar 

  215. Xia M, Zhang C, Boini KM, Thacker AM, Li PL. Membrane raft-lysosome redox signalling platforms in coronary endothelial dysfunction induced by adipokine visfatin. Cardiovasc Res. 2011;89(2):401–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  216. Hashimoto T, Kihara M, Imai N, Yoshida S, Shimoyamada H, Yasuzaki H, Ishida J, Toya Y, Kiuchi Y, Hirawa N, Tamura K, Yazawa T, Kitamura H, Fukamizu A, Umemura S. Requirement of apelin-apelin receptor system for oxidative stress-linked atherosclerosis. Am J Pathol. 2007;171(5):1705–12.

    CAS  PubMed Central  PubMed  Google Scholar 

  217. Foussal C, Lairez O, Calise D, Pathak A, Guilbeau-Frugier C, Valet P, Parini A, Kunduzova O. Activation of catalase by apelin prevents oxidative stress-linked cardiac hypertrophy. FEBS Lett. 2010;584(11):2363–70.

    CAS  PubMed  Google Scholar 

  218. Attané C, Foussal C, Le Gonidec S, Benani A, Daviaud D, Wanecq E, Guzmán-Ruiz R, Dray C, Bezaire V, Rancoule C, Kuba K, Ruiz-Gayo M, Levade T, Penninger J, Burcelin R, Pénicaud L, Valet P, Castan-Laurell I. Apelin treatment increases complete fatty acid oxidation, mitochondrial oxidative capacity, and biogenesis in muscle of insulin-resistant mice. Diabetes. 2012;61(2):310–20.

    PubMed Central  PubMed  Google Scholar 

  219. Weigert J, Neumeier M, Wanninger J, Filarsky M, Bauer S, Wiest R, Farkas S, Scherer MN, Schäffler A, Aslanidis C, Schölmerich J, Buechler C. Systemic chemerin is related to inflammation rather than obesity in type 2 diabetes. Clin Endocrinol (Oxf). 2010;72(3):342–8.

    CAS  Google Scholar 

  220. Kukla M, Zwirska-Korczala K, Hartleb M, Waluga M, Chwist A, Kajor M, Ciupinska-Kajor M, Berdowska A, Wozniak-Grygiel E, Buldak R. Serum chemerin and vaspin in non-alcoholic fatty liver disease. Scand J Gastroenterol. 2010;45(2):235–42.

    CAS  PubMed  Google Scholar 

  221. Yamawaki H, Kuramoto J, Kameshima S, Usui T, Okada M, Hara Y. Omentin, a novel adipocytokine inhibits TNF-induced vascular inflammation in human endothelial cells. Biochem Biophys Res Commun. 2011;408(2):339–43.

    CAS  PubMed  Google Scholar 

  222. Ratziu V, Poynard T. NASH: a hidden and silent fibroser finally revealed? J Hepatol. 2005;42(1):12–4.

    PubMed  Google Scholar 

  223. Ikejima K, Takei Y, Honda H, Hirose M, Yoshikawa M, Zhang YJ, Lang T, Fukuda T, Yamashina S, Kitamura T, Sato N. Leptin receptor-mediated signaling regulates hepatic fibrogenesis and remodeling of extracellular matrix in the rat. Gastroenterology. 2002;122(5):1399–410.

    CAS  PubMed  Google Scholar 

  224. Lu B, Yu L, Li S, Si S, Zeng Y. Alleviation of CCl4-induced cirrhosis in rats by tetramethylpyrazine is associated with downregulation of leptin and TGF-beta1 pathway. Drug Chem Toxicol. 2010;33(3):310–5.

    CAS  PubMed  Google Scholar 

  225. Potter JJ, Rennie-Tankesley L, Mezey E. Influence of leptin in the development of hepatic fibrosis produced in mice by Schistosoma mansoni infection and by chronic carbon tetrachloride administration. J Hepatol. 2003;38(3):281–8.

    CAS  PubMed  Google Scholar 

  226. Choudhury J, Mirshahi F, Murthy KS, Yager DR, Sanyal AJ. Physiologic concentrations of leptin increase collagen production by non-immortalized human hepatic stellate cells. Metabolism. 2006;55(10):1317–22.

    CAS  PubMed  Google Scholar 

  227. Niu L, Wang X, Li J, Huang Y, Yang Z, Chen F, Ni H, Jin Y, Lu X, Cao Q. Leptin stimulates alpha1(I) collagen expression in human hepatic stellate cells via the phosphatidylinositol 3-kinase/Akt signalling pathway. Liver Int. 2007;27(9):1265–72.

    CAS  PubMed  Google Scholar 

  228. Cao Q, Mak KM, Lieber CS. Leptin enhances alpha1(I) collagen gene expression in LX-2 human hepatic stellate cells through JAK-mediated H2O2-dependent MAPK pathways. J Cell Biochem. 2006;97(1):188–97.

    CAS  PubMed  Google Scholar 

  229. Cao Q, Mak KM, Ren C, Lieber CS. Leptin stimulates tissue inhibitor of metalloproteinase-1 in human hepatic stellate cells: respective roles of the JAK/STAT and JAK-mediated H2O2-dependant MAPK pathways. J Biol Chem. 2004;279(6):4292–304. Epub 2003 Nov 18.

    CAS  PubMed  Google Scholar 

  230. Liu Y, Brymora J, Zhang H, Smith B, Ramezani-Moghadam M, George J, Wang J. Leptin and acetaldehyde synergistically promotes αSMA expression in hepatic stellate cells by an interleukin 6-dependent mechanism. Alcohol Clin Exp Res. 2011;35(5):921–8.

    CAS  PubMed  Google Scholar 

  231. Javor ED, Ghany MG, Cochran EK, Oral EA, DePaoli AM, Premkumar A, Kleiner DE, Gorden P. Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy. Hepatology. 2005;41(4):753–60.

    CAS  PubMed  Google Scholar 

  232. Ding X, Saxena NK, Lin S, Xu A, Srinivasan S, Anania FA. The roles of leptin and adiponectin: a novel paradigm in adipocytokine regulation of liver fibrosis and stellate cell biology. Am J Pathol. 2005;166(6):1655–69. Erratum in: Am J Pathol. 2008 Dec;173(6):1929. Xu, Amin [corrected to Xu, Aimin].

    CAS  PubMed Central  PubMed  Google Scholar 

  233. Adachi M, Brenner DA. High molecular weight adiponectin inhibits proliferation of hepatic stellate cells via activation of adenosine monophosphate-activated protein kinase. Hepatology. 2008;47(2):677–85.

    CAS  PubMed  Google Scholar 

  234. Handy JA, Saxena NK, Fu P, Lin S, Mells JE, Gupta NA, Anania FA. Adiponectin activation of AMPK disrupts leptin-mediated hepatic fibrosis via suppressors of cytokine signaling (SOCS-3). J Cell Biochem. 2010;110(5):1195–207.

    CAS  PubMed Central  PubMed  Google Scholar 

  235. Handy JA, Fu PP, Kumar P, Mells JE, Sharma S, Saxena NK, Anania FA. Adiponectin inhibits leptin signalling via multiple mechanisms to exert protective effects against hepatic fibrosis. Biochem J. 2011;440(3):385–95.

    CAS  PubMed Central  PubMed  Google Scholar 

  236. Lim JY, Oh MA, Kim WH, Sohn HY, Park SI. AMP-activated protein kinase inhibits TGF-β-induced fibrogenic responses of hepatic stellate cells by targeting transcriptional coactivator p300. J Cell Physiol. 2012;227(3):1081–9.

    CAS  PubMed  Google Scholar 

  237. Tsochatzis E, Papatheodoridis GV, Hadziyannis E, Georgiou A, Kafiri G, Tiniakos DG, Manesis EK, Archimandritis AJ. Serum adipokine levels in chronic liver diseases: association of resistin levels with fibrosis severity. Scand J Gastroenterol. 2008;43(9):1128–36.

    CAS  PubMed  Google Scholar 

  238. Kakizaki S, Sohara N, Yamazaki Y, Horiguchi N, Kanda D, Kabeya K, Katakai K, Sato K, Takagi H, Mori M. Elevated plasma resistin concentrations in patients with liver cirrhosis. J Gastroenterol Hepatol. 2008;23(1):73–7.

    CAS  PubMed  Google Scholar 

  239. Liu T, Dhanasekaran SM, Jin H, Hu B, Tomlins SA, Chinnaiyan AM, Phan SH. FIZZ1 stimulation of myofibroblast differentiation. Am J Pathol. 2004;164(4):1315–26.

    CAS  PubMed Central  PubMed  Google Scholar 

  240. Tomita K, Tamiya G, Ando S, Ohsumi K, Chiyo T, Mizutani A, Kitamura N, Toda K, Kaneko T, Horie Y, Han JY, Kato S, Shimoda M, Oike Y, Tomizawa M, Makino S, Ohkura T, Saito H, Kumagai N, Nagata H, Ishii H, Hibi T. Tumour necrosis factor alpha signalling through activation of Kupffer cells plays an essential role in liver fibrosis of non-alcoholic steatohepatitis in mice. Gut. 2006;55(3):415–24.

    CAS  PubMed Central  PubMed  Google Scholar 

  241. Kitamura K, Nakamoto Y, Akiyama M, Fujii C, Kondo T, Kobayashi K, Kaneko S, Mukaida N. Pathogenic roles of tumor necrosis factor receptor p55-mediated signals in dimethylnitrosamine-induced murine liver fibrosis. Lab Invest. 2002;82(5):571–83.

    CAS  PubMed  Google Scholar 

  242. Tarrats N, Moles A, Morales A, García-Ruiz C, Fernández-Checa JC, Marí M. Critical role of tumor necrosis factor receptor 1, but not 2, in hepatic stellate cell proliferation, extracellular matrix remodeling, and liver fibrogenesis. Hepatology. 2011;54(1):319–27.

    CAS  PubMed Central  PubMed  Google Scholar 

  243. Principe A, Melgar-Lesmes P, Fernández-Varo G, del Arbol LR, Ros J, Morales-Ruiz M, Bernardi M, Arroyo V, Jiménez W. The hepatic apelin system: a new therapeutic target for liver disease. Hepatology. 2008;48(4):1193–201.

    CAS  PubMed  Google Scholar 

  244. Reichenbach V, Ros J, Fernández-Varo G, Casals G, Melgar-Lesmes P, Campos T, Makriyannis A, Morales-Ruiz M, Jiménez W. Prevention of fibrosis progression in CCl4-treated rats: role of the hepatic endocannabinoid and apelin systems. J Pharmacol Exp Ther. 2012;340(3):629–37.

    CAS  PubMed  Google Scholar 

  245. Ronkainen VP, Ronkainen JJ, Hänninen SL, Leskinen H, Ruas JL, Pereira T, Poellinger L, Vuolteenaho O, Tavi P. Hypoxia inducible factor regulates the cardiac expression and secretion of apelin. FASEB J. 2007;21(8):1821–30.

    CAS  PubMed  Google Scholar 

  246. Daviaud D, Boucher J, Gesta S, Dray C, Guigne C, Quilliot D, Ayav A, Ziegler O, Carpene C, Saulnier-Blache JS, Valet P, Castan-Laurell I. TNFalpha up-regulates apelin expression in human and mouse adipose tissue. FASEB J. 2006;20(9):1528–30.

    CAS  PubMed  Google Scholar 

  247. Pchejetski D, Foussal C, Alfarano C, Lairez O, Calise D, Guilbeau-Frugier C, Schaak S, Seguelas MH, Wanecq E, Valet P, Parini A, Kunduzova O. Apelin prevents cardiac fibroblast activation and collagen production through inhibition of sphingosine kinase 1. Eur Heart J. 2012;33(18):2360–9.

    CAS  PubMed  Google Scholar 

  248. Siddiquee K, Hampton J, Khan S, Zadory D, Gleaves L, Vaughan DE, Smith LH. Apelin protects against angiotensin II-induced cardiovascular fibrosis and decreases plasminogen activator inhibitor type-1 production. J Hypertens. 2011;29(4):724–31.

    CAS  PubMed Central  PubMed  Google Scholar 

  249. Yu XY, Qiao SB, Guan HS, Liu SW, Meng XM. Effects of visfatin on proliferation and collagen synthesis in rat cardiac fibroblasts. Horm Metab Res. 2010;42(7):507–13.

    CAS  PubMed  Google Scholar 

  250. Kukla M, Ciupińska-Kajor M, Kajor M, Wyleżoł M, Żwirska-Korczala K, Hartleb M, Berdowska A, Mazur W. Liver visfatin expression in morbidly obese patients with nonalcoholic fatty liver disease undergoing bariatric surgery. Pol J Pathol. 2010;61(3):147–53.

    PubMed  Google Scholar 

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  1. Center for Liver Diseases and Department of Medicine, Inova Fairfax Hospital, 3300 Gallows Road, Falls Church, VA, 22042, USA

    Ancha Baranova Ph.D., Aybike Birerdinc Ph.D. & Zobair M. Younossi M.D., M.P.H., F.A.C.G., F.A.C.P., A.G.A.F.

  2. Center for Study of Chronic Metabolic Diseases, School of Systems Biology, George Mason University, 4400 University Drive, Fairfax, VA, 22030, USA

    Ancha Baranova Ph.D. & Aybike Birerdinc Ph.D.

  3. Betty and Guy Betty Liver and Obesity Program, Falls Church, VA, USA

    Ancha Baranova Ph.D., Aybike Birerdinc Ph.D. & Zobair M. Younossi M.D., M.P.H., F.A.C.G., F.A.C.P., A.G.A.F.

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Baranova, A., Birerdinc, A., Younossi, Z.M. (2014). Adipokines in Nonalcoholic Fatty Liver Disease. In: Fantuzzi, G., Braunschweig, C. (eds) Adipose Tissue and Adipokines in Health and Disease. Nutrition and Health. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-770-9_17

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