, Volume 11, Issue 1, pp 8–20 | Cite as

Adiponectin: Regulation of its production and its role in human diseases

  • Adeeb Shehzad
  • Waqas Iqbal
  • Omer Shehzad
  • Young Sup LeeEmail author


Adiponectin is a white and brown adipose tissue hormone, also known as gelatin-binding protein-28 (GBP28), AdipoQ, adipocyte complement-related protein (ACRP30), or apM1. Adiponectin circulates in the bloodstream in trimeric, hexameric, and high-molecular-mass species, while different forms of adiponectin have been found to play distinct roles in the balance of energy homoeostasis. Adiponectin is an insulin sensitizing hormone that exerts its action through its receptors AdipoR1, AdipoR2, and T-cadherin. AdipoR1 is expressed abundantly in muscle, whereas AdipoR2 is predominantly expressed in the liver. Adiponectin is inversely proportional to obesity, diabetes, and other insulin-resistant states. In this review we present the current findings regarding the regulation of its production and several new findings pertaining to its biological effects. Adiponectin enhances AMPK and the PPARα pathway in the liver and skeletal muscle. Adiponectin increases fatty acids oxidation, which lowers circulating free fatty acids and prevents insulin resistance. Adiponectin has been reported to exert an antiatherosclerotic effect. It inhibits macrophage activation and foam cell accumulation, while it also augments endothelial nitrous oxide production and protects the vasculature by reducing platelet aggregation and vasodilation. Apart from causing metabolic dysfunction, adiponectin deficiency may also contribute to coronary heart disease, steatohepatitis, insulin resistance, nonalcoholic fatty liver disease, and a wide array of cancers. In this study, we present ample evidence that adiponectin mediates multiple molecular pathways. We therefore support the concept that it shows distinct potential for being of therapeutic value in the treatment of obesity related diseases, ranging from metabolic syndrome to malignancies.

Key words

Adiponectin Regulation Insulin Inflammation Atherosclerosis Fatty acid Obesity Liver disease 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Hug C, Wang J, Ahmad NS, Bogan JS, Tsao TS, Lodish HF, 2004 T-cadherin is a receptor for hexameric and high-molecular-weight forms of Acrp30/adiponectin. Proc Natl Acad Sci USA 101: 10308–10313.CrossRefPubMedGoogle Scholar
  2. 2.
    Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF, 1995 A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem 270: 26746–26749.CrossRefPubMedGoogle Scholar
  3. 3.
    Hu E, Liang P, Spiegelman BM, 1996 AdipoQ is a novel adipose-specific gene dysregulated in obesity. J Biol Chem 271: 10697–10703.CrossRefPubMedGoogle Scholar
  4. 4.
    Maeda K, Okubo K, Shimomura I, Funahashi T, Matsuzawa Y, Matsubara K, 1996 cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (AdiPose Most abundant Gene transcript 1). Biochem Biophys Res Commun 221: 286–289.CrossRefPubMedGoogle Scholar
  5. 5.
    Arita Y, Kihara S, Ouchi N, et al, 1999 Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 257: 79–83.CrossRefPubMedGoogle Scholar
  6. 6.
    Yamauchi T, Kamon J, Ito Y, et al, 2003 Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 423: 762–769.CrossRefPubMedGoogle Scholar
  7. 7.
    Guo Z, Xia Z, Yuen VG, McNeill JH, 2007 Cardiac expression of adiponectin and its receptors in streptozotocin-induced diabetic rats. Metabolism 56: 1363–1371.CrossRefPubMedGoogle Scholar
  8. 8.
    Sun X, He J, Mao C, et al, 2008 Negative regulation of adiponectin receptor 1 promoter by insulin via repressive nuclear inhibitory protein element. FEBS Lett 582: 3401–3407.CrossRefPubMedGoogle Scholar
  9. 9.
    Denzel MS, Scimia MC, Zumstein PM, Walsh K, Ruiz-Lozano P, Ranscht B, 2010 T-cadherin is critical for adiponectin-mediated cardioprotection in mice. J Clin Invest 120: 4342–4352.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Ordelheide AM, Heni M, Gommer N, et al, 2011 The myocyte expression of adiponectin receptors and PPARδ is highly coordinated and reflects lipid metabolism of the human donors. Exp Diabetes Res: 692536.Google Scholar
  11. 11.
    Liu BH, Wang PH, Wang YC, Cheng WM, Mersmann HJ, Ding ST, 2008 Fasting regulates the expression of adiponectin receptors in young growing pigs. J Anim Sci 86: 3377–3384.CrossRefPubMedGoogle Scholar
  12. 12.
    Blümer RM, van Roomen CP, Meijer AJ, Houben-Weerts JH, Sauerwein HP, Dubbelhuis PF, 2008 Regulation of adiponectin secretion by insulin and amino acids in 3T3-L1 adipocytes. Metab Clin Exp 57: 1655–1662.CrossRefPubMedGoogle Scholar
  13. 13.
    Pereira RI, Draznin B, 2005 Inhibition of the phosphatidylinositol 3’-kinase signaling pathway leads to decreased insulin-stimulated adiponectin secretion from 3T3-L1 adipocytes. Metabolism 54: 1636–1643.CrossRefPubMedGoogle Scholar
  14. 14.
    Imagawa A, Funahashi T, Nakamura T, et al, 2002 Elevated serum concentration of adipose-derived factor, adiponectin, in patients with type 1 diabetes. Diabetes Care 25: 1665–1666.CrossRefPubMedGoogle Scholar
  15. 15.
    Semple RK, Soos MA, Luan J, et al, 2006 Elevated plasma adiponectin in humans with genetically defective insulin receptors. J Clin Endocrinol Metab 91: 3219–3223.CrossRefPubMedGoogle Scholar
  16. 16.
    Möhlig M, Wegewitz U, Osterhoff M, et al, 2002 Insulin decreases human adiponectin plasma levels. Horm Metab Res 34: 655–658.CrossRefPubMedGoogle Scholar
  17. 17.
    He W, Barak Y, Hevener A, et al, 2003 Adipose-specific peroxisome proliferator-activated receptor gamma knockout causes insulin resistance in fat and liver but not in muscle. Proc Natl Acad Sci U S A 100: 15712–15717.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Seo JB, Moon HM, Noh MJ, et al, 2004 Adipocyte determination- and differentiation-dependent factor 1/ sterol regulatory element-binding protein 1c regulates mouse adiponectin expression. J Biol Chem 279: 22108–22117.CrossRefPubMedGoogle Scholar
  19. 19.
    Qiang L, Wang H, Farmer SR, 2007 Adiponectin secretion is regulated by SIRT1 and the endoplasmic reticulum oxidoreductase Ero1L alpha. Mol Cell Biol 27: 4698–4707.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Liu M, Zhou L, Xu A, et al, 2008 A disulfide-bond A oxidoreductase-like protein (DsbA-L) regulates adiponectin multimerization. Proc Natl Acad Sci U S A 105: 18302–18307.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Park BH, Qiang L, Farmer SR, 2004 Phosphorylation of C/EBPbeta at a consensus extracellular signal-regulated kinase/glycogen synthase kinase 3 site is required for the induction of adiponectin gene expression during the differentiation of mouse fibroblasts into adipocytes. Mol Cell Biol 24: 8671–8680.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Qiao L, Maclean PS, Schaack J, et al, 2005 C/EBPalpha regulates human adiponectin gene transcription through an intronic enhancer. Diabetes 54: 1744–1754.CrossRefPubMedGoogle Scholar
  23. 23.
    Dubois SG, Heilbronn LK, Smith SR, et al, 2006 Decreased expression of adipogenic genes in obese subjects with type 2 diabetes. Obesity 14: 1543–1552.CrossRefPubMedGoogle Scholar
  24. 24.
    Zhu M, Miura J, Lu LX, et al, 2004 Circulating adiponectin levels increase in rats on caloric restriction: the potential for insulin sensitization. Exp Gerontol 39: 1049–1059.CrossRefPubMedGoogle Scholar
  25. 25.
    Olofsson LE, Orho-Melander M, William-Olsson L, et al, 2008 CCAAT/enhancer binding protein alpha (C/ EBPalpha) in adipose tissue regulates genes in lipid and glucose metabolism and a genetic variation in C/ EBPalpha is associated with serum levels of triglycerides. J Clin Endocrinol Metab 93: 4880–4886.CrossRefPubMedGoogle Scholar
  26. 26.
    Raghow R, Yellaturu C, Deng X, Park EA, Elam MB, 2008 SREBPs: the crossroads of physiological and pathological lipid homeostasis. Trends Endocrinol Metab 19: 65–73.CrossRefPubMedGoogle Scholar
  27. 27.
    Doran AC, Meller N, Cutchins A, et al, 2008 The helix-loop-helix factors Id3 and E47 are novel regulators of adiponectin. Circ Res 103: 624–634.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Kousteni S, 2011 FoxO1: a molecule for all seasons. J Bone Miner Res 26: 912–917.CrossRefPubMedGoogle Scholar
  29. 29.
    Fan W, Imamura T, Sonoda N, et al, 2009 FOXO1 transrepresses peroxisome proliferator-activated receptor gamma transactivation, coordinating an insulin-induced feed-forward response in adipocytes. J Biol Chem 284: 12188–12197.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Qi L, Saberi M, Zmuda E, et al, 2009 Adipocyte CREB promotes insulin resistance in obesity. Cell Metab 3: 277–286.CrossRefGoogle Scholar
  31. 31.
    Kim HB, Kim WH, Han KL, et al, 2010 cAMP-response element binding protein (CREB) positively regulates mouse adiponectin gene expression in 3T3-L1 adipocytes. Biochem Biophys Res Commun 391: 634–639.CrossRefPubMedGoogle Scholar
  32. 32.
    Kim HB, Kong M, Kim TM, et al, 2006 NFATc4 and ATF3 negatively regulate adiponectin gene expression in 3T3-L1 adipocytes. Diabetes 55: 1342–1352.CrossRefPubMedGoogle Scholar
  33. 33.
    Hajri T, Tao H, Wattacheril J, Marks-Shulman P, Abumrad NN, 2010 Regulation of adiponectin production by insulin: interactions with tumor necrosis factor-α and interleukin-6. Am J Physiol Endocrinol Metab doi: 10.1152/ajpendo.00307.Google Scholar
  34. 34.
    Barth N, Langmann T, Schölmerich J, Schmitz G, Schäffler A, 2002 Identification of regulatory elements in the human adipose most abundant gene transcript-1 ( apM-1) promoter: role of SP1/SP3 and TNF-alpha as regulatory pathways. Diabetologia 45: 1425–1433.PubMedGoogle Scholar
  35. 35.
    Zappalà G, Rechler MM, 2009 IGFBP-3, hypoxia and TNF-alpha inhibit adiponectin transcription. Biochem Biophys Res Commun 382: 785–789.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Fasshauer M, Kralisch S, Klier M, et al, 2003 Adiponectin gene expression and secretion is inhibited by interleukin-6 in 3T3-L1 adipocytes. Biochem Biophys Res Commun 301: 1045–1050.CrossRefPubMedGoogle Scholar
  37. 37.
    Chen L, He T, Han Y, Sheng JZ, Jin S, Jin MW, 2011 Pentamethylquercetin improves adiponectin expression in differentiated 3T3-L1 cells via a mechanism that implicates PPARγ together with TNF-α and IL-6. Molecules 16: 5754–5768.CrossRefPubMedGoogle Scholar
  38. 38.
    Thompson SR, Sanders J, Stephens JW, Miller GJ, Humphries SE, 2007 A common interleukin 18 haplotype is associated with higher body mass index in subjects with diabetes and coronary heart disease. Metabolism 56: 662–669.CrossRefPubMedGoogle Scholar
  39. 39.
    Chandrasekar B, Patel DN, Mummidi S, Kim JW, Clark RA, Valente AJ, 2008 Interleukin-18 suppresses adiponectin expression in 3T3-L1 adipocytes via a novel signal transduction pathway involving ERK1/2-dependent NFATc4 phosphorylation. J Biol Chem 283: 4200–4209.CrossRefPubMedGoogle Scholar
  40. 40.
    Sun L, Hu FB, Yu Z, et al, 2008 Lean body mass, interleukin 18, and metabolic syndrome in apparently healthy Chinese. PLoS One 6: e18104.CrossRefGoogle Scholar
  41. 41.
    Liu M, Zhou L, Xu A, et al, 2008 A disulfide-bond A oxidoreductase-like protein (DsbA-L) regulates adiponectin multimerization. Proc Natl Acad Sci U S A 105: 18302–18307.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Wang A, Liu M, Liu X, et al, 2011 Up-regulation of adiponectin by resveratrol: the essential roles of the Akt/ FOXO1 and AMP-activated protein kinase signaling pathways and DsbA-L. J Biol Chem 286: 60–66.CrossRefPubMedGoogle Scholar
  43. 43.
    Hosogai N, Fukuhara A, Oshima K, et al, 2007 Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes 56: 901–911.CrossRefPubMedGoogle Scholar
  44. 44.
    Koh EH, Park JY, Park HS, et al, 2007 Essential role of mitochondrial function in adiponectin synthesis in adipocytes. Diabetes 56: 2973–2981.CrossRefPubMedGoogle Scholar
  45. 45.
    Han KL, Choi JS, Lee JY, et al, 2008 Therapeutic potential of peroxisome proliferators–activated receptor-alpha/ gamma dual agonist with alleviation of endoplasmic reticulum stress for the treatment of diabetes. Diabetes 57: 737–745.CrossRefPubMedGoogle Scholar
  46. 46.
    Soares AF, Guichardant M, Cozzone D, et al, 2005 Effects of oxidative stress on adiponectin secretion and lactate production in 3T3-L1 adipocytes. Free Radical Biol Med 38: 882–889.CrossRefGoogle Scholar
  47. 47.
    Chen B, Wei J, Wang W, et al, 2009 Identification of signaling pathways involved in aberrant production of adipokines in adipocytes undergoing oxidative stress. Arch Med Res 40: 241–248.CrossRefPubMedGoogle Scholar
  48. 48.
    Shimada M, Kawahara H, Ozaki K, et al, 2007 Usefulness of a combined evaluation of the serum adiponectin level, HOMA-IR, and serum type IV collagen 7S level to predict the early stage of nonalcoholic steatohepatitis. Am J Gastroenterol 102: 1931–1938.CrossRefPubMedGoogle Scholar
  49. 49.
    Younossi ZM, Jarrar M, Nugent C, et al, 2008 A novel diagnostic biomarker panel for obesity-related nonalcoholic steatohepatitis (NASH). Obest Surg 18: 1430–1437.CrossRefGoogle Scholar
  50. 50.
    Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K, 2006 Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest 116: 1784–1792.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Polyzos SA, Kountouras J, Zavos C, Tsiaousi E, 2010 The role of adiponectin in the pathogenesis and treatment of non-alcoholic fatty liver disease. Diabetes Obes Metab 12: 365–383.CrossRefPubMedGoogle Scholar
  52. 52.
    Ma H, Gomez V, Lu L, Yang X, Wu X, Xiao SY, 2009 Expression of adiponectin and its receptors in livers of morbidly obese patients with non-alcoholic fatty liver disease. J Gastroenterol Hepatol 24: 233–237.CrossRefPubMedGoogle Scholar
  53. 53.
    Hui JM, Hodge A, Farrell GC, Kench JG, Kriketos A, George J, 2004 Beyond insulin resistance in NASH: TNF-alpha or adiponectin? Hepatology 40: 46–54.CrossRefPubMedGoogle Scholar
  54. 54.
    Hammarstedt A, Sopasakis VR, Gogg S, Jansson PA, Smith U, 2005 Improved insulin sensitivity and adipose tissue dysregulation after short-term treatment with pioglitazone in non-diabetic, insulin-resistant subjects. Diabetologia 48: 96–104.CrossRefPubMedGoogle Scholar
  55. 55.
    Tokushige K, Hashimoto E, Noto H, et al, 2009 Influence of adiponectin gene polymorphisms in Japanese patients with non-alcoholic fatty liver disease. J Gastroenterol 44: 976–982.CrossRefPubMedGoogle Scholar
  56. 56.
    Hui Y, Yu-Yuan L, Yu-Qiang N, et al, 2008 Effect of peroxisome proliferator activated receptors-gamma and co-activator-1alpha genetic polymorphisms on plasma adiponectin levels and susceptibility of non-alcoholic fatty liver disease in Chinese people. Liver Int 28: 385–392.CrossRefPubMedGoogle Scholar
  57. 57.
    Lu G, Chiem A, Anuurad E, et al, 2007 Adiponectin levels are associated with coronary artery disease across Caucasian and African-American ethnicity. Transl Res 149: 317–323.CrossRefPubMedGoogle Scholar
  58. 58.
    El-Menyar A, Rizk N, Al Nabti AD, et al, 2009 Total and high molecular weight adiponectin in patients with coronary artery disease. J Cardiovasc Med 10: 310–315.CrossRefGoogle Scholar
  59. 59.
    Kobayashi H, Ouchi N, Kihara S, et al, 2004 Selective suppression of endothelial cell apoptosis by the high molecular weight form of adiponectin. Circulation Research 94: e27–e31.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Otsuka F, Sugiyama S, Kojima S, et al, 2006 Plasma adiponectin levels are associated with coronary lesion complexity in men with coronary artery disease. J AM COLL CARDIOL 48: 1155–1162.CrossRefPubMedGoogle Scholar
  61. 61.
    Kumada M, Kihara S, Sumitsuji S, et al, 2003 Association of hypoadiponectinemia with coronary artery disease in men. Arterioscler Thromb Vasc Biol 23: 85–89.CrossRefPubMedGoogle Scholar
  62. 62.
    Shibata R, Sato K, Pimentel DR, et al, 2005 Adiponectin protects against myocardial ischemia-reperfusion injury through AMPK- and COX-2-dependent mechanisms. Nat Med 11: 1096–1103.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Okamoto Y, 2011 Adiponectin provides cardiovascular protection in metabolic syndrome. Cardiol Res Pract 2011: 313179.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Hotta K, Funahashi T, Arita Y, et al, 2000 Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol 20: 1595–1599.CrossRefPubMedGoogle Scholar
  65. 65.
    Adamczak M, Wiecek A, Funahashi T, Chudek J, Kokot F, Matsuzawa Y, 2003 Decreased plasma adiponectin concentration in patients with essential hypertension. Am J Hypertens 16: 72–75.CrossRefPubMedGoogle Scholar
  66. 66.
    Kobayashi K, Inoguchi T, Sonoda N, Sekiguchi N, Nawata H, 2005 Adiponectin inhibits the binding of low-density lipoprotein to biglycan, a vascular proteoglycan. Biochem Biophys Res Commun 335: 66–70.CrossRefPubMedGoogle Scholar
  67. 67.
    Al-Daghri NM, Al-Attas OS, Alokail MS, Alkharfy KM, Hussain T, 2011 Adiponectin gene variants and the risk of coronary artery disease in patients with type 2 diabetes. Mol Biol 38: 3703–3708.Google Scholar
  68. 68.
    Chen H, Montagnani M, Funahashi T, Shimomura I, Quon MJ, 2003 Adiponectin stimulates production of nitric oxide in vascular endothelial cells. J Biol Chem 278: 45021–45026.CrossRefPubMedGoogle Scholar
  69. 69.
    Van Berendoncks AM, Garnier A, Beckers P, et al, 2010 Functional adiponectin resistance at the level of the skeletal muscle in mild to moderate chronic heart failure. Circ Heart Fail 3: 185–194.CrossRefPubMedGoogle Scholar
  70. 70.
    Cohen SS, Gammon MD, North KE, et al, 2011 ADIPOQ, ADIPOR1, and ADIPOR2 Polymorphisms in Relation to Serum Adiponectin Levels and BMI in Black and White Women. Obesity (Silver Spring) doi: 10.1038.Google Scholar
  71. 71.
    Haluzík M, Parízková J, Haluzík MM, 2004 Adiponectin and its role in the obesity-induced insulin resistance and related complications. Physiol Res 53: 123–129.PubMedGoogle Scholar
  72. 72.
    Salani B, Briatore L, Andraghetti G, Adami GF, Maggi D, Cordera R, 2006 High-molecular weight adiponectin isoforms increase after biliopancreatic diversion in obese subjects. Obesity 14: 1511–1514.CrossRefPubMedGoogle Scholar
  73. 73.
    Trevaskis JL, Gawronska-Kozak B, Sutton GM, et al, 2007 Role of adiponectin and inflammation in insulin resistance of Mc3r and Mc4r knockout mice. Obesity (Silver Spring) 15: 2664–2672.CrossRefGoogle Scholar
  74. 74.
    Blümer RM, van der Crabben SN, Stegenga ME, et al, 2008 Hyperglycemia prevents the suppressive effect of hyperinsulinemia on plasma adiponectin levels in healthy humans. Am J Physiol Endocrinol Metab 295: E613–617.CrossRefPubMedGoogle Scholar
  75. 75.
    Kelesidis I, Kelesidis T, Mantzoros CS, 2006 Adiponectin and cancer: a systematic review. Br J Cancer 94: 1221–1225.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Chandran M, Phillips SA, Ciaraldi T, Henry RR, 2003 Adiponectin: more than just another fat cell hormone? Diabete Care 26: 2442–2450.CrossRefGoogle Scholar
  77. 77.
    Groth SW, 2003 Adiponectin and polycystic ovary syndrome. Biol Res Nurs 12: 62–72.CrossRefGoogle Scholar

Copyright information

© Hellenic Endocrine Society 2012

Authors and Affiliations

  • Adeeb Shehzad
    • 1
  • Waqas Iqbal
    • 1
  • Omer Shehzad
    • 2
  • Young Sup Lee
    • 1
    Email author
  1. 1.School of Life Sciences, College of Natural SciencesKyungpook National UniversityDaeguKorea
  2. 2.Natural Products Research Institute, College of PharmacySeoul National UniversitySeoulKorea

Personalised recommendations