Clinical Reviews in Bone and Mineral Metabolism

, Volume 7, Issue 3, pp 240–248

Adipokine Effects on Bone

Original Paper


The adipocyte is an important source of factors that act as circulating regulators of bone metabolism. These include estrogens, and the adipokines, leptin, resistin, adiponectin, and probably others. Leptin acts directly on bone cells, and in some experimental models these effects are modified by its actions on the central nervous system, which impact on appetite, body weight, and insulin sensitivity. While not strictly an adipokine, insulin circulates in increased concentrations in obesity and exerts anabolic effects on bone. Adipokine levels correlate with bone turnover, suggesting that they dynamically influence bone metabolism. In postmenopausal women, they may be among the principal regulators of bone turnover, accounting for their increasing importance as determinants of bone density with age. Of the adipokines, adiponectin appears to have the strongest relationships with bone parameters in postmenopausal women.


Adiponectin Leptin Insulin Fat Lean Resistin 


  1. 1.
    Riis BJ, Rodbro P, Christiansen C. The role of serum concentrations of sex steroids and bone turnover in the development and occurrence of postmenopausal osteoporosis. Calcif Tissue Int. 1986;38:318–22.PubMedCrossRefGoogle Scholar
  2. 2.
    Reid IR, Ames R, Evans MC, Sharpe S, Gamble G, France JT, et al. Determinants of total body and regional bone mineral density in normal postmenopausal women—a key role for fat mass. J Clin Endocrinol Metab. 1992;75:45–51.PubMedCrossRefGoogle Scholar
  3. 3.
    Ducy P, Amling M, Takeda S, Priemel M, Schilling AF, Beil FT, et al. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell. 2000;100:197–207.PubMedCrossRefGoogle Scholar
  4. 4.
    Steppan CM, Crawford DT, Chidsey-Frink KL, Ke HZ, Swick AG. Leptin is a potent stimulator of bone growth in ob/ob mice. Regul Pept. 2000;92:73–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Cornish J, Callon KE, Bava U, Lin C, Naot D, Hill BL, et al. Leptin directly regulates bone cell function in vitro and reduces bone fragility in vivo. J Endocrinol. 2002;175:405–15.PubMedCrossRefGoogle Scholar
  6. 6.
    Thomas T, Gori F, Khosla S, Jensen MD, Burguera B, Riggs BL. Leptin acts on human marrow stromal cells to enhance differentiation to osteoblasts and to inhibit differentiation to adipocytes. Endocrinology. 1999;140:1630–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Gordeladze JO, Drevon CA, Syversen U, Reseland JE. Leptin stimulates human osteoblastic cell proliferation, de novo collagen synthesis, and mineralization: impact on differentiation markers, apoptosis, and osteoclastic signaling. J Cell Biochem. 2002;85:825–36.PubMedCrossRefGoogle Scholar
  8. 8.
    Reseland JE, Syversen U, Bakke I, Qvigstad G, Eide LG, Hjertner O, et al. Leptin is expressed in and secreted from primary cultures of human osteoblasts and promotes bone mineralization. J Bone Miner Res. 2001;16:1426–33.PubMedCrossRefGoogle Scholar
  9. 9.
    Iwaniec UT, Shearon CC, Heaney RP, Cullen DM, Yee JA. Leptin increases number of bone nodules in vitro. Bone. 1998;23(5 suppl):S212.Google Scholar
  10. 10.
    Maor G, Rochwerger M, Segev Y, Phillip M. Leptin acts as a growth factor on the chondrocytes of skeletal growth centers. J Bone Miner Res. 2002;17:1034–43.PubMedCrossRefGoogle Scholar
  11. 11.
    Holloway WR, Collier FM, Aitken CJ, Myers DE, Hodge JM, Malakellis M, et al. Leptin inhibits osteoclast generation. J Bone Miner Res. 2002;17:200–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Burguera B, Hofbauer LC, Thomas T, Gori F, Evans GL, Khosla S, et al. Leptin reduces ovariectomy-induced bone loss in rats. Endocrinology. 2001;142:3546–53.PubMedCrossRefGoogle Scholar
  13. 13.
    Elefteriou F, Ahn JD, Takeda S, Starbuck M, Yang XL, Liu XY, et al. Leptin regulation of bone resorption by the sympathetic nervous system and CART. Nature. 2005;434:514–20.PubMedCrossRefGoogle Scholar
  14. 14.
    Takeda S, Elefteriou F, Levasseur R, Liu XY, Zhao LP, Parker KL, et al. Leptin regulates bone formation via the sympathetic nervous system. Cell. 2002;111:305–17.PubMedCrossRefGoogle Scholar
  15. 15.
    Morroni M, De Matteis R, Palumbo C, Ferretti M, Villa I, Rubinacci A, et al. In vivo leptin expression in cartilage and bone cells of growing rats and adult humans. J Anat. 2004;205:291–6.PubMedCrossRefGoogle Scholar
  16. 16.
    Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P. Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science. 1995;269:546–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Iwaniec UT, Boghossian S, Dube MG, Torto R, Arzaga RR, Wronski TJ, et al. Effects of central leptin gene therapy on weight reduction and cancellous bone mass in female rats. J Bone Mineral Res. 2005;20(suppl 1):s13–4.Google Scholar
  18. 18.
    Otukonyong EE, Dube MG, Torto R, Kalra PS, Kalra SP. Central leptin differentially modulates ultradian secretory patterns of insulin, leptin and ghrelin independent of effects on food intake and body weight. Peptides. 2005;26:2559–66.PubMedCrossRefGoogle Scholar
  19. 19.
    Hamrick MW, Ding K, Ponnala S, Ferrari SL, Isales CM. Caloric restriction decreases cortical bone mass but spares trabecular bone in the mouse skeleton: implications for the regulation of bone mass by body weight. J Bone Miner Res. 2008;23:870–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Reid IR, Gamble GD, Grey AB, Black DM, Ensrud KE, Browner WS, et al. Beta-blocker use, BMD, and fractures in the study of osteoporotic fractures. J Bone Mineral Res. 2005;20:613–8.CrossRefGoogle Scholar
  21. 21.
    Reid IR, Lucas J, Wattie D, Horne A, Bolland M, Gamble GD, et al. Effects of a beta-blocker on bone turnover in normal postmenopausal women: a randomized controlled trial. J Clin Endocrinol Metab. 2005;90:5212–6.PubMedCrossRefGoogle Scholar
  22. 22.
    Hamrick MW, Pennington C, Newton D, Xie D, Isales C. Leptin deficiency produces contrasting phenotypes in bones of the limb and spine. Bone. 2004;34:376–83.PubMedCrossRefGoogle Scholar
  23. 23.
    Hamrick MW, Della-Fera MA, Choi YH, Pennington C, Baile CA. Leptin treatment induces loss of bone marrow adipocytes and increases bone formation in leptin-deficient ob/ob mice. J Bone Mineral Res. 2005;20:994–1001.CrossRefGoogle Scholar
  24. 24.
    Elefteriou F, Takeda S, Ebihara K, Magre J, Patano N, Kim CA, et al. Serum leptin level is a regulator of bone mass. Proc Natl Acad Sci USA. 2004;101:3258–63.PubMedCrossRefGoogle Scholar
  25. 25.
    Martin A, David V, Malaval L, Lafage-Proust M, Vico L, Thomas T. Opposite effects of leptin on bone metabolism: a dose-dependent balance related to energy intake and insulin-like growth factor-I pathway. Endocrinology. 2007;148:3419–25.PubMedCrossRefGoogle Scholar
  26. 26.
    Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH, Prentice AM, et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med. 1999;341:879–84.PubMedCrossRefGoogle Scholar
  27. 27.
    Welt CK, Chan JL, Bullen J, Murphy R, Smith P, DePaoli AM, et al. Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med. 2004;351:987–97.PubMedCrossRefGoogle Scholar
  28. 28.
    Prouteau S, Berthamou L, Courteix D. Relationships between serum leptin and bone markers during stable weight, weight reduction and weight regain in male and female judoists. Eur J Endocrinol. 2006;154:389–95.PubMedCrossRefGoogle Scholar
  29. 29.
    Bajoria R, Sooranna SR, Chatterjee R. Leptin and bone turnover in monochorionic twins complicated by twin–twin transfusion syndrome. Osteoporos Int. 2007;18:193–200.PubMedCrossRefGoogle Scholar
  30. 30.
    Roux C, Arabi A, Porcher R, Garnero P. Serum leptin as a determinant of bone resorption in healthy postmenopausal women. Bone. 2003;33:847–52.PubMedCrossRefGoogle Scholar
  31. 31.
    Weiss LA, Barrett-Connor E, von Muhlen D, Clark P. Leptin predicts BMD and bone resorption in older women but not older men: the Rancho Bernardo study. J Bone Mineral Res. 2006;21:758–64.CrossRefGoogle Scholar
  32. 32.
    Nakano Y, Tobe T, ChoiMiura NH, Mazda T, Tomita M. Isolation and characterization of GBP28, a novel gelatin-binding protein purified from human plasma. J Biochem. 1996;120:803–12.PubMedGoogle Scholar
  33. 33.
    Wang Y, Lam KSL, Chan L, Chan KW, Lam JBB, Lam MC, et al. Post-translational modifications of the four conserved lysine residues within the collagenous domain of adiponectin are required for the formation of its high molecular weight oligomeric complex. J Biol Chem. 2006;281:16391–400.PubMedCrossRefGoogle Scholar
  34. 34.
    Suzuki S, Wilson-Kubalek EM, Wert D, Tsao TS, Lee DH. The oligomeric structure of high molecular weight adiponectin. FEBS Lett. 2007;581:809–14.PubMedCrossRefGoogle Scholar
  35. 35.
    Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, et al. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun. 1999;257:79–83.PubMedCrossRefGoogle Scholar
  36. 36.
    Swarbrick MM, Havel PJ. Physiological, pharmacological, and nutritional regulation of circulating adiponectin concentrations in humans. Metab Syndr Relat Disord. 2008;6:87–102.PubMedCrossRefGoogle Scholar
  37. 37.
    Ouchi N, Walsh K. Adiponectin as an anti-inflammatory factor. Clin Chim Acta. 2007;380:24–30.PubMedCrossRefGoogle Scholar
  38. 38.
    Hivert MF, Sullivan LM, Fox CS, Nathan DM, D’Agostino RB Sr, Wilson PW, et al. Associations of adiponectin, resistin, and tumor necrosis factor-alpha with insulin resistance. J Clin Endocrinol Metab. 2008;93:3165–72.PubMedCrossRefGoogle Scholar
  39. 39.
    Hung J, McQuillan BM, Thompson PL, Beilby JP. Circulating adiponectin levels associate with inflammatory markers, insulin resistance and metabolic syndrome independent of obesity. Int J Obesity. 2008;32:772–9.CrossRefGoogle Scholar
  40. 40.
    Wannamethee SG, Tchernova J, Whincup P, Lowe GD, Rumley A, Brown K, et al. Associations of adiponectin with metabolic and vascular risk parameters in the British Regional Heart Study reveal stronger links to insulin resistance-related than to coronory heart disease risk-related parameters. Int J Obesity. 2007;31:1089–98.CrossRefGoogle Scholar
  41. 41.
    Kumada M, Kihara S, Sumitsuji S, Kawamoto T, Matsumoto S, Ouchi N, et al. Association of hypoadiponectinemia with coronary artery disease in men. Arterioscler Thromb Vasc Biol. 2003;23:85–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Hara K, Horikoshi M, Yamauchi T, Yago H, Miyazaki O, Ebinuma H, et al. Measurement of the high-molecular weight form of adiponectin in plasma is useful for the prediction of insulin resistance and metabolic syndrome. Diabetes Care. 2006;29:1357–62.PubMedCrossRefGoogle Scholar
  43. 43.
    Hoffstedt J, Arvidsson E, Sjolin E, Wahlen K, Arner P. Adipose tissue adiponectin production and adiponectin serum concentration in human obesity and insulin resistance. J Clin Endocrinol Metab. 2004;89:1391–6.PubMedCrossRefGoogle Scholar
  44. 44.
    Peake PW, Kriketos AD, Campbell LV, Shen Y, Charlesworth JA. The metabolism of isoforms of human adiponectin: studies in human subjects and in experimental animals. Euro J Endocrinol. 2005;153:409–17.CrossRefGoogle Scholar
  45. 45.
    Imagawa A, Funahashi T, Nakamura T, Moriwaki M, Tanaka S, Nishizawa H, et al. Elevated serum concentration of adipose-derived factor, adiponectin, in patients with type 1 diabetes. Diabetes Care. 2002;25:1665–6.PubMedCrossRefGoogle Scholar
  46. 46.
    Lindstrom T, Frystyk J, Hedman CA, Flyvbjerg A, Arnqvist HJ. Elevated circulating adiponectin in type 1 diabetes is associated with long diabetes duration. Clin Endocrinol. 2006;65:776–82.CrossRefGoogle Scholar
  47. 47.
    Galler A, Gelbrich G, Kratzsch J, Noack N, Kapellen T, Kiess W. Elevated serum levels of adiponectin in children, adolescents and young adults with type 1 diabetes and the impact of age, gender, body mass index and metabolic control: a longitudinal study. Eur J Endocrinol. 2007;157:481–9.PubMedCrossRefGoogle Scholar
  48. 48.
    Leth H, Andersen KK, Frystyk J, Tarnow L, Rossing P, Parving HH, et al. Elevated levels of high-molecular-weight adiponectin in type 1 diabetes. J Clin Endocrinol Metab. 2008;93:3186–91.PubMedCrossRefGoogle Scholar
  49. 49.
    Modan-Moses D, Stein D, Pariente C, Yaroslavsky A, Ram A, Faigin M, et al. Modulation of adiponectin and leptin during refeeding of female anorexia nervosa patients. J Clin Endocrinol Metab. 2007;92:1843–7.PubMedCrossRefGoogle Scholar
  50. 50.
    Dostalova I, Smitka K, Papezova H, Kvasnickova H, Nedvidkova J. Increased insulin sensitivity in patients with anorexia nervosa: the role of adipocytokines. Physiol Res. 2007;56:587–94.PubMedGoogle Scholar
  51. 51.
    Shinoda Y, Yamaguchi M, Ogata N, Akune T, Kubota N, Yamauchi T, et al. Regulation of bone formation by adiponectin through autocrine/paracrine and endocrine pathways. J Cell Biochem. 2006;99:196–208.PubMedCrossRefGoogle Scholar
  52. 52.
    Berner HS, Lyngstadaas SP, Spahr A, Monjo M, Thommesen L, Drevon CA, et al. Adiponectin and its receptors are expressed in bone-forming cells. Bone. 2004;35:842–9.PubMedCrossRefGoogle Scholar
  53. 53.
    Oshima K, Nampei A, Matsuda M, Iwaki M, Fukuhara A, Hashimoto J, et al. Adiponectin increases bone mass by suppressing osteoclast and activating osteoblast. Biochem Biophys Res Commun. 2005;331:520–6.PubMedCrossRefGoogle Scholar
  54. 54.
    Yamaguchi N, Kukita T, Li YJ, Argueta JGM, Saito T, Hanazawa S, et al. Adiponectin inhibits osteoclast formation stimulated by lipopolysaccharide from Actinobacillus actinomycetemcomitans. FEMS Immunol Med Microbiol. 2007;49:28–34.PubMedCrossRefGoogle Scholar
  55. 55.
    Nampei A, Hashimoto J, Maeda K, Ono T, Nakamur N, Ando W, et al. Adiponectin deficiency partially protects against age-related trabecular bone loss in male mice. J Bone Miner Res. 2004;19:S132.Google Scholar
  56. 56.
    Williams GA, Wang Y, Callon KE, Watson M, Lin J, Lam JBB, et al. In vitro and in vivo effects of adiponectin on bone. Endocrinology. 2009 (in press).Google Scholar
  57. 57.
    Jurimae J, Rembel K, Jurimae T, Rehand M. Adiponectin is associated with bone mineral density in perimenopausal women. Horm Metab Res. 2005;37:297–302.PubMedCrossRefGoogle Scholar
  58. 58.
    Lenchik L, Register TC, Hsu FC, Lohman K, Nicklas BJ, Freedman BI, et al. Adiponectin as a novel determinant of bone mineral density and visceral fat. Bone. 2003;33:646–51.PubMedCrossRefGoogle Scholar
  59. 59.
    Richards JB, Valdes AM, Burling K, Perks UC, Spector TD. Serum adiponectin and bone mineral density in women. J Clin Endocrinol Metab. 2007;92:1517–23.PubMedCrossRefGoogle Scholar
  60. 60.
    Cornish J, Callon KE, Lin J-M, Reid IR. Resistin, an adipocytokine, stimulates osteoblast and osteoclast proliferation. Bone. 2006;38(suppl 1):s9.CrossRefGoogle Scholar
  61. 61.
    Thommesein L, Stunes AK, Monjo M, Grosvik K, Tamburstuen MV, Kjobli E, et al. Expression and regulation of resistin in osteoblasts and osteoclasts indicate a role in bone metabolism. J Cell Biochem. 2006;99:824–34.CrossRefGoogle Scholar
  62. 62.
    Dagogojack S, Alali N, Qurttom M. Augmentation of bone mineral density in hirsute women. J Clin Endocrinol Metab. 1997;82:2821–5.CrossRefGoogle Scholar
  63. 63.
    Wetvik J. Radiological features in generalized lipodystrophy. Acta Paediatr. 1996;413:44–51.CrossRefGoogle Scholar
  64. 64.
    Ahmed LA, Joakimsen RM, Berntsen GK, Fonnebo V, Schirmer H. Diabetes mellitus and the risk of non-vertebral fractures: the Tromso study. Osteoporos Int. 2006;17:495–500.PubMedCrossRefGoogle Scholar
  65. 65.
    Reid IR, Evans MC, Cooper GJS, Ames RW, Stapleton J. Circulating insulin levels are related to bone density in normal postmenopausal women. Am J Physiol. 1993;265:E655–9.PubMedGoogle Scholar
  66. 66.
    Stolk RP, Vandaele PLA, Pols HAP, Burger H, Hofman A, Birkenhager JC, et al. Hyperinsulinemia and bone mineral density in an elderly population—the Rotterdam study. Bone. 1996;18:545–9.PubMedCrossRefGoogle Scholar
  67. 67.
    Haffner SM, Bauer RL. The association of obesity and glucose and insulin concentrations with bone density in premenopausal and postmenopausal women. Metab Clin Exp. 1993;42:735–8.PubMedGoogle Scholar
  68. 68.
    Abrahamsen B, Rohold A, Henriksen JE, Beck-Nielsen H. Correlations between insulin sensitivity and bone mineral density in non-diabetic men. Diabetes Med. 2000;17:124–9.CrossRefGoogle Scholar
  69. 69.
    Ahmed LA, Schirmer H, Berntsen GK, Fonnebo V, Joakimsen RMJ. Features of the metabolic syndrome and the risk of non-vertebral fractures: the Tromso study. Osteoporos Int. 2006;17:426–32.PubMedCrossRefGoogle Scholar
  70. 70.
    Grey A, Bolland M, Gamble G, Wattie D, Horne A, Davidson J, et al. The peroxisome proliferator-activated receptor-gamma agonist rosiglitazone decreases bone formation and bone mineral density in healthy postmenopausal women: a randomized, controlled trial. J Clin Endocrinol Metab. 2007;92:1305–10.PubMedCrossRefGoogle Scholar
  71. 71.
    Gimble JM, Robinson CE, Wu X, Kelly KA, Rodriguez BR, Kliewer SA, et al. Peroxisome proliferator-activated receptor-gamma activation by thiazolidinediones induces adipogenesis in bone marrow stromal cells. Mol Pharmacol. 1996;50:1087–94.PubMedGoogle Scholar
  72. 72.
    Klein RF, Allard J, Avnur Z, Nikolcheva T, Rotstein D, Carlos AS, et al. Regulation of bone mass in mice by the lipoxygenase gene Alox15. Science. 2004;303:229–32.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2009

Authors and Affiliations

  1. 1.Faculty of Medical and Health SciencesUniversity of AucklandAucklandNew Zealand
  2. 2.Departments of Medicine and Human Genetics, Lady Davis InstituteMcGill UniversityMontréalCanada
  3. 3.Department of Twin Research and Genetic EpidemiologySt. Thomas’ HospitalLondonUK

Personalised recommendations