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Translational research of novel hormones: lessons from animal models and rare human diseases for common human diseases

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Abstract

Since the 1980s, a number of bioactive molecules, now known as cardiovascular hormones, have been isolated from the heart and blood vessels, particularly from the subset of vascular endothelial cells. The natriuretic peptide family is the prototype of the cardiovascular hormones. Over the following decade, a variety of hormones and cytokines, now known as adipokines or adipocytokines, have also been isolated from adipose tissue. Leptin is the only adipokine demonstrated to cause an obese phenotype in both animals and humans upon deletion. Thus, the past two decades have seen the identification of two important classes of bioactive molecules secreted by newly recognized endocrine cells, both of which differentiate from mesenchymal stem cells. To assess the physiological and clinical implications of these novel hormones, we have investigated their functions using animal models. We have also developed and analyzed mice overexpressing transgenic forms of these proteins and knockout mice deficient in these and related genes. Here, we demonstrate the current state of the translational research of these novel hormones, the natriuretic peptide family and leptin, and discuss how lessons learned from excellent animal models and rare human diseases can provide a better understanding of common human diseases.

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References

  1. Okamoto K, Aoki K (1963) Development of a strain of spontaneously hypertensive rats. Jpn Circ J 27:282–293

    CAS  PubMed  Google Scholar 

  2. Ingalls AM, Dickie MM, Snell GD (1950) Obese, a new mutation in the house mouse. J Heredity 41:317–318

    CAS  Google Scholar 

  3. Nakao K, Ogawa Y, Suga S, Imura H (1992) Molecular biology and biochemistry of the natriuretic peptide system. I: natriuretic peptides. J Hypertens 10:907–912

    CAS  PubMed  Google Scholar 

  4. Nakao K, Ogawa Y, Suga S, Imura H (1992) Molecular biology and biochemistry of the natriuretic peptide system. II: natriuretic peptide receptors. J Hypertens 10:1111–1114

    Article  CAS  PubMed  Google Scholar 

  5. Suga S, Nakao K, Hosoda K, Mukoyama M, Ogawa Y, Shirakami G, Arai H, Saito Y, Kambayashi Y, Inouye K et al (1992) Receptor selectivity of natriuretic peptide family, atrial natriuretic peptide, brain natriuretic peptide, and C-type natriuretic peptide. Endocrinology 130:229–239

    Article  CAS  PubMed  Google Scholar 

  6. Sugawara A, Nakao K, Morii N, Yamada T, Itoh H, Shiono S, Saito Y, Mukoyama M, Arai H, Nishimura K et al (1988) Synthesis of atrial natriuretic polypeptide in human failing hearts. Evidence for altered processing of atrial natriuretic polypeptide precursor and augmented synthesis of beta-human ANP. J Clin Invest 81:1962–1970

    Article  CAS  PubMed  Google Scholar 

  7. Saito Y, Nakao K, Arai H, Nishimura K, Okumura K, Obata K, Takemura G, Fujiwara H, Sugawara A, Yamada T et al (1989) Augmented expression of atrial natriuretic polypeptide gene in ventricle of human failing heart. J Clin Invest 83:298–305

    Article  CAS  PubMed  Google Scholar 

  8. Mukoyama M, Nakao K, Saito Y, Ogawa Y, Hosoda K, Suga S, Shirakami G, Jougasaki M, Imura H (1990) Human brain natriuretic peptide, a novel cardiac hormone. Lancet 335:801–802

    Article  CAS  PubMed  Google Scholar 

  9. Mukoyama M, Nakao K, Saito Y, Ogawa Y, Hosoda K, Suga S, Shirakami G, Jougasaki M, Imura H (1990) Increased human brain natriuretic peptide in congestive heart failure. N Engl J Med 323:757–758

    CAS  PubMed  Google Scholar 

  10. Mukoyama M, Nakao K, Hosoda K, Suga S, Saito Y, Ogawa Y, Shirakami G, Jougasaki M, Obata K, Yasue H et al (1991) Brain natriuretic peptide as a novel cardiac hormone in humans. Evidence for an exquisite dual natriuretic peptide system, atrial natriuretic peptide and brain natriuretic peptide. J Clin Invest 87:1402–1412

    Article  CAS  PubMed  Google Scholar 

  11. Morita E, Yasue H, Yoshimura M, Ogawa H, Jougasaki M, Matsumura T, Mukoyama M, Nakao K (1993) Increased plasma levels of brain natriuretic peptide in patients with acute myocardial infarction. Circulation 88:82–91

    CAS  PubMed  Google Scholar 

  12. Kawakami R, Saito Y, Kishimoto I, Harada M, Kuwahara K, Takahashi N, Nakagawa Y, Nakanishi M, Tanimoto K, Usami S et al (2004) Overexpression of brain natriuretic peptide facilitates neutrophil infiltration and cardiac matrix metalloproteinase-9 expression after acute myocardial infarction. Circulation 110:3306–3312

    Article  CAS  PubMed  Google Scholar 

  13. Arai H, Nakao K, Saito Y, Morii N, Sugawara A, Yamada T, Itoh H, Shiono S, Mukoyama M, Ohkubo H et al (1988) Augmented expression of atrial natriuretic polypeptide gene in ventricles of spontaneously hypertensive rats (SHR) and SHR-stroke prone. Circ Res 62:926–930

    CAS  PubMed  Google Scholar 

  14. Yasue H, Yoshimura M, Sumida H, Kikuta K, Kugiyama K, Jougasaki M, Ogawa H, Okumura K, Mukoyama M, Nakao K (1994) Localization and mechanism of secretion of B-type natriuretic peptide in comparison with those of A-type natriuretic peptide in normal subjects and patients with heart failure. Circulation 90:195–203

    CAS  PubMed  Google Scholar 

  15. Sugawara A, Nakao K, Sakamoto M, Morii N, Yamada T, Itoh H, Shiono S, Imura H (1985) Plasma concentration of atrial natriuretic polypeptide in essential hypertension. Lancet 2:1426–1427

    Article  CAS  PubMed  Google Scholar 

  16. Itoh H, Nakao K, Mukoyama M, Yamada T, Hosoda K, Shirakami G, Morii N, Sugawara A, Saito Y, Shiono S et al (1989) Chronic blockade of endogenous atrial natriuretic polypeptide (ANP) by monoclonal antibody against ANP accelerates the development of hypertension in spontaneously hypertensive and deoxycorticosterone acetate-salt-hypertensive rats. J Clin Invest 84:145–154

    Article  CAS  PubMed  Google Scholar 

  17. Ogawa Y, Nakao K, Mukoyama M, Hosoda K, Shirakami G, Arai H, Saito Y, Suga S, Jougasaki M, Imura H (1991) Natriuretic peptides as cardiac hormones in normotensive and spontaneously hypertensive rats. The ventricle is a major site of synthesis and secretion of brain natriuretic peptide. Circ Res 69:491–500

    CAS  PubMed  Google Scholar 

  18. Saito Y, Nakao K, Nishimura K, Sugawara A, Okumura K, Obata K, Sonoda R, Ban T, Yasue H, Imura H (1987) Clinical application of atrial natriuretic polypeptide in patients with congestive heart failure: beneficial effects on left ventricular function. Circulation 76:115–124

    CAS  PubMed  Google Scholar 

  19. Yoshimura M, Yasue H, Morita E, Sakaino N, Jougasaki M, Kurose M, Mukoyama M, Saito Y, Nakao K, Imura H (1991) Hemodynamic, renal, and hormonal responses to brain natriuretic peptide infusion in patients with congestive heart failure. Circulation 84:1581–1588

    CAS  PubMed  Google Scholar 

  20. Sudoh T, Minamino N, Kangawa K, Matsuo H (1990) C-type natriuretic peptide (CNP): a new member of natriuretic peptide family identified in porcine brain. Biochem Biophys Res Commun 168:863–870

    Article  CAS  PubMed  Google Scholar 

  21. Komatsu Y, Nakao K, Suga S, Ogawa Y, Mukoyama M, Arai H, Shirakami G, Hosoda K, Nakagawa O, Hama N et al (1991) C-type natriuretic peptide (CNP) in rats and humans. Endocrinology 129:1104–1106

    Article  CAS  PubMed  Google Scholar 

  22. Suga S, Nakao K, Itoh H, Komatsu Y, Ogawa Y, Hama N, Imura H (1992) Endothelial production of C-type natriuretic peptide and its marked augmentation by transforming growth factor-beta. Possible existence of “vascular natriuretic peptide system”. J Clin Invest 90:1145–1149

    Article  CAS  PubMed  Google Scholar 

  23. Suga S, Itoh H, Komatsu Y, Ogawa Y, Hama N, Yoshimasa T, Nakao K (1993) Cytokine-induced C-type natriuretic peptide (CNP) secretion from vascular endothelial cells—evidence for CNP as a novel autocrine/paracrine regulator from endothelial cells. Endocrinology 133:3038–3041

    Article  CAS  PubMed  Google Scholar 

  24. Doi K, Itoh H, Komatsu Y, Igaki T, Chun TH, Takaya K, Yamashita J, Inoue M, Yoshimasa T, Nakao K (1996) Vascular endothelial growth factor suppresses C-type natriuretic peptide secretion. Hypertension 27:811–815

    CAS  PubMed  Google Scholar 

  25. Kubo A, Isumi Y, Ishizaka Y, Tomoda Y, Kangawa K, Dohi K, Matsuo H, Minamino N (2001) C-type natriuretic peptide is synthesized and secreted from leukemia cell lines, peripheral blood cells, and peritoneal macrophages. Exp Hematol 29:609–615

    Article  CAS  PubMed  Google Scholar 

  26. Komatsu Y, Nakao K, Itoh H, Suga S, Ogawa Y, Imura H (1992) Vascular natriuretic peptide. Lancet 340:622

    Article  CAS  PubMed  Google Scholar 

  27. Hama N, Itoh H, Shirakami G, Suga S, Komatsu Y, Yoshimasa T, Tanaka I, Mori K, Nakao K (1994) Detection of C-type natriuretic peptide in human circulation and marked increase of plasma CNP level in septic shock patients. Biochem Biophys Res Commun 198:1177–1182

    Article  CAS  PubMed  Google Scholar 

  28. Komatsu Y, Itoh H, Suga S, Ogawa Y, Hama N, Kishimoto I, Nakagawa O, Igaki T, Doi K, Yoshimasa T et al (1996) Regulation of endothelial production of C-type natriuretic peptide in coculture with vascular smooth muscle cells. Role of the vascular natriuretic peptide system in vascular growth inhibition. Circ Res 78:606–614

    CAS  PubMed  Google Scholar 

  29. Morii N, Nakao K, Sugawara A, Sakamoto M, Suda M, Shimokura M, Kiso Y, Kihara M, Yamori Y, Imura H (1985) Occurrence of atrial natriuretic polypeptide in brain. Biochem Biophys Res Commun 127:413–419

    Article  CAS  PubMed  Google Scholar 

  30. Katsuura G, Nakamura M, Inouye K, Kono M, Nakao K, Imura H (1986) Regulatory role of atrial natriuretic polypeptide in water drinking in rats. Eur J Pharmacol 121:285–287

    Article  CAS  PubMed  Google Scholar 

  31. Yamada T, Nakao K, Morii N, Itoh H, Shiono S, Sakamoto M, Sugawara A, Saito Y, Ohno H, Kanai A et al (1986) Central effect of atrial natriuretic polypeptide on angiotensin II-stimulated vasopressin secretion in conscious rats. Eur J Pharmacol 125:453–456

    Article  CAS  PubMed  Google Scholar 

  32. Shirakami G, Nakao K, Yamada T, Itoh H, Mori K, Kangawa K, Minamino N, Matsuo H, Imura H (1988) Inhibitory effect of brain natriuretic peptide on central angiotensin II-stimulated pressor response in conscious rats. Neurosci Lett 91:77–83

    Article  CAS  PubMed  Google Scholar 

  33. Shirakami G, Itoh H, Suga S, Komatsu Y, Hama N, Mori K, Nakao K (1993) Central action of C-type natriuretic peptide on vasopressin secretion in conscious rats. Neurosci Lett 159:25–28

    Article  CAS  PubMed  Google Scholar 

  34. Kawata M, Nakao K, Morii N, Kiso Y, Yamashita H, Imura H, Sano Y (1985) Atrial natriuretic polypeptide: topographical distribution in the rat brain by radioimmunoassay and immunohistochemistry. Neuroscience 16:521–546

    Article  CAS  PubMed  Google Scholar 

  35. Itoh H, Nakao K, Katsuura G, Morii N, Shiono S, Sakamoto M, Sugawara A, Yamada T, Saito Y, Matsushita A et al (1986) Centrally infused atrial natriuretic polypeptide attenuates exaggerated salt appetite in spontaneously hypertensive rats. Circ Res 59:342–347

    CAS  PubMed  Google Scholar 

  36. Itoh H, Nakao K, Morii N, Yamada T, Shiono S, Sakamoto M, Sugawara A, Saito Y, Katsuura G, Shiomi T et al (1986) Central action of atrial natriuretic polypeptide on blood pressure in conscious rats. Brain Res Bull 16:745–749

    Article  CAS  PubMed  Google Scholar 

  37. Morii N, Nakao K, Itoh H, Shiono S, Yamada T, Sugawara A, Saito Y, Mukoyama M, Arai H, Sakamoto M et al (1987) Atrial natriuretic polypeptide in spinal cord and autonomic ganglia. Biochem Biophys Res Commun 145:196–203

    Article  CAS  PubMed  Google Scholar 

  38. Itoh H, Nakao K, Yamada T, Morii N, Shiono S, Sugawara A, Saito Y, Mukoyama M, Arai H, Imura H (1988) Brain renin–angiotensin. Central control of secretion of atrial natriuretic factor from the heart. Hypertension 11:I57–61

    CAS  PubMed  Google Scholar 

  39. Harada M, Itoh H, Nakagawa O, Ogawa Y, Miyamoto Y, Kuwahara K, Ogawa E, Igaki T, Yamashita J, Masuda I et al (1997) Significance of ventricular myocytes and nonmyocytes interaction during cardiocyte hypertrophy: evidence for endothelin-1 as a paracrine hypertrophic factor from cardiac nonmyocytes. Circulation 96:3737–3744

    CAS  PubMed  Google Scholar 

  40. Yamahara K, Itoh H, Chun TH, Ogawa Y, Yamashita J, Sawada N, Fukunaga Y, Sone M, Yurugi-Kobayashi T, Miyashita K et al (2003) Significance and therapeutic potential of the natriuretic peptides/cGMP/cGMP-dependent protein kinase pathway in vascular regeneration. Proc Natl Acad Sci U S A 100:3404–3409

    Article  CAS  PubMed  Google Scholar 

  41. Steinhelper ME, Cochrane KL, Field LJ (1990) Hypotension in transgenic mice expressing atrial natriuretic factor fusion genes. Hypertension 16:301–307

    CAS  PubMed  Google Scholar 

  42. John SW, Krege JH, Oliver PM, Hagaman JR, Hodgin JB, Pang SC, Flynn TG, Smithies O (1995) Genetic decreases in atrial natriuretic peptide and salt-sensitive hypertension. Science 267:679–681

    Article  CAS  PubMed  Google Scholar 

  43. Ogawa Y, Itoh H, Tamura N, Suga S, Yoshimasa T, Uehira M, Matsuda S, Shiono S, Nishimoto H, Nakao K (1994) Molecular cloning of the complementary DNA and gene that encode mouse brain natriuretic peptide and generation of transgenic mice that overexpress the brain natriuretic peptide gene. J Clin Invest 93:1911–1921

    Article  CAS  PubMed  Google Scholar 

  44. Tamura N, Ogawa Y, Chusho H, Nakamura K, Nakao K, Suda M, Kasahara M, Hashimoto R, Katsuura G, Mukoyama M et al (2000) Cardiac fibrosis in mice lacking brain natriuretic peptide. Proc Natl Acad Sci U S A 97:4239–4244

    Article  CAS  PubMed  Google Scholar 

  45. Lopez MJ, Wong SK, Kishimoto I, Dubois S, Mach V, Friesen J, Garbers DL, Beuve A (1995) Salt-resistant hypertension in mice lacking the guanylyl cyclase-A receptor for atrial natriuretic peptide. Nature 378:65–68

    Article  CAS  PubMed  Google Scholar 

  46. Suganami T, Mukoyama M, Sugawara A, Mori K, Nagae T, Kasahara M, Yahata K, Makino H, Fujinaga Y, Ogawa Y et al (2001) Overexpression of brain natriuretic peptide in mice ameliorates immune-mediated renal injury. J Am Soc Nephrol 12:2652–2663

    CAS  PubMed  Google Scholar 

  47. Kasahara M, Mukoyama M, Sugawara A, Makino H, Suganami T, Ogawa Y, Nakagawa M, Yahata K, Goto M, Ishibashi R et al (2000) Ameliorated glomerular injury in mice overexpressing brain natriuretic peptide with renal ablation. J Am Soc Nephrol 11:1691–1701

    CAS  PubMed  Google Scholar 

  48. Makino H, Mukoyama M, Mori K, Suganami T, Kasahara M, Yahata K, Nagae T, Yokoi H, Sawai K, Ogawa Y et al (2006) Transgenic overexpression of brain natriuretic peptide prevents the progression of diabetic nephropathy in mice. Diabetologia 49:2514–2524

    Article  CAS  PubMed  Google Scholar 

  49. Suda M, Ogawa Y, Tanaka K, Tamura N, Yasoda A, Takigawa T, Uehira M, Nishimoto H, Itoh H, Saito Y et al (1998) Skeletal overgrowth in transgenic mice that overexpress brain natriuretic peptide. Proc Natl Acad Sci U S A 95:2337–2342

    Article  CAS  PubMed  Google Scholar 

  50. Chusho H, Ogawa Y, Tamura N, Suda M, Yasoda A, Miyazawa T, Kishimoto I, Komatsu Y, Itoh H, Tanaka K et al (2000) Genetic models reveal that brain natriuretic peptide can signal through different tissue-specific receptor-mediated pathways. Endocrinology 141:3807–3813

    Article  CAS  PubMed  Google Scholar 

  51. Oliver PM, Fox JE, Kim R, Rockman HA, Kim HS, Reddick RL, Pandey KN, Milgram SL, Smithies O, Maeda N (1997) Hypertension, cardiac hypertrophy, and sudden death in mice lacking natriuretic peptide receptor A. Proc Natl Acad Sci U S A 94:14730–14735

    Article  CAS  PubMed  Google Scholar 

  52. Knowles JW, Esposito G, Mao L, Hagaman JR, Fox JE, Smithies O, Rockman HA, Maeda N (2001) Pressure-independent enhancement of cardiac hypertrophy in natriuretic peptide receptor A-deficient mice. J Clin Invest 107:975–984

    Article  CAS  PubMed  Google Scholar 

  53. Kishimoto I, Rossi K, Garbers DL (2001) A genetic model provides evidence that the receptor for atrial natriuretic peptide (guanylyl cyclase-A) inhibits cardiac ventricular myocyte hypertrophy. Proc Natl Acad Sci U S A 98:2703–2706

    Article  CAS  PubMed  Google Scholar 

  54. Holtwick R, Gotthardt M, Skryabin B, Steinmetz M, Potthast R, Zetsche B, Hammer RE, Herz J, Kuhn M (2002) Smooth muscle-selective deletion of guanylyl cyclase-A prevents the acute but not chronic effects of ANP on blood pressure. Proc Natl Acad Sci U S A 99:7142–7147

    Article  CAS  PubMed  Google Scholar 

  55. Holtwick R, van Eickels M, Skryabin BV, Baba HA, Bubikat A, Begrow F, Schneider MD, Garbers DL, Kuhn M (2003) Pressure-independent cardiac hypertrophy in mice with cardiomyocyte-restricted inactivation of the atrial natriuretic peptide receptor guanylyl cyclase-A. J Clin Invest 111:1399–1407

    CAS  PubMed  Google Scholar 

  56. Sabrane K, Kruse MN, Fabritz L, Zetsche B, Mitko D, Skryabin BV, Zwiener M, Baba HA, Yanagisawa M, Kuhn M (2005) Vascular endothelium is critically involved in the hypotensive and hypovolemic actions of atrial natriuretic peptide. J Clin Invest 115:1666–1674

    Article  CAS  PubMed  Google Scholar 

  57. Tamura N, Ogawa Y, Yasoda A, Itoh H, Saito Y, Nakao K (1996) Two cardiac natriuretic peptide genes (atrial natriuretic peptide and brain natriuretic peptide) are organized in tandem in the mouse and human genomes. J Mol Cell Cardiol 28:1811–1815

    Article  CAS  PubMed  Google Scholar 

  58. Kuwahara K, Saito Y, Ogawa E, Takahashi N, Nakagawa Y, Naruse Y, Harada M, Hamanaka I, Izumi T, Miyamoto Y et al (2001) The neuron-restrictive silencer element-neuron-restrictive silencer factor system regulates basal and endothelin 1-inducible atrial natriuretic peptide gene expression in ventricular myocytes. Mol Cell Biol 21:2085–2097

    Article  CAS  PubMed  Google Scholar 

  59. Kuwahara K, Saito Y, Takano M, Arai Y, Yasuno S, Nakagawa Y, Takahashi N, Adachi Y, Takemura G, Horie M et al (2003) NRSF regulates the fetal cardiac gene program and maintains normal cardiac structure and function. EMBO J 22:6310–6321

    Article  CAS  PubMed  Google Scholar 

  60. Chusho H, Tamura N, Ogawa Y, Yasoda A, Suda M, Miyazawa T, Nakamura K, Nakao K, Kurihara T, Komatsu Y et al (2001) Dwarfism and early death in mice lacking C-type natriuretic peptide. Proc Natl Acad Sci U S A 98:4016–4021

    Article  CAS  PubMed  Google Scholar 

  61. Kronenberg HM (2003) Developmental regulation of the growth plate. Nature 423:332–336

    Article  CAS  PubMed  Google Scholar 

  62. Yasoda A, Komatsu Y, Chusho H, Miyazawa T, Ozasa A, Miura M, Kurihara T, Rogi T, Tanaka S, Suda M et al (2004) Overexpression of CNP in chondrocytes rescues achondroplasia through a MAPK-dependent pathway. Nat Med 10:80–86

    Article  CAS  PubMed  Google Scholar 

  63. Tamura N, Doolittle LK, Hammer RE, Shelton JM, Richardson JA, Garbers DL (2004) Critical roles of the guanylyl cyclase B receptor in endochondral ossification and development of female reproductive organs. Proc Natl Acad Sci USA 101:17300–17305

    Article  CAS  PubMed  Google Scholar 

  64. Langenickel TH, Buttgereit J, Pagel-Langenickel I, Lindner M, Monti J, Beuerlein K, Al-Saadi N, Plehm R, Popova E, Tank J et al (2006) Cardiac hypertrophy in transgenic rats expressing a dominant-negative mutant of the natriuretic peptide receptor B. Proc Natl Acad Sci U S A 103:4735–4740

    Article  CAS  PubMed  Google Scholar 

  65. Feil R, Lohmann SM, de Jonge H, Walter U, Hofmann F (2003) Cyclic GMP-dependent protein kinases and the cardiovascular system: insights from genetically modified mice. Circ Res 93:907–916

    Article  CAS  PubMed  Google Scholar 

  66. Pfeifer A, Aszodi A, Seidler U, Ruth P, Hofmann F, Fassler R (1996) Intestinal secretory defects and dwarfism in mice lacking cGMP-dependent protein kinase II. Science 274:2082–2086

    Article  CAS  PubMed  Google Scholar 

  67. Miyazawa T, Ogawa Y, Chusho H, Yasoda A, Tamura N, Komatsu Y, Pfeifer A, Hofmann F, Nakao K (2002) Cyclic GMP-dependent protein kinase II plays a critical role in C-type natriuretic peptide-mediated endochondral ossification. Endocrinology 143:3604–3610

    Article  CAS  PubMed  Google Scholar 

  68. Tsuji T, Kunieda T (2005) A loss-of-function mutation in natriuretic peptide receptor 2 (Npr2) gene is responsible for disproportionate dwarfism in cn/cn mouse. J Biol Chem 280:14288–14292

    Article  CAS  PubMed  Google Scholar 

  69. Sogawa C, Tsuji T, Shinkai Y, Katayama K, Kunieda T (2007) Short-limbed dwarfism: slw is a new allele of Npr2 causing chondrodysplasia. J Heredity 98:575–580

    Article  CAS  Google Scholar 

  70. Jiao Y, Yan J, Jiao F, Yang H, Donahue LR, Li X, Roe BA, Stuart J, Gu W (2007) A single nucleotide mutation in Nppc is associated with a long bone abnormality in lbab mice. BMC Genet 8:16

    Article  PubMed  CAS  Google Scholar 

  71. Tsuji T, Kondo E, Yasoda A, Inamoto M, Kiyosu C, Nakao K, Kunieda T (2008) Hypomorphic mutation in mouse Nppc gene causes retarded bone growth due to impaired endochondral ossification. Biochem Biophys Res Commun 376:186–190

    Article  CAS  PubMed  Google Scholar 

  72. Superti-Furga A, Bonafe L, Rimoin DL (2001) Molecular–pathogenetic classification of genetic disorders of the skeleton. Am J Med Genet 106:282–293

    Article  CAS  PubMed  Google Scholar 

  73. Rousseau F, Bonaventure J, Legeai-Mallet L, Pelet A, Rozet JM, Maroteaux P, Le Merrer M, Munnich A (1994) Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature 371:252–254

    Article  CAS  PubMed  Google Scholar 

  74. Cattaneo R, Villa A, Catagni M, Tentori L (1988) Limb lengthening in achondroplasia by Ilizarov's method. Int Orthop 12:173–179

    Article  CAS  PubMed  Google Scholar 

  75. Yasoda A, Kitamura H, Fujii T, Kondo E, Murao N, Miura M, Kanamoto N, Komatsu Y, Arai H, Nakao K (2009) Systemic administration of C-type natriuretic peptide as a novel therapeutic strategy for skeletal dysplasias. Endocrinology 150:3138–3144

    Article  CAS  PubMed  Google Scholar 

  76. Igaki T, Itoh H, Suga SI, Hama N, Ogawa Y, Komatsu Y, Yamashita J, Doi K, Chun TH, Nakao K (1998) Effects of intravenously administered C-type natriuretic peptide in humans: comparison with atrial natriuretic peptide. Hypertens Res 21:7–13

    Article  CAS  PubMed  Google Scholar 

  77. Bartels CF, Bukulmez H, Padayatti P, Rhee DK, van Ravenswaaij-Arts C, Pauli RM, Mundlos S, Chitayat D, Shih LY, Al-Gazali LI et al (2004) Mutations in the transmembrane natriuretic peptide receptor NPR-B impair skeletal growth and cause acromesomelic dysplasia, type Maroteaux. Am J Hum Genet 75:27–34

    Article  CAS  PubMed  Google Scholar 

  78. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372:425–432

    Article  CAS  PubMed  Google Scholar 

  79. Friedman JM, Halaas JL (1998) Leptin and the regulation of body weight in mammals. Nature 395:763–770

    Article  CAS  PubMed  Google Scholar 

  80. Pelleymounter MA, Cullen MJ, Baker MB, Hecht R, Winters D, Boone T, Collins F (1995) Effects of the obese gene product on body weight regulation in ob/ob mice. Science 269:540–543

    Article  CAS  PubMed  Google Scholar 

  81. Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D, Lallone RL, Burley SK, Friedman JM (1995) Weight-reducing effects of the plasma protein encoded by the obese gene. Science 269:543–546

    Article  CAS  PubMed  Google Scholar 

  82. Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P (1995) Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science 269:546–549

    Article  CAS  PubMed  Google Scholar 

  83. Satoh N, Ogawa Y, Katsuura G, Numata Y, Tsuji T, Hayase M, Ebihara K, Masuzaki H, Hosoda K, Yoshimasa Y et al (1999) Sympathetic activation of leptin via the ventromedial hypothalamus: leptin-induced increase in catecholamine secretion. Diabetes 48:1787–1793

    Article  CAS  PubMed  Google Scholar 

  84. Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, Richards GJ, Campfield LA, Clark FT, Deeds J et al (1995) Identification and expression cloning of a leptin receptor, OB-R. Cell 83:1263–1271

    Article  CAS  PubMed  Google Scholar 

  85. Ogawa Y, Masuzaki H, Isse N, Okazaki T, Mori K, Shigemoto M, Satoh N, Tamura N, Hosoda K, Yoshimasa Y et al (1995) Molecular cloning of rat obese cDNA and augmented gene expression in genetically obese Zucker fatty (fa/fa) rats. J Clin Invest 96:1647–1652

    Article  CAS  PubMed  Google Scholar 

  86. Takaya K, Ogawa Y, Hiraoka J, Hosoda K, Yamori Y, Nakao K, Koletsky RJ (1996) Nonsense mutation of leptin receptor in the obese spontaneously hypertensive Koletsky rat. Nat Genet 14:130–131

    Article  CAS  PubMed  Google Scholar 

  87. Frederich RC, Hamann A, Anderson S, Lollmann B, Lowell BB, Flier JS (1995) Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action. Nat Med 1:1311–1314

    Article  CAS  PubMed  Google Scholar 

  88. Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y, Fei H, Kim S, Lallone R, Ranganathan S et al (1995) Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med 1:1155–1161

    Article  CAS  PubMed  Google Scholar 

  89. Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, Ohannesian JP, Marco CC, McKee LJ, Bauer TL et al (1996) Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 334:292–295

    Article  CAS  PubMed  Google Scholar 

  90. Isse N, Ogawa Y, Tamura N, Masuzaki H, Mori K, Okazaki T, Satoh N, Shigemoto M, Yoshimasa Y, Nishi S et al (1995) Structural organization and chromosomal assignment of the human obese gene. J Biol Chem 270:27728–27733

    Article  CAS  PubMed  Google Scholar 

  91. Satoh N, Ogawa Y, Katsuura G, Tsuji T, Masuzaki H, Hiraoka J, Okazaki T, Tamaki M, Hayase M, Yoshimasa Y et al (1997) Pathophysiological significance of the obese gene product, leptin, in ventromedial hypothalamus (VMH)-lesioned rats: evidence for loss of its satiety effect in VMH-lesioned rats. Endocrinology 138:947–954

    Article  CAS  PubMed  Google Scholar 

  92. Imagawa K, Numata Y, Katsuura G, Sakaguchi I, Morita A, Kikuoka S, Matumoto Y, Tsuji T, Tamaki M, Sasakura K et al (1998) Structure–function studies of human leptin. J Biol Chem 273:35245–35249

    Article  CAS  PubMed  Google Scholar 

  93. Caro JF, Kolaczynski JW, Nyce MR, Ohannesian JP, Opentanova I, Goldman WH, Lynn RB, Zhang PL, Sinha MK, Considine RV (1996) Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance. Lancet 348:159–161

    Article  CAS  PubMed  Google Scholar 

  94. Halaas JL, Boozer C, Blair-West J, Fidahusein N, Denton DA, Friedman JM (1997) Physiological response to long-term peripheral and central leptin infusion in lean and obese mice. Proc Natl Acad Sci U S A 94:8878–8883

    Article  CAS  PubMed  Google Scholar 

  95. Tanaka T, Masuzaki H, Yasue S, Ebihara K, Shiuchi T, Ishii T, Arai N, Hirata M, Yamamoto H, Hayashi T et al (2007) Central melanocortin signaling restores skeletal muscle AMP-activated protein kinase phosphorylation in mice fed a high-fat diet. Cell Metab 5:395–402

    Article  CAS  PubMed  Google Scholar 

  96. Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, Wareham NJ, Sewter CP, Digby JE, Mohammed SN, Hurst JA et al (1997) Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 387:903–908

    Article  CAS  PubMed  Google Scholar 

  97. Strobel A, Issad T, Camoin L, Ozata M, Strosberg AD (1998) A leptin missense mutation associated with hypogonadism and morbid obesity. Nat Genet 18:213–215

    Article  CAS  PubMed  Google Scholar 

  98. Yura S, Ogawa Y, Sagawa N, Masuzaki H, Itoh H, Ebihara K, Aizawa-Abe M, Fujii S, Nakao K (2000) Accelerated puberty and late-onset hypothalamic hypogonadism in female transgenic skinny mice overexpressing leptin. J Clin Invest 105:749–755

    Article  CAS  PubMed  Google Scholar 

  99. Aizawa-Abe M, Ogawa Y, Masuzaki H, Ebihara K, Satoh N, Iwai H, Matsuoka N, Hayashi T, Hosoda K, Inoue G et al (2000) Pathophysiological role of leptin in obesity-related hypertension. J Clin Invest 105:1243–1252

    Article  CAS  PubMed  Google Scholar 

  100. Elefteriou F, Takeda S, Ebihara K, Magre J, Patano N, Kim CA, Ogawa Y, Liu X, Ware SM, Craigen WJ et al (2004) Serum leptin level is a regulator of bone mass. Proc Natl Acad Sci U S A 101:3258–3263

    Article  CAS  PubMed  Google Scholar 

  101. Suganami T, Mukoyama M, Mori K, Yokoi H, Koshikawa M, Sawai K, Hidaka S, Ebihara K, Tanaka T, Sugawara A et al (2005) Prevention and reversal of renal injury by leptin in a new mouse model of diabetic nephropathy. FASEB J 19:127–129

    CAS  PubMed  Google Scholar 

  102. Masuzaki H, Ogawa Y, Hosoda K, Miyawaki T, Hanaoka I, Hiraoka J, Yasuno A, Nishimura H, Yoshimasa Y, Nishi S et al (1997) Glucocorticoid regulation of leptin synthesis and secretion in humans: elevated plasma leptin levels in Cushing's syndrome. J Clin Endocrinol Metab 82:2542–2547

    Article  CAS  PubMed  Google Scholar 

  103. Masuzaki H, Ogawa Y, Sagawa N, Hosoda K, Matsumoto T, Mise H, Nishimura H, Yoshimasa Y, Tanaka I, Mori T et al (1997) Nonadipose tissue production of leptin: leptin as a novel placenta-derived hormone in humans. Nat Med 3:1029–1033

    Article  CAS  PubMed  Google Scholar 

  104. Sagawa N, Mori T, Masuzaki H, Ogawa Y, Nakao K (1997) Leptin production by hydatidiform mole. Lancet 350:1518–1519

    Article  CAS  PubMed  Google Scholar 

  105. Ogawa Y, Masuzaki H, Hosoda K, Aizawa-Abe M, Suga J, Suda M, Ebihara K, Iwai H, Matsuoka N, Satoh N et al (1999) Increased glucose metabolism and insulin sensitivity in transgenic skinny mice overexpressing leptin. Diabetes 48:1822–1829

    Article  CAS  PubMed  Google Scholar 

  106. Masuzaki H, Ogawa Y, Isse N, Satoh N, Okazaki T, Shigemoto M, Mori K, Tamura N, Hosoda K, Yoshimasa Y et al (1995) Human obese gene expression. Adipocyte-specific expression and regional differences in the adipose tissue. Diabetes 44:855–858

    Article  CAS  PubMed  Google Scholar 

  107. Ioffe E, Moon B, Connolly E, Friedman JM (1998) Abnormal regulation of the leptin gene in the pathogenesis of obesity. Proc Natl Acad Sci U S A 95:11852–11857

    Article  CAS  PubMed  Google Scholar 

  108. Masuzaki H, Ogawa Y, Aizawa-Abe M, Hosoda K, Suga J, Ebihara K, Satoh N, Iwai H, Inoue G, Nishimura H et al (1999) Glucose metabolism and insulin sensitivity in transgenic mice overexpressing leptin with lethal yellow agouti mutation: usefulness of leptin for the treatment of obesity-associated diabetes. Diabetes 48:1615–1622

    Article  CAS  PubMed  Google Scholar 

  109. Tanaka T, Hidaka S, Masuzaki H, Yasue S, Minokoshi Y, Ebihara K, Chusho H, Ogawa Y, Toyoda T, Sato K et al (2005) Skeletal muscle AMP-activated protein kinase phosphorylation parallels metabolic phenotype in leptin transgenic mice under dietary modification. Diabetes 54:2365–2374

    Article  CAS  PubMed  Google Scholar 

  110. Kamohara S, Burcelin R, Halaas JL, Friedman JM, Charron MJ (1997) Acute stimulation of glucose metabolism in mice by leptin treatment. Nature 389:374–377

    Article  CAS  PubMed  Google Scholar 

  111. Liu L, Karkanias GB, Morales JC, Hawkins M, Barzilai N, Wang J, Rossetti L (1998) Intracerebroventricular leptin regulates hepatic but not peripheral glucose fluxes. J Biol Chem 273:31160–31167

    Article  CAS  PubMed  Google Scholar 

  112. Cusin I, Zakrzewska KE, Boss O, Muzzin P, Giacobino JP, Ricquier D, Jeanrenaud B, Rohner-Jeanrenaud F (1998) Chronic central leptin infusion enhances insulin-stimulated glucose metabolism and favors the expression of uncoupling proteins. Diabetes 47:1014–1019

    Article  CAS  PubMed  Google Scholar 

  113. Goldstein BJ (1994) Syndrome of extreme insulin resistance. In: Kahn CR, Weir GC (eds) Joslin’s diabetes mellitus. Lea & Febiger, Philadelphia

    Google Scholar 

  114. Andreelli F, Hanaire-Broutin H, Laville M, Tauber JP, Riou JP, Thivolet C (2000) Normal reproductive function in leptin-deficient patients with lipoatrophic diabetes. J Clin Endocrinol Metab 85:715–719

    Article  CAS  PubMed  Google Scholar 

  115. Pardini VC, Victoria IM, Rocha SM, Andrade DG, Rocha AM, Pieroni FB, Milagres G, Purisch S, Velho G (1998) Leptin levels, beta-cell function, and insulin sensitivity in families with congenital and acquired generalized lipoatrophic diabetes. J Clin Endocrinol Metab 83:503–508

    Article  CAS  PubMed  Google Scholar 

  116. Moitra J, Mason MM, Olive M, Krylov D, Gavrilova O, Marcus-Samuels B, Feigenbaum L, Lee E, Aoyama T, Eckhaus M et al (1998) Life without white fat: a transgenic mouse. Genes Dev 12:3168–3181

    Article  CAS  PubMed  Google Scholar 

  117. Shimomura I, Hammer RE, Richardson JA, Ikemoto S, Bashmakov Y, Goldstein JL, Brown MS (1998) Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue: model for congenital generalized lipodystrophy. Genes Dev 12:3182–3194

    Article  CAS  PubMed  Google Scholar 

  118. Ebihara K, Ogawa Y, Masuzaki H, Shintani M, Miyanaga F, Aizawa-Abe M, Hayashi T, Hosoda K, Inoue G, Yoshimasa Y et al (2001) Transgenic overexpression of leptin rescues insulin resistance and diabetes in a mouse model of lipoatrophic diabetes. Diabetes 50:1440–1448

    Article  CAS  PubMed  Google Scholar 

  119. Kobayashi H, Ogawa Y, Shintani M, Ebihara K, Shimodahira M, Iwakura T, Hino M, Ishihara T, Ikekubo K, Kurahachi H et al (2002) A novel homozygous missense mutation of melanocortin-4 receptor (MC4R) in a Japanese woman with severe obesity. Diabetes 51:243–246

    Article  CAS  PubMed  Google Scholar 

  120. Vaisse C, Clement K, Durand E, Hercberg S, Guy-Grand B, Froguel P (2000) Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity. J Clin Invest 106:253–262

    Article  CAS  PubMed  Google Scholar 

  121. Farooqi IS, Yeo GS, Keogh JM, Aminian S, Jebb SA, Butler G, Cheetham T, O'Rahilly S (2000) Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency. J Clin Invest 106:271–279

    Article  CAS  PubMed  Google Scholar 

  122. Oral EA, Simha V, Ruiz E, Andewelt A, Premkumar A, Snell P, Wagner AJ, DePaoli AM, Reitman ML, Taylor SI et al (2002) Leptin-replacement therapy for lipodystrophy. N Engl J Med 346:570–578

    Article  CAS  PubMed  Google Scholar 

  123. Ebihara K, Masuzaki H, Nakao K (2004) Long-term leptin-replacement therapy for lipoatrophic diabetes. N Engl J Med 351:615–616

    Article  CAS  PubMed  Google Scholar 

  124. Ebihara K, Kusakabe T, Hirata M, Masuzaki H, Miyanaga F, Kobayashi N, Tanaka T, Chusho H, Miyazawa T, Hayashi T et al (2007) Efficacy and safety of leptin-replacement therapy and possible mechanisms of leptin actions in patients with generalized lipodystrophy. J Clin Endocrinol Metab 92:532–541

    Article  CAS  PubMed  Google Scholar 

  125. Miyanaga F, Ogawa Y, Ebihara K, Hidaka S, Tanaka T, Hayashi S, Masuzaki H, Nakao K (2003) Leptin as an adjunct of insulin therapy in insulin-deficient diabetes. Diabetologia 46:1329–1337

    Article  CAS  PubMed  Google Scholar 

  126. Kusakabe T, Tanioka H, Ebihara K, Hirata M, Miyamoto L, Miyanaga F, Hige H, Aotani D, Fujisawa T, Masuzaki H et al (2009) Beneficial effects of leptin on glycaemic and lipid control in a mouse model of type 2 diabetes with increased adiposity induced by streptozotocin and a high-fat diet. Diabetologia 52:675–683

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, 606, Japan

    Kazuwa Nakao, Akihiro Yasoda, Ken Ebihara, Kiminori Hosoda & Masashi Mukoyama

  2. Translational Research Center, Kyoto University Graduate School of Medicine, Kyoto, 606, Japan

    Kazuwa Nakao

  3. EBM Research Center, Kyoto University Graduate School of Medicine, Kyoto, 606, Japan

    Kazuwa Nakao

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  1. Kazuwa Nakao
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Nakao, K., Yasoda, A., Ebihara, K. et al. Translational research of novel hormones: lessons from animal models and rare human diseases for common human diseases. J Mol Med 87, 1029–1039 (2009). https://doi.org/10.1007/s00109-009-0515-7

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