, Volume 4, Issue 1–2, pp 15–23 | Cite as

Leptin and the Pituitary

  • Masayuki Sone
  • Robert Y. Osamura


In 1994, Zhang et al. of Rockefeller University in New York reported the first successful complementary DNA (cDNA) cloning of leptin by the positional cloning method. Leptin was identified as the gene of ob/ob mouse in genetic obesity syndromes. It has very strong food intake control, and body weight and energy expenditure. The name “leptin” derived from the Greek word leptos, meaning “thin.” We hereby review major advances leading to our current finding of leptin, leptin receptor and its structure, the outline of homozygote, and also influence of leptin in the pituitary.

(The structure of leptin) The mouse obese gene has been localized to chromosome 6. With human leptin gene on chromosome 7q31.3, its DNA has more than 15000 base pairs and consists of three exons and two introns. For bioactivation of leptin the importance of disulfide-binding site is suggested. Human leptin which replaced the 128-th arginine with glutamine has the function of an aldosteron antagonist, which is reported to have the function of athrocytosis inhibition. The resemblance of leptin precursor of human, mouse and rat is very high, i.e., mouse and rat homology is 96% and mouse and human homology is 83%.

(The structure of leptin receptor) The mutant gene, which is the cause of obesity, was shown on map on diabetic mouse (db/db) chromosome 4, and it was proven to be the same as the leptin receptor gene cloned by Tartaglia et all. Further studies have found the Zucker fatty rat (fa/fa) to be incorporated into a linkage map of rat chromosome 5, whose region of rat is the equivalent to the region of conserved synteny of the db/db mouse gene. The leptin receptor is glycoprotein consisting of a single transmembrane-spanning component. The primary structure of leptin receptor belongs to the cytokine-class1 family, the single membrane-spanning receptor, and is highly related to the gp130 signal-transducing component of the interleukin-6 (IL-6) receptor, the granulocyte colony-stimulating factor (G-CSF) receptor, and the leukemia inhibitory factor (LIF) receptor. The leptin receptor is known to have at least six existing isoforms (Ob-Ra, b, c, d, e, f) from the difference insplicing.

(Homozygote Mutationof Leptinand Leptin Receptor :Hormone Secretion Disorders) The point mutation of ob/ob mouse and the splicing mutation of db/db mouse show remarkable obesity and hyperphagia. These obesity models show a reproduction disorder with both the male and the female, and they develop with homozygote. The cause is thought to be the gonadotropin secretory abnormality in pituitary. Three family lines report the cases of this deficiency, and it is considered that the secretory abnormality in pituitary develops into hypogonadotropic. These patients show low value in plasma FSHβ (follicle stimulating hormone-β) and LHβ (luteinizing hormone-β) which are produced from pituitary, and the plasma GnRH (gonadotropin releasing hormone) level is also low Furthermore, the leptin receptor deficient family line was reported in 1998, in which case only the homozygote developed. The plasma leptin concentration of normal human is about 8.0 ng/ml, and this case with leptin receptor deficiency has high value of 500–700 ng/ml, which is the equivalent to the db/db mouse.

(Role of Leptin in Hypothalamus-Pituitary-Periphery Function) The role of leptin which regulates pituitary hormones suggests the promotion the GHRH (growth hormone releasing hormone) secretion in hypothalamus-pituitary axis, with the possibility of the rise in secretion of GH (growth hormone) in pituitary, i.e. effects of icv (intracerebroventricular) infusion of leptin has spontaneously stimulated GHRH, which promotes GH secretion in the normal rats. On the other hand, topical treatment of GH3 (derived from a rat pituitary GH-secreting cell line) with leptin directly inhibits cell proliferation. The obesity model animals (ob/ob, db/db, fa/fa) have equally plump body compared to the normal models, which shows signs of sufficient growth.

(Localization and Functional Relevance of Leptin and Leptin Receptor in Rodents Pituitary) Aside from being the food intake inhibitor and the energy control factor, leptin takes part in controlling the pituitary hormones. Promoting the secretion of GH, PRL (prolactin), TSHβ (thyroid stimulating hormone-β), FSHβ/LHβ, and inhibiting the secretion of ACTH (adrenocorticotropic hormone) are the major changes of pituitary hormones which are brought on by leptin. The expressive localization is specific, and immunohistochemistry (IHC) method recognized leptin in granular state in FSHβ, LHβ and TSHβ positive cells. In our biochemical examination, the bulk of the expression of leptin is recognized in fraction of the secretory granule. In particular, FSHβ cells had the highest percentage rate of colocalized leptin in rat pituitary. On the other hand, leptin receptor has been reported to be found only in normal rat pituitary, human pituitary adenoma, and respective cell lines in pituitaries by the RT-PCR method until now, but we disclosed for the first time the localization of leptin receptor on the plasma membrane of GH-secreting cells with the IHC method that hasn't been cleared so far. These findings show that leptin and leptin receptor have been expressed in different cells, and that the rat pituitary glands entertain paracrine mechanism between leptin (FSHβ/LHβ cells) and leptin receptor (GH cells). The function of paracrine in this pituitary suggests a new point of view to hypothalamus-pituitary axis, and it shall be concerned with many regions such as hormone secretions and proliferation/inhibition.

(Human Pituitary Adenoma) Preliminary report of leptin and leptin-receptor relationship with pituitary adenoma that has secretion abnormality has been filed, and its manifestation is being observed by the RT-PCR. Leptin and leptin receptor are expressed in most adenoma, and it is thought to function by autocrine and paracrine pathway in the adenomas. Leptin has been located in ACTH-secreting adenoma most frequently, especially in ACTH carcinoma. The leptin receptor is detected in all adenomas with high percentage rate, with both long and short forms, and then many cases of nonfunctioning pituitary adenomas, compared with other adenomas, have been reported to be positive with both long and short forms of leptin receptor as detected by RT-PCR. The HP75 cell line is derived from the nonfunctioning pituitary adenoma, which produces FSHβ and LHβ. The expression of leptin receptor in nonfunctioning pituitary adenoma, and the suppression of HP75 multiplication may lead to the possible hypothesis of leptin becoming one factor for the treatment of pituitary adenoma, especially in gonadotropin adenomas.

leptin leptin receptor pituitary gland immunohistochemistry 


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  1. 1.
    Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature 1994;372:425-432.Google Scholar
  2. 2.
    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;269:546-554.Google Scholar
  3. 3.
    Pelleymounter MA, Cullen MJ, Baker MB, Hecht R, Winters D, Boone T, Collins F. Effects of the obese gene product on body weight regulation in ob/ob mice. Science 1995;269: 540-543.Google Scholar
  4. 4.
    Stephens TW, Basinski M, Bristow PK, Bue Valleskey JM, Burgett SG, Craft L, Hale J, Hoffmann J, Hsiung HM, Kriauciunas A, et al. The role of neuropeptide Y in the antiobesity action of the obese gene product. Nature 1995;377: 530-532.Google Scholar
  5. 5.
    Meister B, Arvidsson U. The hormone leptin reduces body weight. A mutant gene makes the mouse obese. Lakartidningen 1996;93:247-251.Google Scholar
  6. 6.
    Coleman DL. Obese and diabetes: Two mutant genes causing diabetes-obesity syndromes in mice. Diabetologia 1978; 14:141-148.Google Scholar
  7. 7.
    Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D, Lallone RL, Burley SK, Friedman JM. Weightreducing effects of the plasma protein encoded by the obese gene. Science 1995;269:543-546.Google Scholar
  8. 8.
    Wang J, Liu R, Hawkins M, Barzilai N, Rossetti L. A nutrient-sensing pathway regulates leptin gene expression in muscle and fat. Nature 1998;393:684-688.Google Scholar
  9. 9.
    Jin L, Burguera BG, Couce ME, Scheithauer BW, Lamsan J, Eberhardt NL, Kulig E, Lloyd RV. Leptin and leptin receptor expression in normal and neoplastic human pituitary: Evidence of a regulatory role for leptin on pituitary cell proliferation. J Clin Endocrinol Metab 1999;84:2903-2911.Google Scholar
  10. 10.
    Jin L, Zhang S, Burguera BG, Couce ME, Osamura RY, Kulig E, Lloyd RV. Leptin and leptin receptor expression in rat and mouse pituitary cells. Endocrinology 2000;141:333-339.Google Scholar
  11. 11.
    Martinez Anso E, Lostao MP, Martinez JA. Immunohistochemical localization of leptin in rat kidney. Kidney Int 1999;55:1129-1130.Google Scholar
  12. 12.
    Senaris R, Garcia Caballero T, Casabiell X, Gallego R, Castro R, Considine RV, Dieguez C, Casanueva FF. Synthesis of leptin in human placenta. Endocrinology 1997;138:4501-4504.Google Scholar
  13. 13.
    Masuzaki H, Ogawa Y, Sagawa N, Hosoda K, Matsumoto T, Mise H, Nishimura H, Yoshimasa Y, Tanaka I, Mori T, Nakao K. Nonadipose tissue production of leptin: leptin as a novel placenta-derived hormone in humans. Nat Med 1997;3:1029-1033.Google Scholar
  14. 14.
    Smith Kirwin SM, O'Connor DM, De Johnston J, Lancey ED, Hassink SG, Funanage VL. Leptin expression in human mammary epithelial cells and breast milk. J Clin Endocrinol Metab 1998;83:1810-1813.Google Scholar
  15. 15.
    Hwang CS, Loftus TM, Mandrup S, Lane MD. Adipocyte differentiation and leptin expression. Ann Rev Cell Dev Biol 1997;13:231-259.Google Scholar
  16. 16.
    Elmquist JK, Maratos Flier E, Saper CB, Flier JS. Unraveling the central nervous system pathways underlying responses to leptin. Nat Neurosci 1998;1:445-450.Google Scholar
  17. 17.
    Baskin DG, Schwartz MW, Seeley RJ, Woods SC, Porte D Jr, Breininger JF, Jonak Z, Schaefer J, Krouse M, Burghardt C, Campfield LA, Burn P, Kochan JP. Leptin receptor longform splice-variant protein expression in neuron cell bodies of the brain and co-localization with neuropeptide Y mRNA in the arcuate nucleus.J Histochem Cytochem 1999;47: 353-362.Google Scholar
  18. 18.
    Bado A, Levasseur S, Attoub S, Kermorgant S, Laigneau JP, Bortoluzzi MN, Moizo L, Lehy T, Guerre Millo M, Le Marchand Brustel Y, Lewin MJ. The stomach is a source of leptin. Nature 1998;394:790-793.Google Scholar
  19. 19.
    Rock FL, Altmann SW, van Heek M, Kastelein RA, Bazan JF. The leptin haemopoietic cytokine fold is stabilized by an intrachain disulfide bond. Horm Metab Res 1996;28:649-652.Google Scholar
  20. 20.
    Green ED, Maffei M, Braden VV, Proenca R, DeSilva U, Zhang Y, Chua SC Jr, Leibel RL, Weissenbach J, Friedman JM. The human obese (OB) gene: RNA expression pattern and mapping on the physical, cytogenetic, and genetic maps of chromosome 7. Genome Res 1995;5:5-12.Google Scholar
  21. 21.
    Brunner L, Whitebread S, Leconte I, Stricker Krongrad A, Cumin F, Chiesi M, Levens N. A peptide leptin antagonist reduces food intake in rodents. Int J Obes Relat Metab Disord 1999;23:463-469.Google Scholar
  22. 22.
    Andersson LB. Genes and obesity. Ann Med 1996;28:5-7.Google Scholar
  23. 23.
    Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y, Fei H, Kim S, Lallone R, Ranganathan S, et al. Leptin levels in human and rodent: Measurement of plasma leptin and ob RNAin obese and weight-reduced subjects. Nat Med 1995;1:1155-1161.Google Scholar
  24. 24.
    Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, Richards GJ, Campfield LA, Clark FT, Deeds J, et al. Identification and expression cloning of a leptin receptor, OB-R. Cell 1995;83:1263-1271.Google Scholar
  25. 25.
    Lee GH, Proenca R, Montez JM, Carroll KM, Darvishzadeh JG, Lee JI, Friedman JM. Abnormal splicing of the leptin receptor in diabetic mice. Nature 1996;379:632-635.Google Scholar
  26. 26.
    Chen H, Charlat O, Tartaglia LA, Woolf EA, Weng X, Ellis SJ, Lakey ND, Culpepper J, Moore KJ, Breitbart RE, Duyk GM, Tepper RI, Morgenstern JP. Evidence that the diabetes gene encodes the leptin receptor: Identification of a mutation in the leptin receptor gene in db/db mice. Cell 1996;84: 491-495.Google Scholar
  27. 27.
    Truett GE, Jacob HJ, Miller J, Drouin G, Bahary N, Smoller JW, Lander ES, Leibel RL. Genetic map of rat chromosome 5 including the fatty (fa) locus.MammGenome 1995;6:25-30.Google Scholar
  28. 28.
    Chua SC Jr, Chung WK, Wu Peng XS, Zhang Y, Liu SM, Tartaglia L, Leibel RL. Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor. Science 1996;271:994-996.Google Scholar
  29. 29.
    Phillips MS, Liu Q, Hammond HA, Dugan V, Hey PJ, Caskey CJ, Hess JF. Leptin receptor missense mutation in the fatty Zucker rat. Nat Genet 1996;13:18-19.Google Scholar
  30. 30.
    Tartaglia LA. The leptin receptor. J Biol Chem 1997;272: 6093-6096.Google Scholar
  31. 31.
    Ohmichi M, Hirota K, Koike K, Kurachi H, Ohtsuka S, Matsuzaki N, Yamaguchi M, Miyake A, Tanizawa O. Binding sites for interleukin-6 in the anterior pituitary gland. Neuroendocrinology 1992;55:199-203.Google Scholar
  32. 32.
    Hakansson ML, Meister B. Transcription factor STAT3 in leptin target neurons of the rat hypothalamus. Neuroendocrinology 1998;68:420-427.Google Scholar
  33. 33.
    Bjorbaek C, Uotani S, da Silva B, Flier JS. Divergent signaling capacities of the long and short isoforms of the leptin receptor. J Biol Chem 1997;272:32686-32695.Google Scholar
  34. 34.
    Vaisse C, Halaas JL, Horvath CM, Darnell JE Jr, Stoffel M, Friedman JM. Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice. Nat Genet 1996;14:95-97.Google Scholar
  35. 35.
    Cheung CC, Thornton JE, Kuijper JL, Weigle DS, Clifton DK, Steiner RA. Leptin is a metabolic gate for the onset of puberty in the female rat. Endocrinology 1997;138:855-858.Google Scholar
  36. 36.
    Chehab FF, Lim ME, Lu R. Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin.Nat Genet 1996;12:318-320.Google Scholar
  37. 37.
    Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, Wareham NJ, Sewter CP, Digby JE, Mohammed SN, Hurst JA, Cheetham CH, Earley AR, Barnett AH, Prins JB, O'Rahilly S. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 1997; 387:903-908.Google Scholar
  38. 38.
    Strobel A, Issad T, Camoin L, Ozata M, Strosberg AD. A leptin missense mutation associated with hypogonadism and morbid obesity. Nat Genet 1998;18:213-215.Google Scholar
  39. 39.
    Clement K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, Cassuto D, Gourmelen M, Dina C, Chambaz J, Lacorte JM, Basdevant A, Bougneres P, Lebouc Y, Froguel P, Guy Grand B. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 1998;392:398-401.Google Scholar
  40. 40.
    Ahima RS, Dushay J, Flier SN, Prabakaran D, Flier JS. Leptin accelerates the onset of puberty in normal female mice. J Clin Invest 1997;99:391-395.Google Scholar
  41. 41.
    Chehab FF, Mounzih K, Lu R, Lim ME. Early onset of reproductive function in normal female mice treated with leptin. Science 1997;275:88-90.Google Scholar
  42. 42.
    Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos Flier E, Flier JS. Role of leptin in the neuroendocrine response to fasting. Nature 1996;382:250-252.Google Scholar
  43. 43.
    Tena Sempere M, Pinilla L, Gonzalez LC, Dieguez C, Casanueva FF, Aguilar E. Leptin inhibits testosterone secretion from adult rat testis in vitro.J Endocrinol 1999;161:211-218.Google Scholar
  44. 44.
    Zachow RJ, Magoffin DA. Direct intraovarian effects of leptin: impairment of the synergistic action of insulin-like growth factor-I on follicle-stimulating hormone-dependent estradiol-17 beta production by rat ovarian granulosa cells. Endocrinology 1997;138:847-850.Google Scholar
  45. 45.
    Yu WH, Kimura M, Walczewska A, Karanth S, McCann SM. Role of leptin in hypothalamic-pituitary function. Proc Natl Acad Sci USA 1997;94:1023-1028.Google Scholar
  46. 46.
    McCann SM, Kimura M, Walczewska A, Karanth S, Rettori V, Yu WH. Hypothalamic control of FSH and LH by FSHRF, LHRH, cytokines, leptin and nitric oxide. Neuroimmunomodulation 1998;5:193-202.Google Scholar
  47. 47.
    Zamorano PL, Mahesh VB, De Sevilla LM, Chorich LP, Bhat GK, Brann DW. Expression and localization of the leptin receptor in endocrine and neuroendocrine tissues of the rat. Neuroendocrinology 1997;65:223-228.Google Scholar
  48. 48.
    Carro E, Senaris R, Considine RV, Casanueva FF, Dieguez C. Regulation of in vivo growth hormone secretion by leptin. Endocrinology 1997;138:2203-2206.Google Scholar
  49. 49.
    Cai A, Hyde JF. Upregulation of leptin receptor gene expression in the anterior pituitary of human growth hormone-releasing hormone transgenic mice. Endocrinology 1998;139:420-423.Google Scholar
  50. 50.
    Tannenbaum GS, Gurd W, Lapointe M. Leptin is a potent stimulator of spontaneous pulsatile growth hormone (GH) secretion and the GH response to GH-releasing hormone. Endocrinology 1998;139:3871-3875.Google Scholar
  51. 51.
    Cocchi D, De Gennaro Colonna V, Bagnasco M, Bonacci D, Muller EE. Leptin regulates GH secretion in the rat by acting on GHRH and somatostatinergic functions. J Endocrinol 1999;162:95-99.Google Scholar
  52. 52.
    Ducy P, Amling M, Takeda S, Priemel M, Schilling AF, Beil FT, Shen J, Vinson C, Rueger JM, Karsenty G. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell 2000;100:197-207.Google Scholar
  53. 53.
    Steppan CM, Crawford DT, Chidsey Frink KL, Ke H, Swick AG. Leptin is a potent stimulator of bone growth in ob/ob mice. Regul Pept 2000;92:73-78.Google Scholar
  54. 54.
    Shimon I, Yan X, Magoffin DA, Friedman TC, Melmed S. Intact leptin receptor is selectively expressed in human fetal pituitary and pituitary adenomas and signals human fetal pituitary growth hormone secretion. J Clin Endocrinol Metab 1998;83:4059-4064.Google Scholar
  55. 55.
    Aubert ML, Pierroz DD, Gruaz NM, d'Alleves V, Vuagnat BA, Pralong FP, Blum WF, Sizonenko PC. Metabolic control of sexual function and growth: Role of neuropeptide Y and leptin. Mol Cell Endocrinol 1998;140:107-113.Google Scholar
  56. 56.
    Morash B, Li A, Murphy PR, Wilkinson M, Ur E. Leptin gene expression in the brain and pituitary gland. Endocrinology 1999;140:5995-5998.Google Scholar
  57. 57.
    Vidal S, Cohen SM, Horvath E, Kovacs K, Scheithauer BW, Burguera BG, Lloyd RV. Subcellular localization of leptin in non-tumorous and adenomatous human pituitaries: An immuno-ultrastructural study. J Histochem Cytochem 2000; 48:1147-1152.Google Scholar
  58. 58.
    Dieterich KD, Lehnert H. Expression of leptin receptor mRNA and the long form splice variant in human anterior pituitary and pituitary adenoma. Exp Clin Endocrinol Diabetes 1998;106:522-525.Google Scholar
  59. 59.
    Saito S, Kahara M, Yamada M, Ogura K, Kimura M, Yoneda N, Aono T. Leptin and female sexual function. World of Obstetrics & Gynecology (Jpn) 1999;511-518.Google Scholar
  60. 60.
    Mise H, Sagawa N, Matsumoto T, Yura S, Nanno H, Itoh H, Mori T, Masuzaki H, Hosoda K, Ogawa Y, Nakao K. Augmented placental production of leptin in preeclampsia: possible involvement of placental hypoxia. J Clin Endocrinol Metab 1998;83:3225-3229.Google Scholar
  61. 61.
    Andersen B, Rosenfeld MG. Pit-1 determines cell types during development of the anterior pituitary gland. A model for transcriptional regulation of cell phenotypes in mammalian organogenesis. J Biol Chem 1994;269:29335-29338.Google Scholar
  62. 62.
    Nishimura S, Ogawa Y, Nakao K. The meaning that leptin is physiological, and meaning in obesity, New Horizon for Medicine (Jpn), Gendaiiryou Publishers 2000;1811-1816.Google Scholar
  63. 63.
    Masuzaki H, Ogawa Y, Nakao K. The role of leptin in human obesity and related diseases-recent progress and future directions. In: The State-of-the-Art Drug Discovery: Strategic Approach and Novel Drugs (Jpn), Kyouritu Publishers 2000;1125-1132.Google Scholar
  64. 64.
    Masayuki Sone, Hidetaka Nagata, Susumu Takekoshi, R. Yoshiyuki Osamura. Expression of and localization of leptin receptor in the normal rat pituitary gland. Cell Tissue Res 305:351-356, 2001.Google Scholar

Copyright information

© Kluwer Academic Publishers 2001

Authors and Affiliations

  • Masayuki Sone
    • 1
  • Robert Y. Osamura
    • 1
  1. 1.Department of PathologyTokai University School of MedicineIsehara, KanagawaJapan

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