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Leptin Inhibits Cortisol and Corticosterone Secretion in Pathologic Human Adrenocortical Cells

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Abstract

Regulation of adrenal corticosteroid secretion by leptin may involve interactions at multiple levels of the hypothalamic-pituitary-adrenal axis. To investigate the possible direct effects of leptin on corticosteroid secretion of human adrenocortical adenomas, cells from adrenocortical adenomas causing primary aldosteronism (n = 1) and Cushing's syndrome (n = 1), as well as cells from nonhyperfunctioning adrenocortical adenomas (n = 5) were isolated and incubated for 2 h with human recombinant leptin (1–1000 ng/ml) in the presence and absence of adrenocorticotrop hormone (ACTH), then cortisol, corticosterone and aldosterone concentrations in incubating media were determined using radioimmunoassays. It was found that leptin effectively and dose-dependently inhibited basal and ACTH-stimulated cortisol and corticosterone secretion in the three types of human adrenocortical adenoma cells. The inhibiting effect of basal corticosterone secretion was detectable in the presence of leptin concentration as low as 1 ng/ml, with decreases of corticosterone secretion to 34 ± 4%, 57 ± 11% and 79 ± 9% in Cushing's syndrome, primary aldosteronism, and nonhyperfunctioning adrenocortical adenoma cells, respectively. The inhibition of basal cortisol secretion in the presence of low concentration of leptin was less prominent, but 10 ng/ml leptin significantly diminished basal cortisol secretion to 81 <6 9% in adrenocortical adenoma cells from Cushing's syndrome, to 68 ± 6% in4 adenoma cells from primary aldosteronism, and to 83 ± 8% in cells from nonhyperfunctioning adenomas. The inhibition of ACTH-stimulated cortisol and corticosterone secretion by leptin was similar to those found in cells without ACTH stimulation. By contrast, leptin even at 1000 ng/ml concentration exerted no clear effect on basal and ACTH-stimulated aldosterone secretion in cells from primary aldosteronism and in those nonhyperfunctioning adenoma cells in which aldosterone secretion was detectable. These results indicate that leptin is a potent inhibitor of cortisol and corticosterone secretion in human adenomatous adrenocortical cells. The inhibition of these corticosteroids by leptin may represent a potentially important interaction that exists between leptin and the hypothalamic-pituitary-adrenal axis.

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References

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

    Google Scholar 

  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. 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;269:546–549.

    Google Scholar 

  5. Casanueva FF, Dieguez C. Neuroendocrine regulation and actions of leptin. Front Neuroendocrinol 1999;20:317–363.

    Google Scholar 

  6. Ahima RS, Saper CB, Flier JS, Elmquist JK. Leptin regulation of neuroendocrine systems. Front Neuroendocrinol 2000;21:263–307.

    Google Scholar 

  7. 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 

  8. Yu WH, Kimura M, Walcewska A, Karanth S, McCann SM. Role of leptin in hypothalamic-pituitary function. Proc Natl Acad Sci USA 1997;94:1023–1028.

    Google Scholar 

  9. 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 

  10. Larsson H, Ahren B. Short-term dexamethasone treatment increases plasma leptin independently of changes in insulin sensitivity in healthy women. J Clin Endocrinol Metab 1996;81:4428–4432.

    Google Scholar 

  11. Legradi G, Emerson CH, Ahima RS, Flier JS, Lechman RM. Leptin prevents fasting-induced suppression of prothyrotropin-releasing hormone messenger ribonucleic acid in neurons of the hypothalamic paraventricular nucleus. Endocrinology 1997;138:2569–2576.

    Google Scholar 

  12. 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 

  13. Heiman ML, Ahima RS, Craft LS, Schoner B, Stephens TW, Flier JS. Leptin inhibition of the hypothalamic-pituitaryadrenal axis in response to stress. Endocrinology 1997;138: 3859–3863.

    Google Scholar 

  14. Costa A, Poma A, Martignoni E, Nappi G, Úr E, Grossman A. Stimulation of corticotropin-releasing hormone release by the obese (ob) gene product, leptin, from hypothalamic explants. Neuroreport 1997;8:1131–1134.

    Google Scholar 

  15. Schwartz MW, Seeley RJ, Campfield LA, Burn P, Baskin DG. Identification of targets of leptin action in rat hypothalamus. J Clin Invest 1996;98:1101–1106.

    Google Scholar 

  16. Ahima RS, Kelly J, Elmquist JK, Flier JS.Distinct physiologic and neural responses to decreased leptin and mild hyperleptinemia. Endocrinology 1999;140:4923–4931.

    Google Scholar 

  17. Stephens TW, Basinski M, Bristow PK, Bue-Valleskey JM, Burgett SG, Craft L, Hale J, Hoffmann J, Hsiung HM, Kriaciunas A. The role of neuropeptide Y in the antiobesity action of the obese gene product.Nature 1995;377: 530–532.

    Google Scholar 

  18. Malendowicz LK, Tortorella C, Nowak KW, Nussdorfer GG, Hochól A, Majchrzak M. Leptin prolonged administration inhibits the growth and glucocorticoid secretion of rat adrenal cortex. Endocrine Res 2000;26:141–152.

    Google Scholar 

  19. Raber J, Chen SZ, Mucke L, Feng LL. Corticotropin-releasing factor and adrenocorticotropic hormone as potential central mediators of OB effects. J Biol Chem 1997;272:15057–15060.

    Google Scholar 

  20. Van Dijk G, Donahay JCK, Thiele TE, Scheurink AJW, Steffens AB, Wilkinson CW, Tenenbaum R, Campfield LA, Burn P, Seeley RJ, Woods SC. Central leptin stimulates corticosterone secretion at the onset of the dark phase. Diabetes 1997;46:1911–1914.

    Google Scholar 

  21. Al-Barazajni KA, Buckingham RE, Arch JRS, Haynes A, Mossakowska DE, McBay DL, Holmes SD, McHale MT, Wang XM, Gloger SS. Effects of intracerebroventricular infusion of leptin in obese Zucker rats. Obesity Res 1997;-5:387–394.

    Google Scholar 

  22. Lado-Abeal J, Mrotek JJ, Stocco DM, Norman RL.Effect of leptin on ACTH-stimulated secretion of cortisol in rhesus macaques and on human adrenal carcinoma cells. Eur J Endocrinol 1999;141:534–538.

    Google Scholar 

  23. Pralong FP, Roduit R, Waeber G, Castillo E, Mosimann F, Thorens B, Gaillard RC. Leptin inhibits directly glucocorticoid secretion by normal human and rat adrenal gland. Endocrinology 1998;139:4264–4268.

    Google Scholar 

  24. Bornstein RS, Uhlmann K, Haidan A, Ehrhart-Bornstein M, Scherbaum WA. Evidence for a novel peripheral action of leptin as a metabolic signal to the adrenal gland. Leptin inhibits cortisol release directly.Diabetes 1997;46:1235–1238.

    Google Scholar 

  25. Kruse M, Bornstein SR, Uhlmann K, Paeth G, Scherbaum WA. Leptin down-regulates the steroid producing system in the adrenal. Endocrine Res 1998;24:587–590.

    Google Scholar 

  26. Malendowicz LK, Nussdorfer GG, Markowska A. Effects of recombinant murine leptin on steroid secretion of dispersed rat adrenocortical cells. J Steroid Biochem Molec Biol 1997;-63:123–125.

    Google Scholar 

  27. Glasow A, Haidan A, Hilbers U, Breidert M, Gillespie J, Scherbaum WA, Chrousos GP, Bornstein SR. Expression of ob receptor in normal human adrenals: differential regulation of adrenocortical and adrenomedullary function by leptin. J Clin Endocrinol Metab 1998;83:4459–4466.

    Google Scholar 

  28. Glasow A, Bornstein R, Chrousos GP, Brown JW, Scherbaum WA. Detection of ob-receptor in human adrenal neoplasms and effect of leptin in adrenal cell proliferation. Horm Metab Res 1999;31:247–251.

    Google Scholar 

  29. Rácz K, Varga I, Kiss R, Gláz E.ACTHsensitivity of isolated human pathological adrenocortical cells: variability of responses in aldosterone, corticosterone, deoxycorticosterone and cortisol secretion. J Steroid Biochem 1984;20:1187–1194.

    Google Scholar 

  30. Varga I, Rácz K, Kiss R, Fütő L, Tóth M, Sergev O, Gláz E. Direct inhibitory effect of etomidate on corticosteroid secretion in human pathological adrenocortical cells.Steroids 1993;58:64–68.

    Google Scholar 

  31. Vecsei P, Onyechi J, Hornung J, Dietz R, Mast G, Holber H. Use of corticosteroid antibodies for the study of corticosteroid biosynthesis in vitro.J Steroid Biochem 1975;6:383–387.

    Google Scholar 

  32. Vecsei P.Glucocorticoids: cortisol, cortisone, corticosterone, compound S and their metabolites. In: Jaffe BM, Behrman HR, Eds. Methods of Hormone Radioimmunoassay. New York: Academic Press, 1979; 767–796.

  33. Gláz E, Rácz K, Varga I, Kiss R, Tóth M, Fütő L. Mineralocorticoid production of adrenal cortical adenomas. J Steroid Biochem Molec Biol 1993;45:57–64.

    Google Scholar 

  34. Rácz K, Pinet F, Marton T, Szende B, Gláz E, Corvol P. Expression of steroidogenic enzyme messenger ribonucleic acids and corticosteroid secretion in aldosterone-producing and “nonfunctioning” adrenal adenomas. J Clin Endocrinol Metab 1993;77:677–682.

    Google Scholar 

  35. Beuschlein F, Schulze E, Mora P, Gensheimer HP, Maser-Gluth C, Allolio B, Reincke M. Steroid 21-hydroxylase mutations and 21-hydroxylase messenger ribonucleic acid expression in human adrenocortical tumors. J Clin Endocrinol Metab 1998;83:2585–2588.

    Google Scholar 

  36. Tataranni PA, Larson DE, Snitker S, Young JB, Flatt JP, Ravussin E.Effects of glucocorticoids on energy metabolism and food intake in humans. Am J Physiol 1996;271: E317–E325.

    Google Scholar 

  37. Hauner H, Shimid P, Pfeiffer EF. Glucocorticoids and insulin promote the differentiation of human adipocyte precursor cells into fat cells. J Clin Endocrinol Metab 1987;84:832–835.

    Google Scholar 

  38. Weinstein SP, Paquin T, Pritsker A, Haber RS.Glucocorticoid-induced insulin resistance: dexamethasone inhibits the activation of glucose transport in rat sceletal muscle by both insulin and non-insulin related stimuli. Diabetes 1995;44: 441–445.

    Google Scholar 

  39. Larsson H, Ahren B.Short-term dexamethasone treatment increases plasma leptin independently of changes in insulin sensitivity in healthy women.J Clin Endocrinol Metab 1996;81:4428–4432.

    Google Scholar 

  40. Considine RV, Nyce MR, Kolaczynsky JW, Zhang PL, Ohannesian JP, Moore JH. Dexamethasone stimulates leptin release from human adipocytes: unexpected inhibition by insulin. J Cell Biochem 1997;65:254–258.

    Google Scholar 

  41. Leal-Cerro A, Considine RV, Peino RV, Venegas E, Astorga R, Casanueva FF, Dieguez C. Serum immunoreactive-leptin levels are increased in patients with Cushing's syndrome. Horm Metab Res 1996;28:711–713.

    Google Scholar 

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

    Google Scholar 

  43. Widjaja A, Schürmeyer TH, Von zur Mühlen A, Brabant G. Determinants of serum leptin levels in Cushing's syndrome. J Clin Endocrinol Metab 1998;83:600–603.

    Google Scholar 

  44. Rebuffé-Scrive M, Krotkiewski M, Elfverson J, Björntorp P. Muscle and adipose tissue morphology and metabolism in Cushing's syndrome.J Clin Endocrinol Metab 1988;67: 1122–1128.

    Google Scholar 

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Szücs, N., Varga, I., Jakab, C. et al. Leptin Inhibits Cortisol and Corticosterone Secretion in Pathologic Human Adrenocortical Cells. Pituitary 4, 71–77 (2001). https://doi.org/10.1023/A:1012990928218

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