Skip to main content

Influence of Cortisol Status on Leptin Secretion

Pituitary volume 4, pages 111–116 (2001)Cite this article

Abstract

The discovery of the adipocyte-produced hormone leptin has changed the field of obesity research and our understanding of energy homeostasis. It is now accepted that leptin is the afferent loop informing the hypothalamus about the states of fat stores, with hypothalamic efferents regulating appetite and energy expenditure. I addition, leptin has a role as a metabolic adaptator in overweight and fasting states. New and previously unsuspected neuroendocrine roles have emerged for leptin. Leptin participates in the expression of CRH in the hypothalamus, interacts at the adrenal level with ACTH, and is regulated by glucocorticoids. Since leptin and cortisol show an inverse circadian rhythm, it has suggested that a regulatory feedback is present. However glucocorticoids appears to play a modulatory, but not essential roles in generating leptin diurnal rhythm. Glucocortiocids act directly on the adipose tissue and increase leptin syntesis and secretion in humans. Leptin levels are markedly increased in Cushing's syndrome patients and in others pseudo-Cushing's syndrome states. Glucocorticoids appears to act as a key modulator of body weight and food intake, promoting leptin secretion by adipocytes, limiting central leptin induced effects and favoring those of the NPY. Furthermore the modulatory role of glucocorticoids could be altered in obesity, but the precise mode of action remains to be established. The relevance of this finding merits further studies.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

References

  1. Zang Y, Proenca R, Maffei M, Barrone M, Leopold L, Friedman J. Positional cloning of the mouse obese gen and its human homologue. Nature 1994;372:425–432.

    Google Scholar 

  2. Banks WA, Kastin AJ, Huang W, Jampan JB, Maness LM, Leptin enters the brain by a saturable system independent of insulin. 1Peptides 1996;17:305–311.

    Google Scholar 

  3. Seeley RJ, Yagaloff KA, Fisher SL, Burn P, Thiele TE, van Dijk G, Baskin DG, Schwartz MW. Melanocortin receptors in leptin effects. Nature 1997;390:349.

    Google Scholar 

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

    Google Scholar 

  5. Licinio J, Manzoros C, Negrao AB, Cizza G, Wong ML, Bongiorno PB, Chrousos GP, Karp B, Allen C, Flier JS, Gold PW. Human leptin levels are pulsatile and inversely related to pituitary-adrenal function. Nat Med 1997;3:575–579.

    Google Scholar 

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

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

    Google Scholar 

  9. Fehm HL, Smolnik R, Kern W, McGregor GP, Bickel U, Born J. The melanocortin melanocyte-stimulating hormone/ adrenocorticotropin(4-10) decreases body fat in humans. J Clin Endocrinol Metab 2001;86:1144–1148.

    Google Scholar 

  10. Hakansson ML, Brown H, Ghilardi N, Skoda RC, Meister B. Leptin receptor immunoreactivity in chemically de~ned target neurons of the hypothalamus. J Neurosci 1998;18:559–572.

    Google Scholar 

  11. Wardlaw SL. Clinical review 127: Obesity as a neuroendocrine disease: lessons to be learned from proopiomelanocortin and the melanocortin receptor mutations in mice and men. J Clin Endocrinol Metab 2001;86:1442–1446.

    Google Scholar 

  12. 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 

  13. Cai A, Hyde JF. Upregulation of leptin receptor gene expression in the anterior pituitary of human growth hormonereleasing hormone transgenic mice. Endocrinology 1998;139: 420–423.

    Google Scholar 

  14. Cai A, Hyde JF. The human growth hormone-releasing hormore transgenic mouse as a model of modest obesity: Differential changes in leptin receptor (OBR) gene expression in the anterior pituitary and hypothalamus after fasting and OBR localization in somatotrophs. Endocrinology 1999;140: 3609–1364.

    Google Scholar 

  15. 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 

  16. 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 

  17. 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 

  18. Vidal S, Cohen SM, Horvath E, Kovacs K, Scheithauer BW, Burguera BG, Lloyd RV. Subcellular localization of leptin in non-tumorous and denomatous human pituitaries: An immuno-ultrastructural study. J Histochem Cytochem 2000; 48:1147–1152.

    Google Scholar 

  19. Korbonits M, Kaltsas G, Edwards R, Grossman AB. Are leptin and ACTH released together from pituitary cortictrophs into the circulation? P3-238. The Endocrine Society's 83rd Annual Meeting. 2001 Denver, June 20–23.

  20. Hanew K. Te heffects of human leptin on pituitary functions in man. P1-609. The Endocrine Society's 83rd Annual Meeting. 2001 Denvr, June 20–23.

  21. Zakrzewska KE, Cusin I, Sainsbury A, Rohner-Jeanrenaud F, Jeanrenaud B. Glucocorticoids as counterregulatory hormones of leptin: Toward an understanding of leptin resistance. Diabetes 1997;46:717–719.

    Google Scholar 

  22. Sinha MK, Opentanova I, Ohannesian JP, Kolaczynski JW, Heiman ML, Hale j, Becker GW, Bowsher RR, Stephens TW, Caro JF. Evidence of free and bound leptin in human circulation. Studies in lean and obese subjects and during short-term fasting. J Clin Invest 1996;15:1277–1282.

    Google Scholar 

  23. Mercer JG, Hoggard N, Williams LM, Lawrence CB, Hannah LT, Trayhurn P. Localization of leptin receptor mRNA and the long form splice variant (Ob-Rb) in mouse hypothalamus and adjacent brain regions by in situ hybridization. FEBS Lett 1996;387:113–116.

    Google Scholar 

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

    Google Scholar 

  25. Glasow A, Haidan A, Hiblers 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 

  26. Licinio J, Mantzoros C, Negrao AB, Cizza G, Wong ML, Bongiorno PB, Chrousos GP, Karp B, Allen C, Flier JS, Gold PW. Human leptin levels are pulsatile and inversely related to pituitary-adrenal function. Nat Med 1997;3:575–579.

    Google Scholar 

  27. Nishiyama M, Makino S, Suemaru S, Nanamiya W, Asaba K, Kaneda T, Mimoto T, Nishioka T, Takao T, Hashimoto K. Glucocorticoid effects on the diurnal rhythm of circulating leptin levels. Horm Res 2000;54:69–73.

    Google Scholar 

  28. Lewandowski K, Randeva HS, O'Callaghan CJ, Horn R, Medley GF, Hillhouse EW, Brabant G, O'Hare P. Effects of insulin and glucocorticoids on the leptin system are mediated through free leptin. Clin Endocrinol 2001;54:533–539.

    Google Scholar 

  29. Gong DW, Bi S, Pratley RE, Weintraub BD. Genomic structure and promoter analysis of the human obese gene. J Biol Chem 1996;27:3971–3974.

    Google Scholar 

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

    Google Scholar 

  31. Clinical review 127: Obesity as a neuroendocrine disease: lessons to be learned from proopiomelanocortin and melanocortin receptor mutations in mice and men. J Clin Endocrinol Metab200;86:1442–1446.

  32. Gaillard RC, Spinedi E, Chautard T, Pralong FP. Cytokines, leptin, and the hypothalamo-pituitary-adrenal axis. Ann NY Acad Sci 2000;917:647–657.

    Google Scholar 

  33. Bornstein SR, 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 

  34. De Vos P, Saladin R, Auwerx J, Staels B. Induction of ob gene expression by corticosteroids is accompanied by body weight loss and reduced food intake. J Biol Chem 1995; 270:15958–15961.

    Google Scholar 

  35. Slieker LJ, Sloop KW, Surface PL, Kriauciunas A, LaQuier F, Manetta J, BueValleskey J, Stephens TW. Regulation of expression of ob mRNA and protein by glucocorticoids and cAMP. J Biol Chem 1996;271:5301–5304.

    Google Scholar 

  36. Dagogo-Jack S, Selke G, Melson AK, Newcomer JW. Robust leptin secretory responses to dexamethasone in obese subjects. J Clin Endocrinol Metab 1997;82:3230–3233.

    Google Scholar 

  37. Miell JP, Englaro P, Blum WF. Dexamethasone induces an acute and sustained rise in circulating leptin levels in normal human subjects. Horm Metab Res 1996; 28:704–707.

    Google Scholar 

  38. Papaspyrou-Rao S, Schneider SH, Petersen RN, Fried SK. Dexamethasone increases leptin expression in humans in vivo. J Clin Endocrinol Metab 1997;82:1635–1637.

    Google Scholar 

  39. Newcomer JW, Selke G, Melson AK, Gross J, Vogler GP, Dagogo-Jack S. Dose-dependent cortisol-induced increases in plasma leptin concentration in healthy humans. Arch Gen Psychiatry 1998;55:995–1000.

    Google Scholar 

  40. Nye EJ, Bornstein SR, Grice JE, Tauchnitz R, Hockings GI, Strakosch CR, Jackson RV, Torpy DJ. Interactions between the stimulated hypothalamic-pituitary-adrenal axis and leptin in humans. J Neuroendocrinol 2000;12:141–145.

    Google Scholar 

  41. Newcomer JW, Selke G, Melson AK, Gross J, Vogler GP, Dagogo-Jack S. Dose-dependent cortisol-induced increases in plasma leptin concentration in healthy humans. Arch Gen Psychiatry 1998;55:995–1000.

    Google Scholar 

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

    Google Scholar 

  43. Giovambattista A, Chisari AN, Gaillard RC, Spinedi E. Food intake-induced leptin secretion modulates hypothalamo-pituitary-adrenal axis response and hypothalamic Ob-Rb expression to insulin administration. Neuroendocrinology 2000;72:341–349.

    Google Scholar 

  44. Lin RC, Wang WY, Morris BJ. High penetrance, overweight, and glucocorticoid receptor variant: Case-control study. BMJ 1999;319:1337–1338.

    Google Scholar 

  45. Rosmond R, Chagnon YC, Holm G, Chagnon M, Perusse L, Lindell K, Carlsson B, Bouchard C, Bjorntorp P.A glucocorticoid receptor gene marker is associated with abdominal obesity, leptin, and dysregulation of the hypothalamic-pituitary-adrenal axis. Obes Res 2000;8:211–218.

    Google Scholar 

  46. Rosmond R, Bouchard C, Bjorntorp P. Tsp509I polymorphism in exon 2 of the glucocorticoid receptor gene in relation to obesity and cortisol secretion: Cohort study. BMJ 2001;322:652–653.

    Google Scholar 

  47. Henrichs SC, Menzaghi F, Merlo-Pich E, Hanger RL, Koob GF. Corticotropin-releasing factor in the paraventricular nucleus modulates feeding induced by neuropeptide Y. Brain Res 1993;611:18–24.

    Google Scholar 

  48. Tataranni PA, Larson DE, Snitker S, Young JB, Flatt JP, Ravussin E. Effects of glucocorticoids on energy metabolism and food intake in humans.AmJ Physiol 1996;34:E317–325.

    Google Scholar 

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

    Google Scholar 

  50. Camp~eld LA, Smith FJ. The pathogenesis of obesity. Baillieres Best Pract Res Clin Endocrinol Metab. 1999;13:103–30.

    Google Scholar 

  51. Leal-Cerro A, Considine RV, Peino R, 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 

  52. Weise M, Abad V, Considine RV, Nieman L, Rother KI. Leptin secretion in Cushing's syndrome: Preservation of diurnal rhythm and absent response to corticotropin-releasing hormone. J Clin Endocrinol Metab 1999;84:2075–2079.

    Google Scholar 

  53. Pralong FP, Gomez F, Guillou L, Mosimann F, Franscella S, Gaillard RC.Food-dependent Cushing's syndrome: Possible involvement of leptin in cortisol hypersecretion. J Clin Endocrinol Metab 1999;84:3817–3822.

    Google Scholar 

  54. Veldman RG, Frolich M, Pincus SM, Veldhuis JD, Roelfsema F. Hyperleptinemia in women with Cushing's disease is driven by high-amplitude pulsatile, but orderly and eurhythmic, leptin secretion. Eur J Endocrinol 2001;144: 21–27.

    Google Scholar 

  55. Cizza G, Lotsikas AJ, Licinio J, Gold PW, Chrousos GP. Plasma leptin levels do not change in patients with Cushing's disease shortly after correction of hypercortisolism. J Clin Endocrinol Metab 1997;82:2747–2750.

    Google Scholar 

  56. Brabant G, Horn R, von zur Muhlen A, Mayr B, Wurster U, Heidenreich F, Schnabel D, Gruters-Kieslich A, Zimmermann-Belsing T, Feldt-Rasmussen U. Free and protein bound leptin are distinct and independently controlled factors in energy regulation. Diabetologia 2000;43:438–442.

    Google Scholar 

  57. Jeanrenaud B, Rohner-Jeanrenaud F. CNS-periphery relationships and body weight homeostasis: In_uence of the glucocorticoid status. Int J Obes Relat Metab Disord 2000;24Suppl 2:S74–76.

    Google Scholar 

  58. Bjorntorp P, Rosmond R. Obesity and cortisol. Nutrition 2000;16:924–936.

    Google Scholar 

  59. Cavagnini F, Croci M, Putignano P, Petroni ML, Invitti C. Glucocorticoids and neuroendocrine function. Int J Obes Relat Metab Disord 2000;24Suppl 2:S77–79.

    Google Scholar 

  60. Bjorntorp P, Rosmond R. The metabolic syndrome—a neuroendocrine disorder? Br J Nutr 2000 Mar;83Suppl1:S49–57.

    Google Scholar 

  61. Hrnciar J, Okapcova J, Lepej J, Gabor D. Relation between levels of leptin, insulin and cortisol in persons with the 5H (X) syndrome. Vnitr Lek 1999;45:703–707.

    Google Scholar 

  62. Bjorntorp P, Rosmond R. Obesity and cortisol. Nutrition 2000;16:924–936.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Endocrinology, H.U. Virgen del Rocío, Sevilla, Spain

    Alfonso Leal-Cerro, Alfonso Soto, Maria A Martínez, C. Dieguez & Felipe F. Casanueva

  2. Department of Medicine, Endocrine Area Complejo Hospitalario Universitario de Santiago, Spain

    Alfonso Leal-Cerro, Alfonso Soto, Maria A Martínez, C. Dieguez & Felipe F. Casanueva

  3. Department of Physiology, University of Santiago, Santiago de Compostela, Spain

    Alfonso Leal-Cerro, Alfonso Soto, Maria A Martínez, C. Dieguez & Felipe F. Casanueva

Authors
  1. Alfonso Leal-Cerro
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alfonso Soto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maria A Martínez
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C. Dieguez
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Felipe F. Casanueva
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Leal-Cerro, A., Soto, A., Martínez, M.A. et al. Influence of Cortisol Status on Leptin Secretion. Pituitary 4, 111–116 (2001). https://doi.org/10.1023/A:1012903330944

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1012903330944

  • leptin
  • obesity
  • glucocorticoid
  • Cushing's syndrome