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Human leptin levels are pulsatile and inversely related to pituitary–ardenal function

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Abstract

Leptin communicates nutritional status to regulatory centers in the brain1,2. Because peripheral leptin influences the activity of the highly pulsatile adrenal and gonadal axes3,4, we sought to determine whether leptin levels in the blood are pulsatile. We measured circulating leptin levels every 7 minutes for 24 hours, in six healthy men, and found that total circulating leptin levels exhibited a pattern indicative of pulsatile release, with 32.0 ± 1.5 pulses every 24 hours and a pulse duration of 32.8 ± 1.6 minutes. We also show an inverse relation between rapid fluctuations in plasma levels of leptin and those of adrenocorticotropic hormone (ACTH) and cortisol that could not be accounted for on the basis of glucocorticoid suppression of leptin. As leptin levels are pulsatile, we propose that a key function of the CNS is regulated by a peripheral pulsatile signal. In a separate pilot study we compared leptin pulsatility in 414 plasma samples collected every 7 minutes for 24 hours from one obese woman and one normal-weight woman. We found that high leptin levels in the obese subject were due solely to increased leptin pulse height; all concentration-independent pulsatility parameters were almost identical in the two women. Leptin pulsatility therefore can be preserved in the obese.

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References

  1. Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432 (1994).

    Article  CAS  Google Scholar 

  2. Spiegelman, B.M. & Flier, J.S. Adipogenesis and obesity: Rounding out the big picture. Cell 87, 377–389 (1996).

    Article  CAS  Google Scholar 

  3. Ahima, R.S. et al. Role of leptin in the neuroendocrine response to fasting. Nature 382, 250–252 (1996).

    Article  CAS  Google Scholar 

  4. Chehab, F.F., Lim, M.E. & Lu, R. Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin. Nature Genet. 12, 318–320 (1996).

    Article  CAS  Google Scholar 

  5. Oerter, K.E., Guardabasso, V. & Rodbard, D. Detection and characterization of peaks and estimation of instantaneous secretory rate for episodic pulsatile hormone secretion. Comput. Biomed. Res. 19, 170–191 (1986).

    Article  CAS  Google Scholar 

  6. Houseknecht, K.R. et al. Evidence for the existence of leptin binding to proteins in serum of rodents and humans: Modulation with obesity. Diabetes 45, 1638–1643 (1996).

    Article  CAS  Google Scholar 

  7. Veldhuis, J.D. & Johnson, M.L. Cluster analysis: A simple, versatile, and robust algorithm for endocrine pulse detection. Am. J. Physiol. 250, E486493 (1986).

    Article  CAS  Google Scholar 

  8. Licinio, J. et al. Twenty-four hour concentrations of circulating interleukin-2 in healthy women exhibit episodic fluctuations: Analysis of integrated basal levels and discrete pulse properties. Endocrine 1, 120–128 (1993).

    Google Scholar 

  9. Sinha, M.K. et al. Nocturnal rise of leptin in lean, obese, and non-insulin-dependent diabetes mellitus subjects. J. clin. Invest. 97, 1344–1347 (1996).

    Article  CAS  Google Scholar 

  10. Jenkins, G.M. & Watts, D.G. Spectral Analysis and Its Applications. (Holden Day, San Francisco, CA,1968).

  11. Chrousos, G.P. et al. The corticotropin-releasing factor stimulation test: An aid in the evaluation of patients with Cushing's syndrome. N. Engl. J. Med. 310, 622–626 (1984).

    Article  CAS  Google Scholar 

  12. Sutton, R.E., Koob, G.F., LeMoal, M., Rivier, J. & Vale, W. Corticotropin-releasing factor produces behavioural activation in rats. Nature 297, 331–333 (1982).

    Article  CAS  Google Scholar 

  13. Gold, P.W., Kaye, W., Robertson, G.L. & Ebert, M. Abnormalities in plasma and cerebrospinal-fluid arginine vasopressin in patients with anorexia nervosa. N. Engl. J. Med. 308, 1117–1123 (1983).

    Article  CAS  Google Scholar 

  14. Gold, P.W. et al. Responses to corticotropin-releasing hormone in the hypercortisolism of depression and Cushing's disease: Pathophysiologic and diagnostic implications. N. Engl. J. Med. 314, 1329–1335 (1986).

    Article  CAS  Google Scholar 

  15. Fehm, W.G., Bachholz, G., Born, J., Voigt, K. & Fehm, H.L. Vasopressin but not oxytocin enhances cortical arousal: An integrative hypothesis on behavioral effects of neurohypophyseal hormones. Psychopharmacology (Berl) 94, 496–500 (1988).

    Article  Google Scholar 

  16. Schwartz, M.W., Seeley, R.J., Campfield, L.A., Burn, P. & Baskin, D.G. Identification of targets of leptin action in rat hypothalamus. J. Clin. Invest. 98, 1101–1106 (1996).

    Article  CAS  Google Scholar 

  17. Schwartz, M.W., Dallman, M.F. & Woods, S.C. Hypothalamic response to starvation: Implications for the study of wasting disorders. Am. J. Physiol. 269, R949–R957 (1995).

    CAS  Google Scholar 

  18. Sinha, M.K. et al. Ultradian oscillations of leptin secretion in humans. Biochem. Biophys. Res. Commun. 228, 733–738 (1996).

    Article  CAS  Google Scholar 

  19. Homburg, R. et al. One hundred pregnancies after treatment with pulsatile luteinising hormone releasing hormone to induce ovulation. Br. Med. J. 298, 809–812 (1989).

    Article  CAS  Google Scholar 

  20. Zinaman, M.J., Cartledge, T., Tomai, T., Tippett, P. & Merriam, G.R., Pulsatile GnRH stimulates normal cyclic ovarian function in amenorrheic lactating postpartum women. J. Clin. Endocrinol. Metab. 80, 2088–2093 (1995).

    CAS  PubMed  Google Scholar 

  21. Aulitzky, W., Frick, J. & Hadziselimovic, F. Pulsatile LHRH therapy in patients with oligozoospermia and disturbed LH puisatility. Int. J. Androl. 12, 265–272 (1989).

    Article  CAS  Google Scholar 

  22. Turzillo, A.M., Juengel, J.L. & Nett, T.M. Pulsatile gonadotropin-releasing hormone (GnRH) increases concentrations of GnRH receptor messenger ribonucleic acid and numbers of GnRH receptors during luteolysis in the ewe. Biol. Reprod. 53, 418–423 (1995).

    Article  CAS  Google Scholar 

  23. Haisenleder, D.J., Ortolano, G.A., Yasin, M., Dalkin, A.C. & Marshall, J.C. Regulation of gonadotropin subunit messenger ribonucleic acid expression by gonadotropin-releasing hormone pulse amplitude in vitro. Endocrinology 132, 1292–1296 (1993).

    Article  CAS  Google Scholar 

  24. Haisenleder, D.J., Dalkin, A.C., Ortolano, G.A., Marshall, J.C. & Shupnik, M.A. A pulsatile gonadotropin-releasing hormone stimulus is required to increase transcription of the gonadotropin subunit genes: Evidence for differential regulation of transcription by pulse frequency in vivo. Endocrinology 128, 509–517 (1991).

    Article  CAS  Google Scholar 

  25. Veldhuis, J.D. The hypothalamic pulse generator: The reproductive core. Clin. Obstet. Gynecol. 33, 538–550 (1990).

    Article  CAS  Google Scholar 

  26. Maiter, D., Underwood, L.E., Maes, M., Davenport, M.L. & Ketelslegers, J.M. Different effects of intermittent and continuous growth hormone (GH) administration on serum somatomedin-C/insulin-like growth factor I and liver GH receptors in hypophysectomized rats. Endocrinology 123, 1053–1059 (1988).

    Article  CAS  Google Scholar 

  27. López-Fernández, J. et al. Growth hormone induces somatostatin and insulin-like growth factor I gene expression in the cerebral hemispheres of aging rats. Endocrinology 137, 4384–4391 (1996).

    Article  Google Scholar 

  28. Glaum, S.R. et al. Leptin, the obese gene product, rapidly modulates synaptic transmission in the hypothalamus. Mol. Pharmacol. 50, 230–235 (1996).

    CAS  PubMed  Google Scholar 

  29. Campfield, L.A., Smith, F.J., Guisez, Y., Devos, R. & Burn, P. Recombinant mouse OB protein: Evidence for a peripheral signal linking adiposity and central neural networks. Science 269, 546–549 (1995).

    Article  CAS  Google Scholar 

  30. Michelson, D. et al. Multiple sclerosis is associated with alterations in hypothalamic-pituitary-adrenal axis function. J. Clin. Endocrinol. Metab. 79, 848–853 (1994).

    CAS  PubMed  Google Scholar 

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Author notes

  1. Julio Licinio and Christos Mantzoros: These authors contributed equally to this work.

Authors and Affiliations

  1. Clinical Neuroendocrinology Branch, National Institute of Mental Health, National Institutes of Health, Building 10, Room 2D46,10 Center Drive, Bethesda, MD, 20892-1284, USA

    Julio Licinio, Anadré B. Negrão, Giovanni Cizza, Ma-Li Wong, Peter B. Bongiorno, Brian Karp & Philip W. Gold

  2. Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center,Harvard Medical School, 330 Brookline Avenue, Boston, MA, 02215, USA

    Christos Mantzoros & Jeffrey S. Flier

  3. Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Building 10, Room 10N262,10 Center Drive, Bethesda, MD, 20892-1862, USA

    Giovanni Cizza & George P. Chrousos

  4. Warren Grant Magnuson Clinical Center, National Institutes of Health, Building 10, Room 7D55,10 Center Drive, Bethesda, MD, 20892-1664, USA

    Christine Allen

Authors
  1. Julio Licinio
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  2. Christos Mantzoros
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  3. Anadré B. Negrão
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  4. Giovanni Cizza
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  5. Ma-Li Wong
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  6. Peter B. Bongiorno
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  7. George P. Chrousos
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  8. Brian Karp
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  9. Christine Allen
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  10. Jeffrey S. Flier
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  11. Philip W. Gold
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Licinio, J., Mantzoros, C., Negrão, A. et al. Human leptin levels are pulsatile and inversely related to pituitary–ardenal function. Nat Med 3, 575–579 (1997). https://doi.org/10.1038/nm0597-575

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  • DOI: https://doi.org/10.1038/nm0597-575

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