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Endocrine Division (M.L.H., L.S.C., T.W.S.) and Research Technologies and Proteins Division (B.S.), Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46250; and Department of Medicine, Division of Endocrinology, Beth Israel Deaconess Medical Center and Harvard Medical School (R.S.A., J.S.F.), Boston, Massachusetts 02215
Address all correspondence and requests for reprints to: Mark L. Heiman, Endocrine Division, Lilly Research Laboratories, Eli Lilly and Company, Corporate Center, Mail Drop 0540, Indianapolis, Indiana 46250. E-mail: Heiman_Mark_L{at}Lilly.com
Leptin is a newly identified protein hormone that is synthesized and secreted by adipose tissue. Absence of the mature hormone is responsible for the obese phenotype of ob/ob mice. The hypothalamic-pituitary-adrenal axis (HPAA) is activated in ob/ob mice, and chronic administration of leptin to ob/ob mice decreases plasma corticosterone levels, suggesting that the adipose hormone is capable of inhibiting the HPAA. The aim of this study was to determine whether leptin feeds back acutely to inhibit the HPAA of normal mice and rats. Male C57BL mice were injected ip with 100 µl saline and 2 or 4 µg/g BW mouse leptin in saline vehicle, and 4 h later they were subjected to 2 h of restraint stress by taping the hind limbs together or no stress. Hind leg restraint stimulated the HPAA as measured by significant (P < 0.05) elevation of both ACTH and corticosterone. Pretreatment with recombinant mouse leptin blocked the stress-mediated stimulation of both plasma hormones. To determine whether this inhibition was exerted at the hypothalamic level through inhibition of CRH, we studied leptin action on isolated rat hypothalami perifused with Krebs-Ringer buffer containing glucose (5.5 mM). CRH secretion was stimulated by decreasing the glucose concentration of the buffer to 1.1 mM. A surge of CRH was released over a 2-h period (basal integrated release was 14.4 ± 1.6 pg/2 h, n = 5 and increased to 34.7 ± 3.1 pg/2 h, n = 14). This response was blocked by mouse leptin in a dose-dependent manner (integrated stimulated CRH secretion was 30.6 ± 2.5 pg/2 h, n = 5; 20.5 ± 3.6 pg/2 h, n = 7; 15.3 ± 4.3 pg/2 h, n = 3 for 1 nM, 3 nM and 30 nM, respectively). Leptin did not alter secretion of ACTH from rat primary cultured pituitary cells. These data demonstrate that leptin can inhibit hypothalamic CRH release, either directly or indirectly through another hypothalamic neuropeptide such as neuropeptide-Y. Dysfunctional leptin, insufficient leptin levels, or leptin resistance should each result in a partial open loop, thereby accounting for elevated glucocorticoid levels that accompany and contribute to many obese phenotypes. Leptins ability to inhibit CRH release is the likely explanation for its ability to inhibit activation of the HPAA in response to stress.
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K. Proulx, S. Clavel, G. Nault, D. Richard, and C.-D. Walker High Neonatal Leptin Exposure Enhances Brain GR Expression and Feedback Efficacy on the Adrenocortical Axis of Developing Rats Endocrinology, November 1, 2001; 142(11): 4607 - 4616. [Abstract] [Full Text] [PDF] |
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D. S. Jessop, M. F. Dallman, D. Fleming, and S. L. Lightman Resistance to Glucocorticoid Feedback in Obesity J. Clin. Endocrinol. Metab., September 1, 2001; 86(9): 4109 - 4114. [Abstract] [Full Text] [PDF] |
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K. Pacak and M. Palkovits Stressor Specificity of Central Neuroendocrine Responses: Implications for Stress-Related Disorders Endocr. Rev., August 1, 2001; 22(4): 502 - 548. [Abstract] [Full Text] [PDF] |
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L. Ghizzoni, G. Mastorakos, M. E. Street, G. Mazzardo, A. Vottero, M. Vanelli, and S. Bernasconi Leptin, Cortisol, and GH Secretion Interactions in Short Normal Prepubertal Children J. Clin. Endocrinol. Metab., August 1, 2001; 86(8): 3729 - 3734. [Abstract] [Full Text] [PDF] |
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J. D. Veldhuis, S. M. Pincus, M. C. Garcia-Rudaz, M. G. Ropelato, M. E. Escobar, and M. Barontini Disruption of the Synchronous Secretion of Leptin, LH, and Ovarian Androgens in Nonobese Adolescents with the Polycystic Ovarian Syndrome J. Clin. Endocrinol. Metab., August 1, 2001; 86(8): 3772 - 3778. [Abstract] [Full Text] [PDF] |
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N. Cherradi, A. M. Capponi, R. C. Gaillard, and F. P. Pralong Decreased Expression of Steroidogenic Acute Regulatory Protein: A Novel Mechanism Participating in the Leptin-Induced Inhibition of Glucocorticoid Biosynthesis Endocrinology, August 1, 2001; 142(8): 3302 - 3308. [Abstract] [Full Text] [PDF] |
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J. Dahlgren, C. Nilsson, E. Jennische, H.-P. Ho, E. Eriksson, A. Niklasson, P. Bjorntorp, K. A. Wikland, and A. Holmang Prenatal cytokine exposure results in obesity and gender-specific programming Am J Physiol Endocrinol Metab, August 1, 2001; 281(2): E326 - E334. [Abstract] [Full Text] [PDF] |
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M. Korotkova, B. Gabrielsson, L. A. Hanson, and B. Strandvik Maternal essential fatty acid deficiency depresses serum leptin levels in suckling rat pups J. Lipid Res., March 1, 2001; 42(3): 359 - 365. [Abstract] [Full Text] |
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A. Lacroix, N. N'Diaye, J. Tremblay, and P. Hamet Ectopic and Abnormal Hormone Receptors in Adrenal Cushing's Syndrome Endocr. Rev., February 1, 2001; 22(1): 75 - 110. [Abstract] [Full Text] |
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G. Mazzocchi, L. K. Malendowicz, L. Gottardo, F. Aragona, and G. G. Nussdorfer Orexin A Stimulates Cortisol Secretion from Human Adrenocortical Cells through Activation of the Adenylate Cyclase-Dependent Signaling Cascade J. Clin. Endocrinol. Metab., February 1, 2001; 86(2): 778 - 782. [Abstract] [Full Text] |
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M. Bergendahl, A. Iranmanesh, C. Pastor, W. S. Evans, and J. D. Veldhuis Homeostatic Joint Amplification of Pulsatile and 24-Hour Rhythmic Cortisol Secretion by Fasting Stress in Midluteal Phase Women: Concurrent Disruption of Cortisol-Growth Hormone, Cortisol-Luteinizing Hormone, and Cortisol-Leptin Synchrony J. Clin. Endocrinol. Metab., November 1, 2000; 85(11): 4028 - 4035. [Abstract] [Full Text] |
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S. Nagatani, Y. Zeng, D. H. Keisler, D. L. Foster, and C. A. Jaffe Leptin Regulates Pulsatile Luteinizing Hormone and Growth Hormone Secretion in the Sheep Endocrinology, November 1, 2000; 141(11): 3965 - 3975. [Abstract] [Full Text] [PDF] |
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M. Jang, A. Mistry, A. G. Swick, and D. R. Romsos Leptin Rapidly Inhibits Hypothalamic Neuropeptide Y Secretion and Stimulates Corticotropin-Releasing Hormone Secretion in Adrenalectomized Mice J. Nutr., November 1, 2000; 130(11): 2813 - 2820. [Abstract] [Full Text] [PDF] |
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B. E. Levin, D. Richard, C. Michel, and R. Servatius Differential stress responsivity in diet-induced obese and resistant rats Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2000; 279(4): R1357 - R1364. [Abstract] [Full Text] [PDF] |
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M. S. M. Ip, K. S. L. Lam, C.-m. Ho, K. W. T. Tsang, and W.-k. Lam Serum Leptin and Vascular Risk Factors in Obstructive Sleep Apnea Chest, September 1, 2000; 118(3): 580 - 586. [Abstract] [Full Text] [PDF] |
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L. Jenni, S. Jenni-Eiermann, F. Spina, and H. Schwabl Regulation of protein breakdown and adrenocortical response to stress in birds during migratory flight Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2000; 278(5): R1182 - R1189. [Abstract] [Full Text] [PDF] |
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R. Faggioni, A. Moser, K. R. Feingold, and C. Grunfeld Reduced Leptin Levels in Starvation Increase Susceptibility to Endotoxic Shock Am. J. Pathol., May 1, 2000; 156(5): 1781 - 1787. [Abstract] [Full Text] [PDF] |
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J. Raber, S. F. Akana, S. Bhatnagar, M. F. Dallman, D. Wong, and L. Mucke Hypothalamic-Pituitary-Adrenal Dysfunction in Apoe-/- Mice: Possible Role in Behavioral and Metabolic Alterations J. Neurosci., March 1, 2000; 20(5): 2064 - 2071. [Abstract] [Full Text] [PDF] |
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M. Landt Leptin Binding and Binding Capacity in Serum Clin. Chem., March 1, 2000; 46(3): 379 - 384. [Abstract] [Full Text] [PDF] |
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M. Bergendahl, A. Iranmanesh, W. S. Evans, and J. D. Veldhuis Short-Term Fasting Selectively Suppresses Leptin Pulse Mass and 24-Hour Rhythmic Leptin Release in Healthy Midluteal Phase Women without Disturbing Leptin Pulse Frequency or Its Entropy Control (Pattern Orderliness) J. Clin. Endocrinol. Metab., January 1, 2000; 85(1): 207 - 213. [Abstract] [Full Text] |
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R. S. Ahima, J. Kelly, J. K. Elmquist, and J. S. Flier Distinct Physiologic and Neuronal Responses to Decreased Leptin and Mild Hyperleptinemia Endocrinology, November 1, 1999; 140(11): 4923 - 4931. [Abstract] [Full Text] |
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E. A. Nillni and K. A. Sevarino The Biology of pro-Thyrotropin-Releasing Hormone-Derived Peptides Endocr. Rev., October 1, 1999; 20(5): 599 - 648. [Abstract] [Full Text] |