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Leptin Inhibition of the Hypothalamic-Pituitary-Adrenal Axis in Response to Stress¹

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. Leptin’s 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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				D.L. Foster and S. Nagatani Physiological Perspectives on Leptin as a Regulator of Reproduction: Role in Timing Puberty Biol Reprod, February 1, 1999; 60(2): 205 - 215. [Abstract] [Full Text] [PDF]

				A. Glasow, A. Haidan, U. Hilbers, M. Breidert, J. Gillespie, W. A. Scherbaum, G. P. Chrousos, and S. R. Bornstein Expression of Ob Receptor in Normal Human Adrenals: Differential Regulation of Adrenocortical and Adrenomedullary Function by Leptin J. Clin. Endocrinol. Metab., December 1, 1998; 83(12): 4459 - 4466. [Abstract] [Full Text]

				P. M. Smith, V. Mollaret, and A. V. Ferguson Leptin acts in the rat hypothalamic paraventricular nucleus to induce gastric mucosal damage Am J Physiol Regulatory Integrative Comp Physiol, December 1, 1998; 275(6): R2081 - R2084. [Abstract] [Full Text] [PDF]

				F. P. Pralong, R. Roduit, G. Waeber, E. Castillo, F. Mosimann, B. Thorens, and R. C. Gaillard Leptin Inhibits Directly Glucocorticoid Secretion by Normal Human and Rat Adrenal Gland Endocrinology, October 1, 1998; 139(10): 4264 - 4268. [Abstract] [Full Text] [PDF]

				M. A. Pelleymounter, M. J. Cullen, D. Healy, R. Hecht, D. Winters, and M. McCaleb Efficacy of exogenous recombinant murine leptin in lean and obese 10- to 12-mo-old female CD-1 mice Am J Physiol Regulatory Integrative Comp Physiol, October 1, 1998; 275(4): R950 - R959. [Abstract] [Full Text] [PDF]

				G. Trottier, K. G. Koski, T. Brun, D. J. Toufexis, D. Richard, and C.-D. Walker Increased Fat Intake during Lactation Modifies Hypothalamic-Pituitary-Adrenal Responsiveness in Developing Rat Pups: A Possible Role for Leptin Endocrinology, September 1, 1998; 139(9): 3704 - 3711. [Abstract] [Full Text] [PDF]

				K. Arvaniti, Y. Deshaies, and D. Richard Effect of leptin on energy balance does not require the presence of intact adrenals Am J Physiol Regulatory Integrative Comp Physiol, July 1, 1998; 275(1): R105 - R111. [Abstract] [Full Text] [PDF]

				G. S. Wand and H. Schumann Relationship between Plasma Adrenocorticotropin, Hypothalamic Opioid Tone, and Plasma Leptin J. Clin. Endocrinol. Metab., June 1, 1998; 83(6): 2138 - 2142. [Abstract] [Full Text]

				J. S. Flier What's in a Name? In Search of Leptin's Physiologic Role J. Clin. Endocrinol. Metab., May 1, 1998; 83(5): 1407 - 1413. [Full Text]

				D. Torpy, S. Bornstein, G Cizza, and G. Chrousos The Effects of Glucocorticoids on Leptin Levels in Humans May Be Restricted to Acute Pharmacologic Dosinga J. Clin. Endocrinol. Metab., May 1, 1998; 83(5): 1821 - 1822. [Full Text]

				S. R. Bornstein, E. L. Webster, D. J. Torpy, S. J. Richman, N. Mitsiades, M. Igel, D. B. Lewis, K. C. Rice, H. G. Joost, M. Tsokos, et al. Chronic Effects of a Nonpeptide Corticotropin-Releasing Hormone Type I Receptor Antagonist on Pituitary-Adrenal Function, Body Weight, and Metabolic Regulation Endocrinology, April 1, 1998; 139(4): 1546 - 1555. [Abstract] [Full Text] [PDF]

				G. P. Chrousos Editorial: Ultradian, Circadian, and Stress-Related Hypothalamic-Pituitary-Adrenal Axis Activity--A Dynamic Digital-to-Analog Modulation Endocrinology, February 1, 1998; 139(2): 437 - 440. [Full Text] [PDF]

				J. K. Elmquist, R. S. Ahima, C. F. Elias, J. S. Flier, and C. B. Saper Leptin activates distinct projections from the dorsomedial and ventromedial hypothalamic nuclei PNAS, January 20, 1998; 95(2): 741 - 746. [Abstract] [Full Text] [PDF]