It is known that the neonatal treatment of rats with monosodium L-glutamate (MSG) induces several metabolic abnormalities, resulting in enhanced adiposity and hyperleptinemia. Our study was designed to explore the consequences of MSG-induced chronic hyperleptinemia on adrenal sensitivity to the inhibitory effect of exogenous leptin. Neonatal male rats treated with MSG or vehicle (controls, CTR) were followed during 150 days in order to study changes observed over development in body weight, food consumption as well as in vivo hypothalamo-pituitary-adrenal (HPA) axis and adipocyte functions. During adulthood, adrenal response to adrenocorticotropin (ACTH) was evaluated both in vitro and in vivo in order to determine the adrenal sensitivity to the inhibitory effect of leptin. For this purpose, sham-operated as well as CTR and MSG rats with bilateral adrenal enucleation (AE) were used. Our results indicate that: (1) between 30 and 150 days of age, MSG animals developed hypophagia, accompanied by arrest in body weight gain, and concomitant enhanced basal levels of all HPA axis components and of leptin; (2) adrenals from of 150-day- old MSG rats displayed an in vitro adrenocortical hyperresponse to ACTH stimulation as well as an adrenal refractoriness to the physiological inhibitory effect of leptin on ACTH-stimulated glucocorticoid output, and (3) bilateral AE in adult MSG-treated rats transiently reversed the MSG-induced hyperleptinemia, restoring normal leptin levels as well as a normal adrenal sensitivity to the inhibitory effect of leptin. Our data indicate that adrenal exposure to the chronically high plasma leptin levels observed in MSG rats is involved in the loss of the inhibitory regulatory effect of leptin at the adrenal level, being therefore, at least in part, responsible for the increased total and free glucocorticoid production measured in MSG adult rats. Furthermore, this study strongly suggests that the adrenal overfunction, frequently associated with different phenotypes of obesity, could be due to an adrenal resistance to the leptin-negative regulation.

Keywords:
Monosodium L-glutamate, Adrenocorticotropin, Glucocorticoid, Leptin, Adrenal enucleation, Obesity, Adipocytes, Adrenal steroids
1.
Olney JW, Sharpe LG: Brain lesions in an infant rhesus monkey treated with monosodium glutamate. Science 1969;166:386–388.
2.
Burde RM, Schainker B, Kayes J: Acute effect of oral and subcutaneous administration of monosodium glutamate on the arcuate nucleus of the hypothalamus in mice and rats. Nature 1971;233:58–60.
3.
Redding TW, Schally AV, Arimura A, Wakabayashi I: Effect of monosodium glutamate on some endocrine functions. Neuroendocrinology 1971;8:245–255.
4.
Nemeroff CB, Grant LD, Bissette G, Erin GN, Harrell LE, Prange AJ: Growth, endocrinological and behavioral deficits after monosodium L-glutamate in the neonatal rat: Possible involvement of arcuate dopamine neuron damage. Psychoneuroendocrinology 1977;2:179–196.
5.
Holzwarth-McBride MA, Sladek JR Jr, Knigge KM: Monosodium glutamate-induced lesions of the arcuate nucleus. II. Fluorescence histochemistry of catecholamines. Anat Rec 1976;186:197–205.
6.
Krieger DT, Liotta AS, Nicholsen G, Kizer JS: Brain ACTH and endorphin reduced in rats with monosodium glutamate-induced arcuate nuclear lesions. Nature 1979;278:562–563.
7.
Pelletier G: Ultrastructural localization of neuropeptide Y in the hypothalamus. Ann NY Acad Sci 1990;611:232–246.
8.
Billington CJ, Briggs JE, Harker S, Grace M, Levine AS: Neuropeptide Y in hypothalamic paraventricular nucleus: A center coordinating energy metabolism. Am J Physiol 1994;266:R1765–R1770.
9.
Malabu UH, Kilpatrick A, Ware M, Vernon RG, Williams G: Increased neuropeptide Y concentrations in specific hypothalamic regions of lactating rats: Possible relationship to hyperphagia and adaptive changes in energy balance. Peptides 1994;15:83–87.
10.
Miller RJ, Dawson G: Neuoreceptors: An overview; in Pepeu G, Kuhar MJ, Enna SJ (eds): Receptor for Neurotransmitters and Peptide Hormones. New York, Raven Press, 1979, pp 11–19.
11.
DePaolo LV, Negro-Vilar A: Neonatal monosodium glutamate treatment alters the response of median eminence luteinizing hormone-releasing hormone nerve terminals to potassium and prostaglandin E2. Endocrinology 1982;110:835–841.
12.
Spinedi E, Johnston CA, Negro-Vilar A: Increased responsiveness of the hypothalamic-pituitary axis after neurotoxin-induced hypothalamic denervation. Endocrinology 1984;115:267–272.
13.
Nemeroff CB, Konkol RJ, Bissette G, Youngblood W, Martin JB, Brazeau P, Rone MS, Prange AJ Jr, Breese GR, Kizer JS: Analysis of the disruption in hypothalamic-pituitary regulation in rats treated neonatally with monosodium L-glutamate: Evidence for the involvement of tuberoinfundibular cholinergic and dopaminergic systems in neuroendocrine regulation. Endocrinology 1977;101:613–622.
14.
Greeley GH Jr, Nicholson GF, Nemeroff CB, Youngblood WW, Kizer JS: Direct evidence that the arcuate nucleus-median eminence tuberoinfundibular system is not of primary importance in the feedback regulation of luteinizing hormone and follicle-stimulating hormone secretion in the castrated rat. Endocrinology 1978;103:170–175.
15.
Badger TM, Millard WJ, Martin JB, Rosenblum PM, Levenson SE: Hypothalamic-pituitary function in adult rats treated neonatally with monosodium glutamate. Endocrinology 1982;111:2031–2038.
16.
Bliss EL, Ailion J, Zwanziger J: Metabolism of norepinephrine, serotonin and dopamine in rat brain with stress. J Pharmacol Exp Ther 1968;164:122–134.
17.
Palkovits M, Brownstein M, Kizer JS, Saavedra JM, Kopin IJ: Effect of stress on serotonin concentration and tryptophan hydroxylase activity of brain nuclei. Neuroendocrinology 1976;22:298–304.
18.
Morris MJ, Tortelli CF, Filippis A, Proietto J: Reduced BAT function as a mechanism for obesity in the hypophagic, neuropeptide Y-deficient monosodium glutamate-treated rat. Regul Pept 1998;75–76:441–447.
19.
Dawson R, Pelleymounter MA, Millard WJ, Liu S, Eppler B: Attenuation of leptin-mediated effects by monosodium glutamate-induced arcuate nucleus damage. Am J Physiol 1997;273:E202–E206.
20.
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.
21.
Perone MJ, Chisari AN, Gomez Dumm CL, Spinedi E, Estivariz FE: Bilateral adrenal enucleation-induced changes in adenohypophyseal pro-opiomelanocortin (POMC)-related peptides synthesis and secretion: A comparative study with adrenalectomized rats. J Endocrinol Invest 1997;20:172–182.
22.
Spinedi E, Aguado L, Basilotta G, Carrizo D: Angiotensin II and glucocorticoid release: Direct effect at the adrenal level and modulation of the adrenocorticotropin-induced glucocorticoid release. J Endocrinol Invest 1989;12:321–327.
23.
Chisari A, Spinedi E, Voirol MJ, Giovambattista A, Gaillard RC: A phospholipase A2-related snake venom (from Crotalus durissus terrificus) stimulates neuroendocrine and immune functions: Determination of different sites of action. Endocrinology 1998;139:617–625.
24.
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.
25.
Magarinos AM, Estivariz F, Morado MI, De Nicola AF: Regulation of the central nervous system-pituitary-adrenal axis in rats after neonatal treatment with monosodium glutamate. Neuroendocrinology 1988;48:105–111.
26.
Spinedi E, Negro-Vilar A: Arginine vasopressin and adrenocorticotropin release: Correlation between binding characteristics and biological activity in anterior pituitary dispersed cells. Endocrinology 1984;114:2247–2251.
27.
Zar JH: Biostatistical Analysis. Englewood Cliffs, Prentice-Hall, 1974.
28.
Ulrich-Lai YM, Engeland WC: Hyperinnervation during adrenal regeneration influences the rate of functional recovery. Neuroendocrinology 2000;71:107–123.
29.
Spinedi E, Gaillard RC: A regulatory loop between the hypothalamo-pituitary-adrenal axis and circulating leptin: A physiological role of ACTH. Endocrinology 1998;139:4016–4020.
30.
Olney JW: Brain lesions, obesity and other disturbances in mice treated with monosodium glutamate. Science 1969;164:719–721.
31.
Cowley MA, Smart JL, Rubinstein M, Cerdan MG, Diano S, Horvath TL, Cone RD, Low MJ: Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 2001;411:480–484.
32.
Kalra SP, Dube MG, Pu S, Xu B, Horvath TL, Kalra PS: Interacting appetite-regulating pathways in the hypothalamic regulation of body weight. Endocr Rev 1999;20:68–100.
33.
Dolnikoff M, Martin-Hidalgo A, Machado UF, Lima FB, Herrera E: Decreased lipolysis and enhanced glycerol and glucose utilization by adipose tissue prior to development of obesity in monosodium glutamate-treated rats. Int J Obes Relat Metab Disord 2001;25:426–433.
34.
Ochi M, Sawada T, Kusunoki T, Hattori T: Morphology and cell dynamics of adipose tissue in hypothalamic obese mice. Am J Physiol 1988;254:R740–R745.
35.
Oida K, Nakai T, Hayashi T, Miyabo S, Takeda R: Plasma lipoproteins of monosodium glutamate-induced obese rats. Int J Obes 1984;8:385–391.
36.
Larsen PJ, Mikkelsen JD, Jessop D, Lightman SL, Chowdrey HS: Neonatal monosodium glutamate treatment alters both the activity and the sensitivity of the rat hypothalamo-pituitary-adrenocortical axis. J Endocrinol 1994;141:497–503.
37.
Skultetyova I, Kiss A, Jezova D: Neurotoxic lesions induced by monosodium glutamate result in increased adenopituitary proopiomelanocortin gene expression and decreased corticosterone clearance in rats. Neuroendocrinology 1998;67:412–420.
38.
Proulx K, Clavel S, Nault G, Richard D, Walker CD: High neonatal leptin exposure enhances brain GR expression and feedback efficacy on the adrenocortical axis of developing rats. Endocrinology 2001;142:4607–4616.
39.
Macho L, Jezova D, Zorad S, Fickova M: Postnatal monosodium glutamate treatment results in attenuation of corticosterone metabolic rate in adult rats. Endocr Regul 1999;33:61–67.
40.
Dolnikoff MS, Kater CE, Egami M, de Andrade IS, Marmo MR: Neonatal treatment with monosodium glutamate increases plasma corticosterone in the rat. Neuroendocrinology 1988;48:645–649.
41.
Renz M, Tomlinson E, Hultgren B, Levin N, Gu Q, Shimkets RA, Lewin DA, Stewart TA: Quantitative expression analysis of genes regulated by both obesity and leptin reveals a regulatory loop between leptin and pituitary-derived ACTH. J Biol Chem 2000;275:10429–10436.
42.
Norman D, Isidori AM, Frajese V, Caprio M, Chew SL, Grossman AB, Clark AJ, Besser GM, Fabbri A: ACTH and α-MSH inhibit leptin expression and secretion in 3T3-L1 adipocytes: Model for a central-peripheral melanocortin-leptin pathway. Mol Cell Endocrinol 2003;200:99–109.
43.
Takahashi A, Ikarashi Y, Ishimaru H, Maruyama Y: Compensation between sympathetic nerves and adrenal medullary activity: Effects of adrenodemedullation and chemical sympathectomy on catecholamine turnover. Life Sci 1993;53:1567–1572.
44.
Scriba D, Aprath-Husmann I, Blum WF, Hauner H. Catecholamines suppress leptin release from in vitro differentiated subcutaneous human adipocytes in primary culture via β1- and β2-adrenergic receptors. Eur J Endocrinol 2000;143:439–445.
45.
Gettys TW, Harkness PJ, Watson PM: The β3-adrenergic receptor inhibits insulin-stimulated leptin secretion from isolated rat adipocytes. Endocrinology 1996;137:4054–4057.
46.
Nakagawa T, Ukai K, Ohyama T, Gomita Y, Okamura H: Effects of chronic administration of sibutramine on body weight, food intake and motor activity in neonatally monosodium glutamate-treated obese female rats: Relationship of antiobesity effect with monoamines. Exp Anim 2000;49:239–249.
47.
Leigh FS, Kaufman LN, Young JB: Diminished epinephrine excretion in genetically obese (ob/ob) mice and monosodium glutamate-treated rats. Int J Obes Relat Metab Disord 1992;16:597–604.
48.
Slieker LJ, Slop KW, Surface PL, Kriauciunas A, LaQuier F, Manetta J, Bue-Valleskey J, Stephens TW: Regulation of expression of Ob mRNA and protein by glucocorticoids and camp. J Biol Chem 1996;27:5301–5304.
49.
DeVries AC, Joh HD, Bernard O, Hattori K, Hurn PD, Traystman RJ, Alkayed NJ: Social stress exacerbates stroke outcome by suppressing Bcl-2 expression. Proc Natl Acad Sci USA 2001;98:11824–11828.
50.
Sapolsky RM, Pulsinelli WA: Glucocorticoids potentiate ischemic injury to neurons: Therapeutic implications. Science 1985;229:1397–1400.
51.
Cameron HA, Gould E: Adult neurogenesis is regulated by adrenal steroids in the dentate gyrus. Neuroscience 1994;61:203–209.
52.
Holsboer F, Barden N: Antidepressants and hypothalamic-pituitary-adrenocortical regulation. Endocr Rev 1996;17:187–205.
53.
Joels M: Corticosteroid actions in the hippocampus. J Neuroendocrinol 2001;13:657–669.
© 2003 S. Karger AG, Basel
2003
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.