In rats, neonatal treatment with monosodium L-glutamate (MSG) induces several metabolic and neuroendocrine abnormalities, which result in hyperadiposity. No data exist, however, regarding neuroendocrine, immune and metabolic responses to acute endotoxemia in the MSG-damaged rat. We studied the consequences of MSG treatment during the acute phase response of inflammatory stress. Neonatal male rats were treated with MSG or vehicle (controls, CTR) and studied at age 90 days. Pituitary, adrenal, adipo-insular axis, immune, metabolic and gonadal functions were explored before and up to 5 h after single sub-lethal i.p. injection of bacterial lipopolysaccharide (LPS; 150 µg/kg). Our results showed that, during the acute phase response of inflammatory stress in MSG rats: (1) the corticotrope-adrenal, leptin, insulin and triglyceride responses were higher than in CTR rats, (2) pro-inflammatory (TNFα) cytokine response was impaired and anti-inflammatory (IL-10) cytokine response was normal, and (3) changes in peripheral estradiol and testosterone levels after LPS varied as in CTR rats. These data indicate that metabolic and neroendocrine-immune functions are altered in MSG-damaged rats. Our study also suggests that the enhanced corticotrope-corticoadrenal activity in MSG animals could be responsible, at least in part, for the immune and metabolic derangements characterizing hypothalamic obesity.

Keywords:
ACTH, Glucocorticoid, Cytokines, Leptin, Insulin
1.
Olney JW, Sharpe LG: Brain lesions in an infant rhesus monkey treated with monsodium 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: Neuroreceptors: 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.
Perello M, Gaillard RC, Chisari A, Spinedi E: Adrenal enucleation in MSG-damaged hyperleptinemic male rats transiently restores adrenal sensitivity to leptin. Neuroendocrinology 2003;78:176–184.
14.
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 (MSG): evidence for the involvement of tuberoinfundibular cholinergic and dopaminergic systems in neuroendocrine regulation. Endocrinology 1977;101:613–622.
15.
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.
16.
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.
17.
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.
18.
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.
19.
Dinarello CA: Interleukin-1 and the pathogenesis of the acute phase-response. N Engl J Med 1984;31:1413–1418.
20.
Kreuger JM, Waler J, Dinarello CA, Wolff SM, Chedid L: Sleep-promoting effects of endogenous pyrogen (interleukin-1). Am J Physiol 1984;246:R994–R999.
21.
Spinedi E, Hadid R, Daneva T, Gaillard RC: Cytokines stimulate the CRH but not the vasopressin neuronal system: evidence for a median eminence site of interleukin-6 action. Neuroendocrinology 1992;56:46–53.
22.
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.
23.
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.
24.
Moreno G, Perello M, Camihort G, Luna G, Console G, Gaillard RC, Spinedi E: Impact of transient correction of increased adrenocortical activity in hypothalamo-damaged, hyperadipose female rat. Int J Obesity 2006;30:73–82.
25.
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.
26.
Perello M, Moreno G, Camihort G, Luna G, Console G, Gaillard RC, Spinedi E: Nature of changes in adrenocortical function in chronic hyperleptinemic female rats. Endocrine 2004;24:167–175.
27.
Giovambattista A, Chisari AN, Corro L, Gaillard RC, Spinedi E: Metabolic, neuroendocrine and immune functions in basal conditions and during the acute-phase response to endotoxic shock in undernourished rats. Neuroimmunomodulation 2000;7:92–98.
28.
Chautard T, Spinedi E, Voirol M, Pralong FP, Gaillard RC: Role of glucocorticoids in the response of the hypothalamo-corticotrope, immune and adipose systems to repeated endotoxin administration. Neuroendocrinology 1999;69:360–369.
29.
Chisari A, Spinedi E, Voirol M-J, 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.
30.
Spinedi E, Giacomini M, Jacquier MC, Gaillard RC: Changes in the hypothalamo-corticotrope axis after bilateral adrenalectomy: evidence for a median eminence site of glucocorticoid action. Neuroendocrinology 1991;53:160–170.
31.
Perello M, Moreno G, Gaillard RC, Spinedi E: Glucocorticoid-dependency of increased adiposity in a model of hypothalamic obesity. Neuro Endocrinol Lett 2004;25:119–126.
32.
Castrogiovanni D, Perello M, Gaillard RC, Spinedi E: Modulatory role of testosterone in plasma leptin turnover in rats. Endocrine 2003;22:203–210.
33.
Zar JH: Biostatistical Analysis. Englewood Cliffs. Prentice-Hall, 1974.
34.
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.
35.
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.
36.
Karalis K, Mastorakos G, Sano H, Wilder RL, Chrousos GP: Somatostatin may participate in the antiinflammatory actions of glucocorticoids. Endocrinology 1995;136:4133–4138.
37.
Sewter C, Berger D, Considine RV, Medina G, Rochford J, Ciaraldi T, Henry R, Dohm L, Flier JS, O’Rahilly S, Vidal-Puig AJ: Human obesity and type 2 diabetes are associated with alterations in SREBP1 isoform expression that are reproduced ex vivo by tumor necrosis factor-alpha. Diabetes 2002;51:1035–1041.
38.
Yamakawa T, Tanaka S, Yamakawa Y, Kiuchi Y, Isoda F, Kawamoto S, Okuda K, Sekihara H: Augmented production of tumor necrosis factor-alpha in obese mice. Clin Immunol Immunopathol 1995;75:51–56.
39.
Yelich MR, Havdala HS, Filkins JP: Dexamethasone alters glucose, lactate, and insulin dyshomeostasis during endotoxicosis in the rat. Circ Shock 1987;22:155–171.
40.
Balbo SL, Grassiolli S, Ribeiro RA, Bonfleur ML, Gravena C, Brito Mdo N, Andreazzi AE, Mathias PC, Torrezan R: Fat storage is partially dependent on vagal activity and insulin secretion of hypothalamic obese rat. Endocrine 2007;31:142–148.
41.
Balbo SL, Bonfleur ML, Carneiro EM, Amaral ME, Filiputti E, Mathias PC: Parasympathetic activity changes insulin response to glucose and neurotransmitters. Diabetes Metab 2002;28:3S13–3S17.
42.
Marissal-Arvy N, Gaumont A, Langlois A, Dabertrand F, Bouchecareilh M, Tridon C, Mormede P: Strain differences in hypothalamic pituitary adrenocortical axis function and adipogenic effects of corticosterone in rats. J Endocrinol 2007;195:473–484.
43.
Macho L, Ficková M, Jezová , Zórad S: Late effects of postnatal administration of monosodium glutamate on insulin action in adult rats. Physiol Res 2000;49:S79–S85.
44.
Cornell RP: Hyperinsulinemia elicited by interleukin-1 and nonlethal endotoxemia in rats. Circ Shock 1989;28:121–130.
45.
Exton JH: Regulation of gluconeogenesis by glucocorticoids. Monogr Endocrinol 1979;12:535–546.
46.
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 (MSG) treated-rats. Int J Obes Relat Metab Disord 2001;25:426–433.
47.
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.
48.
Wilsdorf A, Remke H, Müller F: Glucose utilization in adipose tissue of rats in chronic somatotropin deficiency (in German). Biomed Biochim Acta 1989;48:51–56.
49.
Harris HW, Kasravi FB: Lipoprotein-bound LPS induces cytokine tolerance in hepatocytes. J Endotoxin Res 2003;9:45–50.
50.
Harris HW, Gosnell JE, Kumwenda ZL: The lipemia of sepsis: triglyceride-rich lipoproteins as agents of innate immunity. J Endotoxin Res 2000;6:421–430.
51.
Christeff N, Benassayag C, Carli-Vielle C, Carli A, Nunez EA: Elevated oestrogen and reduced testosterone levels in the serum of male septic shock patients. J Steroid Biochem 1988;29:435–440.
52.
Christeff N, Auclair MC, Dehennin L, Thobie N, Benassayag C, Carli A, Nunez EA: Effect of the aromatase inhibitor, 4 hydroxyandrostenedione, on the endotoxin-induced changes in steroid hormones in male rats. Life Sci 1992;50:1459–1468.
53.
Daneva T, Spinedi E, Hadid R, Jacquier MC, Giacomini M, Gaillard RC: Transient sex-related changes in the mice hypothalamo-pituitary-adrenal axis during the acute phase of the inflammatory process. Mediators Inflamm 1993;2:123–127.
54.
Grossman CJ: Regulation of the immune system by sex steroids. Endocr Rev 1984;5:435–455.
55.
Bergen HT, Mizuno TM, Taylor J, Mobbs CV: Hyperphagia and weight gain after gold-thioglucose: relation to hypothalamic neuropeptide Y and proopiomelanocortin. Endocrinology 1998;139:4483–4488.
56.
Maiter D, Underwood LE, Martin JB, Koenig JI: Neonatal treatment with monosodium glutamate: effects of prolonged growth hormone (GH)-releasing hormone deficiency on pulsatile GH secretion and growth in female rats. Endocrinology 1991;128:1100–1106.
57.
Nemeroff CB, Lipton MA, Kizer JS: Models of neuroendocrine regulation: use of monosodium glutamate as an investigational tool. Dev Neurosci 1978;1:102–109.
58.
Felies M, von Hörsten S, Pabst R, Nave H: Neuropeptide Y stabilizes body temperature and prevents hypotension in endotoxaemic rats. J Physiol 2004;561:245–252.
59.
Hauser GJ, Myers AK, Dayao EK, Zukowska-Grojec Z: Neuropeptide Y infusion improves hemodynamics and survival in rat endotoxic shock. Am J Physiol 1993;265:H1416–H1423.
60.
Moreno G, Perelló M, Gaillard RC, Spinedi E: Orexin a stimulates hypothalamic-pituitary-adrenal (HPA) axis function, but not food intake, in the absence of full hypothalamic NPY-ergic activity. Endocrine 2005;26:99–106.
© 2008 S. Karger AG, Basel
2008
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.