Chronic blockade of the melanocortin 4 receptor subtype leads to obesity independently of neuropeptide Y action, with no adverse effects on the gonadotropic and somatotropic axes

Détails

ID Serval
serval:BIB_D2F6AF31039B
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Chronic blockade of the melanocortin 4 receptor subtype leads to obesity independently of neuropeptide Y action, with no adverse effects on the gonadotropic and somatotropic axes
Périodique
Endocrinology
Auteur(s)
Raposinho  P. D., Castillo  E., d'Alleves  V., Broqua  P., Pralong  F. P., Aubert  M. L.
ISSN
0013-7227 (Print)
Statut éditorial
Publié
Date de publication
12/2000
Volume
141
Numéro
12
Pages
4419-27
Notes
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Dec
Résumé
Neuropeptide Y (NPY) is a powerful orexigenic factor, and alphaMSH is a melanocortin (MC) peptide that induces satiety by activating the MC4 receptor subtype. Genetic models with disruption of MC4 receptor signaling are associated with obesity. In the present study, a 7-day intracerebroventricular infusion to male rats of either the MC receptor antagonist SHU9119 or porcine NPY (10 nmol/day) was shown to strongly stimulate food and water intake and to markedly increase fat pad mass. Very high plasma leptin levels were found in NPY-treated rats (27.1 +/- 1.8 ng/ml compared with 9.9 +/- 0.9 ng/ml in SHU9119-treated animals and 2.1 +/- 0.2 ng/ml in controls). As expected, NPY infusion induced hypogonadism, characterized by an impressive decrease in seminal vesicle and prostate weights. No such effects were seen with the SHU9119 infusion. Similarly, whereas the somatotropic axis of NPY-treated rats was fully inhibited, this axis was normally activated in the obese SHU9119-treated rats. Chronic infusion of SHU9119 strikingly reduced hypothalamic gene expression for NPY (65.2 +/- 3.6% of controls), whereas gene expression for POMC was increased (170 +/- 19%). NPY infusion decreased hypothalamic gene expression for both POMC and NPY (70 +/- 9% and 75.4 +/- 9.5%, respectively). In summary, blockade of the MC4 receptor subtype by SHU9119 was able to generate an obesity syndrome with no apparent side-effects on the reproductive and somatotropic axes. In this situation, it is unlikely that hyperphagia was driven by increased NPY release, because hypothalamic NPY gene expression was markedly reduced, suggesting that hyperphagia mainly resulted from loss of the satiety signal driven by MC peptides. NPY infusion produced hypogonadism and hyposomatotropism in the face of markedly elevated plasma leptin levels and an important reduction in hypothalamic POMC synthesis. In this situation NPY probably acted both by exacerbating food intake through Y receptors and by reducing the satiety signal driven by MC peptides.
Mots-clé
Adipose Tissue Animals Body Composition Drinking/drug effects Eating/drug effects Gene Expression/drug effects Gonadotropins/*metabolism Growth Hormone/*metabolism Hypogonadism/chemically induced Hypothalamus/metabolism Leptin/analysis Male Melanocyte-Stimulating Hormones/pharmacology Neuropeptide Y/genetics/*pharmacology Obesity/*etiology Organ Size/drug effects Pituitary Gland/anatomy & histology/chemistry Pro-Opiomelanocortin/genetics Rats Rats, Sprague-Dawley Receptor, Melanocortin, Type 4 Receptors, Corticotropin/*antagonists & inhibitors/*physiology Receptors, LHRH/analysis Satiation/drug effects Signal Transduction alpha-MSH/pharmacology
Pubmed
Web of science
Création de la notice
25/01/2008 17:26
Dernière modification de la notice
03/03/2018 21:40
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