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Immunoglobulin G modulation of the melanocortin 4 receptor signaling in obesity and eating disorders
Melanocortin 4 receptor (MC4R) plays a key role in regulation of appetite activated by its main ligand α-melanocyte-stimulating hormone (α-MSH) in both central and peripheral targets. α-MSH also binds to circulating immunoglobulins (Igs) but the functional significance of such immune complexes (ICs)...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372612/ https://www.ncbi.nlm.nih.gov/pubmed/30755592 http://dx.doi.org/10.1038/s41398-019-0422-9 |
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author | Lucas, Nicolas Legrand, Romain Bôle-Feysot, Christine Breton, Jonathan Coëffier, Moïse Akkermann, Kirsti Järv, Anu Harro, Jaanus Déchelotte, Pierre Fetissov, Sergueï O. |
author_facet | Lucas, Nicolas Legrand, Romain Bôle-Feysot, Christine Breton, Jonathan Coëffier, Moïse Akkermann, Kirsti Järv, Anu Harro, Jaanus Déchelotte, Pierre Fetissov, Sergueï O. |
author_sort | Lucas, Nicolas |
collection | PubMed |
description | Melanocortin 4 receptor (MC4R) plays a key role in regulation of appetite activated by its main ligand α-melanocyte-stimulating hormone (α-MSH) in both central and peripheral targets. α-MSH also binds to circulating immunoglobulins (Igs) but the functional significance of such immune complexes (ICs) in MC4R signaling in normal and pathological conditions of altered appetite has remained unknown. To address this question, we analyzed plasma levels, affinity kinetics, and binding epitopes of α-MSH-reactive IgG extracted from plasma samples of female patients with hyperphagic obesity, anorexia nervosa, bulimia nervosa, binge-eating disorder, and healthy controls. Ability of α-MSH/IgG IC to bind and activate human MC4R were studied in vitro and to influence feeding behavior in vivo in rodents. We found that α-MSH-reactive IgG were low in obese but increased in anorectic and bulimic patients and displayed different epitope and kinetics of IC formation. Importantly, while α-MSH/IgG IC from all subjects were binding and activating MC4R, the receptor binding affinity was decreased in obesity. Additionally, α-MSH/IgG IC had lower MC4R-mediated cAMP activation threshold as compared with α-MSH alone in all but not obese subjects. Furthermore, the cellular internalization rate of α-MSH/IgG IC by MC4R-expressing cells was decreased in obese but increased in patients with anorexia nervosa. Moreover, IgG from obese patients prevented central anorexigenic effect of α-MSH. These findings reveal that MC4R is physiologically activated by IC formed by α-MSH/IgG and that different levels and molecular properties of α-MSH-reactive IgG underlie biological activity of such IC relevant to altered appetite in obesity and eating disorders. |
format | Online Article Text |
id | pubmed-6372612 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-63726122019-02-15 Immunoglobulin G modulation of the melanocortin 4 receptor signaling in obesity and eating disorders Lucas, Nicolas Legrand, Romain Bôle-Feysot, Christine Breton, Jonathan Coëffier, Moïse Akkermann, Kirsti Järv, Anu Harro, Jaanus Déchelotte, Pierre Fetissov, Sergueï O. Transl Psychiatry Article Melanocortin 4 receptor (MC4R) plays a key role in regulation of appetite activated by its main ligand α-melanocyte-stimulating hormone (α-MSH) in both central and peripheral targets. α-MSH also binds to circulating immunoglobulins (Igs) but the functional significance of such immune complexes (ICs) in MC4R signaling in normal and pathological conditions of altered appetite has remained unknown. To address this question, we analyzed plasma levels, affinity kinetics, and binding epitopes of α-MSH-reactive IgG extracted from plasma samples of female patients with hyperphagic obesity, anorexia nervosa, bulimia nervosa, binge-eating disorder, and healthy controls. Ability of α-MSH/IgG IC to bind and activate human MC4R were studied in vitro and to influence feeding behavior in vivo in rodents. We found that α-MSH-reactive IgG were low in obese but increased in anorectic and bulimic patients and displayed different epitope and kinetics of IC formation. Importantly, while α-MSH/IgG IC from all subjects were binding and activating MC4R, the receptor binding affinity was decreased in obesity. Additionally, α-MSH/IgG IC had lower MC4R-mediated cAMP activation threshold as compared with α-MSH alone in all but not obese subjects. Furthermore, the cellular internalization rate of α-MSH/IgG IC by MC4R-expressing cells was decreased in obese but increased in patients with anorexia nervosa. Moreover, IgG from obese patients prevented central anorexigenic effect of α-MSH. These findings reveal that MC4R is physiologically activated by IC formed by α-MSH/IgG and that different levels and molecular properties of α-MSH-reactive IgG underlie biological activity of such IC relevant to altered appetite in obesity and eating disorders. Nature Publishing Group UK 2019-02-12 /pmc/articles/PMC6372612/ /pubmed/30755592 http://dx.doi.org/10.1038/s41398-019-0422-9 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Lucas, Nicolas Legrand, Romain Bôle-Feysot, Christine Breton, Jonathan Coëffier, Moïse Akkermann, Kirsti Järv, Anu Harro, Jaanus Déchelotte, Pierre Fetissov, Sergueï O. Immunoglobulin G modulation of the melanocortin 4 receptor signaling in obesity and eating disorders |
title | Immunoglobulin G modulation of the melanocortin 4 receptor signaling in obesity and eating disorders |
title_full | Immunoglobulin G modulation of the melanocortin 4 receptor signaling in obesity and eating disorders |
title_fullStr | Immunoglobulin G modulation of the melanocortin 4 receptor signaling in obesity and eating disorders |
title_full_unstemmed | Immunoglobulin G modulation of the melanocortin 4 receptor signaling in obesity and eating disorders |
title_short | Immunoglobulin G modulation of the melanocortin 4 receptor signaling in obesity and eating disorders |
title_sort | immunoglobulin g modulation of the melanocortin 4 receptor signaling in obesity and eating disorders |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372612/ https://www.ncbi.nlm.nih.gov/pubmed/30755592 http://dx.doi.org/10.1038/s41398-019-0422-9 |
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