Cargando…
Pharmacological targeting of glutamatergic neurons within the brainstem for weight reduction
Food intake and body weight are tightly regulated by neurons within specific brain regions, including the brainstem, where acute activation of dorsal raphe nucleus (DRN) glutamatergic neurons expressing the glutamate transporter Vglut3 (DRN(Vglut3)) drive a robust suppression of food intake and enha...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9684079/ https://www.ncbi.nlm.nih.gov/pubmed/36411386 http://dx.doi.org/10.1038/s42255-022-00677-8 |
_version_ | 1784835197502488576 |
---|---|
author | Schneeberger, Marc Brice, Nicola L. Pellegrino, Kyle Parolari, Luca Shaked, Jordan T. Page, Keith J. Marchildon, François Barrows, Douglas W. Carroll, Thomas S. Topilko, Thomas Mulligan, Victoria M. Newman, Robert Doyle, Kevin Bürli, Roland Barker, Daniel F. Glen, Angela Ortuño, María José Nectow, Alexander R. Renier, Nicolas Cohen, Paul Carlton, Mark Heintz, Nathaniel Friedman, Jeffrey M. |
author_facet | Schneeberger, Marc Brice, Nicola L. Pellegrino, Kyle Parolari, Luca Shaked, Jordan T. Page, Keith J. Marchildon, François Barrows, Douglas W. Carroll, Thomas S. Topilko, Thomas Mulligan, Victoria M. Newman, Robert Doyle, Kevin Bürli, Roland Barker, Daniel F. Glen, Angela Ortuño, María José Nectow, Alexander R. Renier, Nicolas Cohen, Paul Carlton, Mark Heintz, Nathaniel Friedman, Jeffrey M. |
author_sort | Schneeberger, Marc |
collection | PubMed |
description | Food intake and body weight are tightly regulated by neurons within specific brain regions, including the brainstem, where acute activation of dorsal raphe nucleus (DRN) glutamatergic neurons expressing the glutamate transporter Vglut3 (DRN(Vglut3)) drive a robust suppression of food intake and enhance locomotion. Activating Vglut3 neurons in DRN suppresses food intake and increases locomotion, suggesting that modulating the activity of these neurons might alter body weight. Here, we show that DRN(Vglut3) neurons project to the lateral hypothalamus (LHA), a canonical feeding center that also reduces food intake. Moreover, chronic DRN(Vglut3) activation reduces weight in both leptin-deficient (ob/ob) and leptin-resistant diet-induced obese (DIO) male mice. Molecular profiling revealed that the orexin 1 receptor (Hcrtr1) is highly enriched in DRN Vglut3 neurons, with limited expression elsewhere in the brain. Finally, an orally bioavailable, highly selective Hcrtr1 antagonist (CVN45502) significantly reduces feeding and body weight in DIO. Hcrtr1 is also co-expressed with Vglut3 in the human DRN, suggesting that there might be a similar effect in human. These results identify a potential therapy for obesity by targeting DRN(Vglut3) neurons while also establishing a general strategy for developing drugs for central nervous system disorders. |
format | Online Article Text |
id | pubmed-9684079 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-96840792022-11-25 Pharmacological targeting of glutamatergic neurons within the brainstem for weight reduction Schneeberger, Marc Brice, Nicola L. Pellegrino, Kyle Parolari, Luca Shaked, Jordan T. Page, Keith J. Marchildon, François Barrows, Douglas W. Carroll, Thomas S. Topilko, Thomas Mulligan, Victoria M. Newman, Robert Doyle, Kevin Bürli, Roland Barker, Daniel F. Glen, Angela Ortuño, María José Nectow, Alexander R. Renier, Nicolas Cohen, Paul Carlton, Mark Heintz, Nathaniel Friedman, Jeffrey M. Nat Metab Article Food intake and body weight are tightly regulated by neurons within specific brain regions, including the brainstem, where acute activation of dorsal raphe nucleus (DRN) glutamatergic neurons expressing the glutamate transporter Vglut3 (DRN(Vglut3)) drive a robust suppression of food intake and enhance locomotion. Activating Vglut3 neurons in DRN suppresses food intake and increases locomotion, suggesting that modulating the activity of these neurons might alter body weight. Here, we show that DRN(Vglut3) neurons project to the lateral hypothalamus (LHA), a canonical feeding center that also reduces food intake. Moreover, chronic DRN(Vglut3) activation reduces weight in both leptin-deficient (ob/ob) and leptin-resistant diet-induced obese (DIO) male mice. Molecular profiling revealed that the orexin 1 receptor (Hcrtr1) is highly enriched in DRN Vglut3 neurons, with limited expression elsewhere in the brain. Finally, an orally bioavailable, highly selective Hcrtr1 antagonist (CVN45502) significantly reduces feeding and body weight in DIO. Hcrtr1 is also co-expressed with Vglut3 in the human DRN, suggesting that there might be a similar effect in human. These results identify a potential therapy for obesity by targeting DRN(Vglut3) neurons while also establishing a general strategy for developing drugs for central nervous system disorders. Nature Publishing Group UK 2022-11-21 2022 /pmc/articles/PMC9684079/ /pubmed/36411386 http://dx.doi.org/10.1038/s42255-022-00677-8 Text en © The Author(s) 2022, corrected publication 2022 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Schneeberger, Marc Brice, Nicola L. Pellegrino, Kyle Parolari, Luca Shaked, Jordan T. Page, Keith J. Marchildon, François Barrows, Douglas W. Carroll, Thomas S. Topilko, Thomas Mulligan, Victoria M. Newman, Robert Doyle, Kevin Bürli, Roland Barker, Daniel F. Glen, Angela Ortuño, María José Nectow, Alexander R. Renier, Nicolas Cohen, Paul Carlton, Mark Heintz, Nathaniel Friedman, Jeffrey M. Pharmacological targeting of glutamatergic neurons within the brainstem for weight reduction |
title | Pharmacological targeting of glutamatergic neurons within the brainstem for weight reduction |
title_full | Pharmacological targeting of glutamatergic neurons within the brainstem for weight reduction |
title_fullStr | Pharmacological targeting of glutamatergic neurons within the brainstem for weight reduction |
title_full_unstemmed | Pharmacological targeting of glutamatergic neurons within the brainstem for weight reduction |
title_short | Pharmacological targeting of glutamatergic neurons within the brainstem for weight reduction |
title_sort | pharmacological targeting of glutamatergic neurons within the brainstem for weight reduction |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9684079/ https://www.ncbi.nlm.nih.gov/pubmed/36411386 http://dx.doi.org/10.1038/s42255-022-00677-8 |
work_keys_str_mv | AT schneebergermarc pharmacologicaltargetingofglutamatergicneuronswithinthebrainstemforweightreduction AT bricenicolal pharmacologicaltargetingofglutamatergicneuronswithinthebrainstemforweightreduction AT pellegrinokyle pharmacologicaltargetingofglutamatergicneuronswithinthebrainstemforweightreduction AT parolariluca pharmacologicaltargetingofglutamatergicneuronswithinthebrainstemforweightreduction AT shakedjordant pharmacologicaltargetingofglutamatergicneuronswithinthebrainstemforweightreduction AT pagekeithj pharmacologicaltargetingofglutamatergicneuronswithinthebrainstemforweightreduction AT marchildonfrancois pharmacologicaltargetingofglutamatergicneuronswithinthebrainstemforweightreduction AT barrowsdouglasw pharmacologicaltargetingofglutamatergicneuronswithinthebrainstemforweightreduction AT carrollthomass pharmacologicaltargetingofglutamatergicneuronswithinthebrainstemforweightreduction AT topilkothomas pharmacologicaltargetingofglutamatergicneuronswithinthebrainstemforweightreduction AT mulliganvictoriam pharmacologicaltargetingofglutamatergicneuronswithinthebrainstemforweightreduction AT newmanrobert pharmacologicaltargetingofglutamatergicneuronswithinthebrainstemforweightreduction AT doylekevin pharmacologicaltargetingofglutamatergicneuronswithinthebrainstemforweightreduction AT burliroland pharmacologicaltargetingofglutamatergicneuronswithinthebrainstemforweightreduction AT barkerdanielf pharmacologicaltargetingofglutamatergicneuronswithinthebrainstemforweightreduction AT glenangela pharmacologicaltargetingofglutamatergicneuronswithinthebrainstemforweightreduction AT ortunomariajose pharmacologicaltargetingofglutamatergicneuronswithinthebrainstemforweightreduction AT nectowalexanderr pharmacologicaltargetingofglutamatergicneuronswithinthebrainstemforweightreduction AT reniernicolas pharmacologicaltargetingofglutamatergicneuronswithinthebrainstemforweightreduction AT cohenpaul pharmacologicaltargetingofglutamatergicneuronswithinthebrainstemforweightreduction AT carltonmark pharmacologicaltargetingofglutamatergicneuronswithinthebrainstemforweightreduction AT heintznathaniel pharmacologicaltargetingofglutamatergicneuronswithinthebrainstemforweightreduction AT friedmanjeffreym pharmacologicaltargetingofglutamatergicneuronswithinthebrainstemforweightreduction |