Human Semaphorin 3 Variants Link Melanocortin Circuit Development and Energy Balance.

Détails

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Etat: Public
Version: Final published version
ID Serval
serval:BIB_574ED2DF7FB5
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Human Semaphorin 3 Variants Link Melanocortin Circuit Development and Energy Balance.
Périodique
Cell
Auteur(s)
van der Klaauw A.A., Croizier S., Mendes de Oliveira E., Stadler LKJ, Park S., Kong Y., Banton M.C., Tandon P., Hendricks A.E., Keogh J.M., Riley S.E., Papadia S., Henning E., Bounds R., Bochukova E.G., Mistry V., O'Rahilly S., Simerly R.B., Minchin JEN, Barroso I., Jones E.Y., Bouret S.G., Farooqi I.S.
Collaborateur(s)
INTERVAL, UK10K Consortium
ISSN
1097-4172 (Electronic)
ISSN-L
0092-8674
Statut éditorial
Publié
Date de publication
2019
Peer-reviewed
Oui
Volume
176
Numéro
4
Pages
729-742.e18
Langue
anglais
Résumé
Hypothalamic melanocortin neurons play a pivotal role in weight regulation. Here, we examined the contribution of Semaphorin 3 (SEMA3) signaling to the development of these circuits. In genetic studies, we found 40 rare variants in SEMA3A-G and their receptors (PLXNA1-4; NRP1-2) in 573 severely obese individuals; variants disrupted secretion and/or signaling through multiple molecular mechanisms. Rare variants in this set of genes were significantly enriched in 982 severely obese cases compared to 4,449 controls. In a zebrafish mutagenesis screen, deletion of 7 genes in this pathway led to increased somatic growth and/or adiposity demonstrating that disruption of Semaphorin 3 signaling perturbs energy homeostasis. In mice, deletion of the Neuropilin-2 receptor in Pro-opiomelanocortin neurons disrupted their projections from the arcuate to the paraventricular nucleus, reduced energy expenditure, and caused weight gain. Cumulatively, these studies demonstrate that SEMA3-mediated signaling drives the development of hypothalamic melanocortin circuits involved in energy homeostasis.
Mots-clé
AgRP, Neuropilins, Plexins, Pomc, Semaphorin 3s, hypothalamus, obesity
Pubmed
Web of science
Open Access
Oui
Création de la notice
21/02/2019 9:26
Dernière modification de la notice
20/08/2019 15:11
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