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

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Version: Final published version
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Serval ID
serval:BIB_574ED2DF7FB5
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Human Semaphorin 3 Variants Link Melanocortin Circuit Development and Energy Balance.
Journal
Cell
Author(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.
Working group(s)
INTERVAL, UK10K Consortium
ISSN
1097-4172 (Electronic)
ISSN-L
0092-8674
Publication state
Published
Issued date
07/02/2019
Peer-reviewed
Oui
Volume
176
Number
4
Pages
729-742.e18
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
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.
Keywords
Adolescent, Adult, Animals, Body Weight, Cell Line, Child, Child, Preschool, Disease Models, Animal, Eating, Energy Metabolism/genetics, Female, Genetic Variation/genetics, Homeostasis, Humans, Hypothalamus/metabolism, Leptin/metabolism, Male, Melanocortins/metabolism, Mice, Mice, Inbred C57BL, Middle Aged, Nerve Tissue Proteins/metabolism, Neurons/metabolism, Obesity/genetics, Obesity/metabolism, Receptors, Cell Surface/metabolism, Semaphorins/genetics, Semaphorins/metabolism, Young Adult, Zebrafish, AgRP, Neuropilins, Plexins, Pomc, Semaphorin 3s, hypothalamus, obesity
Pubmed
Web of science
Open Access
Yes
Create date
21/02/2019 9:26
Last modification date
16/12/2019 7:19
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