Human Semaphorin 3 Variants Link Melanocortin Circuit Development and Energy Balance.
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
Receptors, Cell Surface
/ metabolism
Semaphorins
/ genetics
Young Adult
Zebrafish
AgRP
Neuropilins
Plexins
Pomc
Semaphorin 3s
hypothalamus
obesity
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
07 02 2019
07 02 2019
Historique:
received:
04
12
2017
revised:
28
08
2018
accepted:
05
12
2018
pubmed:
22
1
2019
medline:
4
12
2019
entrez:
22
1
2019
Statut:
ppublish
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.
Identifiants
pubmed: 30661757
pii: S0092-8674(18)31623-4
doi: 10.1016/j.cell.2018.12.009
pmc: PMC6370916
pii:
doi:
Substances chimiques
Leptin
0
Melanocortins
0
Nerve Tissue Proteins
0
Receptors, Cell Surface
0
Semaphorins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
729-742.e18Subventions
Organisme : Medical Research Council
ID : MR/L003120/1
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RG/13/13/30194
Pays : United Kingdom
Organisme : Department of Health
ID : BTRU-2014-10024
Pays : United Kingdom
Organisme : NIDDK NIH HHS
ID : R01 DK118401
Pays : United States
Organisme : Medical Research Council
ID : MR/S025685/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 098497/Z/12/Z
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 100574/Z/12/Z
Pays : United Kingdom
Organisme : NIDDK NIH HHS
ID : R01 DK084142
Pays : United States
Organisme : Medical Research Council
ID : MC_UU_12012/1
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0900554
Pays : United Kingdom
Organisme : Wellcome Trust
ID : WT098051
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C375/A17721
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 099038/Z/12/Z
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RG/10/17/28553
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 203141/Z/16/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00014/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/M000141/1
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RG/18/13/33946
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_12012/5
Pays : United Kingdom
Organisme : NIDDK NIH HHS
ID : R01 DK102780
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Informations de copyright
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
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