期刊
CELL
卷 176, 期 4, 页码 729-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2018.12.009
关键词
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资金
- Wellcome [099038/Z/12/Z, 098497/Z/12/Z, WT098051, 203141/Z/16/Z]
- Medical Research Council (MRC) [MRC_MC_UU_12012/5]
- National Institute of Health Research (NIHR), Cambridge Biomedical Research Centre
- Bernard Wolfe Health Neuroscience Endowment
- Brazilian National Council for Scientific and Technological Development-CNPq [233690/2014-0]
- University of Edinburgh
- British Heart Foundation (BHF) Centre of Research Excellence Fellowship
- NIH [DK84142, DK102780, DK118401]
- Cancer Research UK
- UK MRC [C375/A17721, MR/M000141/1, MR/L003120/1]
- NIHR
- NIHR BioResource
- NIHR Cambridge Biomedical Research Centre
- NIHR Blood and Transplant Research Unit in Donor Health and Genomics [NIHR BTRU-2014-10024]
- BHF [RG/13/13/30194]
- NIHR Cambridge BRC
- Wellcome Strategic Award [100574/Z/12/Z]
- Wellcome Trust [098497/Z/12/Z, 099038/Z/12/Z] Funding Source: Wellcome Trust
- MRC [MC_UU_00014/1, MC_UU_12012/1, MR/S025685/1, MR/L003120/1, MR/M000141/1, MC_UU_12012/5, G0900554] Funding Source: UKRI
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.
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