Human Semaphorin 3 Variants Link Melanocortin Circuit Development and Energy Balance.
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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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1097-4172
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Wellcome Trust (099038/Z/12/Z)
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
Medical Research Council (G0900554)
Medical Research Council (MC_UU_12012/1)
Medical Research Council (MC_UU_12012/5)
Medical Research Council (MR/L003120/1)
Wellcome Trust (098497/Z/12/Z)
British Heart Foundation (None)
British Heart Foundation (RG/18/13/33946)
MRC (MC_UU_00014/1)
Medical Research Council (MC_PC_12012)