Human Semaphorin 3 Variants Link Melanocortin Circuit Development and Energy Balance

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van Der Klaauw, Agatha | Croizier, Sophie | Mendes de Oliveira, Edson | Stadler, Lukas K.J. | Park, Soyoung | Kong, Youxin | Banton, Matthew | Tandon, Panna | Hendricks, Audrey | Keogh, Julia | Riley, Susanna | Papadia, Sofia | Henning, Elana | Bounds, Rebecca | Bochukova, Elena | Mistry, Vanisha | O’rahilly, Stephen | Simerly, Richard | Minchin, James E.N. | Barroso, Inês | Jones, E. Yvonne | Bouret, Sébastien, G. | Farooqi, I. Sadaf

Edité par CCSD ; Elsevier -

International audience. 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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