Human Semaphorin 3 Variants Link Melanocortin Circuit Development and Energy Balance

Autor: Van Der Klaauw, AA, Croizier, S, De Oliveira, E, Stadler, LKJ, Park, S, Kong, Y, Banton, MC, Tandon, P, Hendricks, AE, Keogh, JM, Riley, SE, Papadia, S, Henning, E, Bounds, R, Bochukova, EG, Mistry, V, O'Rahilly, S, Simerly, RB, Interval, Consortium, Uk10K, Minchin, JEN, Barroso, I, Jones, EY, Bouret, SG, Farooqi, IS
Přispěvatelé: University of Cambridge [UK] (CAM), Addenbrooke's Hospital, Cambridge University NHS Trust, University of Southern California (USC), Université de Lausanne = University of Lausanne (UNIL), University of Oxford, Pathogénèse des Infections vasculaires / Pathogenesis of Vascular Infections, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plymouth University, University of Edinburgh, The Wellcome Trust Sanger Institute [Cambridge], University of Colorado [Denver], Queen Mary University of London (QMUL), Vanderbilt University [Nashville], Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Studies in humans were supported by Wellcome (AAvdK, IB, ISF, 099038/Z/12/Z, 098497/Z/12/Z, WT098051), the Medical Research Council (MRC) (ISF, SOR, MRC_MC_UU_12012/5), the National Institute of Health Research (NIHR), Cambridge Biomedical Research Centre (ISF, IB, SOR), and the Bernard Wolfe Health Neuroscience Endowment (ISF). E.M.d.O. was supported by the Brazilian National Council for Scientific and Technological Development- CNPq (233690/2014-0). J.E.N.M. was supported by a joint University of Edinburgh and British Heart Foundation (BHF) Centre of Research Excellence Fellowship. S.G.B. was supported by the NIH (DK84142, DK102780, and DK118401). Structural analysis was performed by Y.K. and E.Y.J., who are supported by Cancer Research UK and the UK MRC (C375/A17721 and MR/M000141/1 to E.Y.J.) and Wellcome (203141/Z/16/Z, supporting the Wellcome Centre for Human Genetics). Whole-exome sequencing was performed as part of the UK10K consortium (a full list of investigators who contributed to the generation of the data is available from https://www.uk10k.org/). Participants in the INTERVAL randomized controlled trial were recruited with the active collaboration of NHS Blood and Transplant England (https://www.nhsbt.nhs.uk/), which has supported field work and other elements of the trial. DNA extraction and genotyping was co-funded by the NIHR, the NIHR BioResource (https://bioresource.nihr.ac.uk/), and the NIHR Cambridge Biomedical Research Centre (www.cambridgebrc.nihr.org.uk/). The academic coordinating center for INTERVAL was supported by core funding from the NIHR Blood and Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-2014-10024), UK MRC (MR/L003120/1), BHF (RG/13/13/30194), and NIHR Cambridge BRC. A complete list of the investigators and contributors to the INTERVAL trial is provided (Moore et al., 2014)., CCSD, Accord Elsevier, Université de Lausanne (UNIL), University of Oxford [Oxford], Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC)), van der Klaauw, Agatha [0000-0001-6971-8828], Stadler, Lukas [0000-0002-7028-4390], Papadia, Sofia [0000-0002-9222-3812], O'Rahilly, Stephen [0000-0003-2199-4449], Barroso, Ines [0000-0001-5800-4520], Farooqi, Ismaa [0000-0001-7609-3504], Apollo - University of Cambridge Repository, INTERVAL, UK10K Consortium
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Zdroj: Cell
Cell, 2019, 176 (4), pp.729-742.e18. ⟨10.1016/j.cell.2018.12.009⟩
Van Der Klaauw, A A, Croizier, S, Mendes De Oliveira, E, Stadler, L K J, 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, J E N, Barroso, I & Jones, E Y & Bouret, S G & Farooqi, I S 2019, ' Human semaphorin 3 variants link melanocortin circuit development and energy balance ', Cell, vol. 176, no. 4, pp. 729-742 . https://doi.org/10.1016/j.cell.2018.12.009
Cell, Elsevier, 2019, 176 (4), pp.729-742.e18. ⟨10.1016/j.cell.2018.12.009⟩
Cell, vol. 176, no. 4, pp. 729-742.e18
ISSN: 0092-8674
1097-4172
Popis: Summary 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.
Graphical Abstract
Highlights • Rare variants affecting Semaphorin 3 signaling are associated with human obesity • Disruption of Semaphorin 3 signaling leads to weight gain in zebrafish and mice • Semaphorin 3 signaling promotes the development of hypothalamic melanocortin circuits
Semaphorin 3 signaling promotes the development of hypothalamic circuits, and human variants are associated with obesity.
Databáze: OpenAIRE
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