ArticleCell2019
Human Semaphorin 3 Variants Link Melanocortin Circuit Development and Energy Balance.
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Article in Cell, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 81 papers, 1 of them a synthesis that pooled it.
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81citing papers in PubMed, 1 pooled it
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Who cites it
81 citing papers in PubMed, 1 synthesis or guideline pooled it, 146 citations in OpenAlex.
- Hyperphagia in rare melanocortin-4 receptor pathway diseases: therapeutic options and assessing treatment response.Reviews in endocrine & metabolic disorders · 2025Pooled it
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- Bidirectional crosstalk between obesity and the lymphatic system: a novel pathway in obesity pathogenesis and treatment.International journal of obesity (2005) · 2026Review
- The Clinical Phenotype and Genetic Analysis of Monogenic Non Syndromic Obesity Caused by MC4R Gene Variation.Molecular genetics & genomic medicine · 2026Article
- A patient with ROHHAD syndrome and leptin-melanocortin pathway gene variations. Correlation or just a coincidence? Case report.Hormones (Athens, Greece) · 2026Review
- Hypothalamic obesity.Reviews in endocrine & metabolic disorders · 2026Review
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- The genetics of obesity: aetiology, prevention and therapy.Nature metabolism · 2026Review
- SLIT3 fragments orchestrate neurovascular expansion and thermogenesis in brown adipose tissue.Nature communications · 2026Article
- Semaphorin 7A regulates axon outgrowth in subcutaneous white adipose tissue.Molecular metabolism · 2026Article
- SEMA3E promotes beige adipocyte differentiation and thermogenesis via β-catenin signaling in mice.Apoptosis : an international journal on programmed cell death · 2026Article
- Exploring Autosomal Dominant Non-Syndromic Monogenic Obesity: From Genes to Therapy.Current issues in molecular biology · 2026Review
- Loss of epigenetic adaptation to a high-fat diet in alpha-synuclein transgenic mice.Frontiers in cellular neuroscience · 2026Article
- Genetic Polymorphisms Associated with Obesity in Southeast Asian Populations: A Systematic Review without Meta-Analysis.The Malaysian journal of medical sciences : MJMS · 2025Review
- Global mapping of RNA NBiomarker research · 2025Article
- Oxytocin neurons drive melanocortin circuit maturation via vesicle release during a neonatal critical period.PLoS biology · 2025Article
- The long-term impact of obesity in pregnancy on offspring hypothalamic feeding pathways.Royal Society open science · 2025Review
- Urea cycle dysregulation: a new frontier in cancer metabolism and immune evasion.Cell communication and signaling : CCS · 2025Review
- Article
- Genetic etiology and clinical features of non-syndromic pediatric obesity in the Chinese population: a large cohort study.BMC pediatrics · 2025Article
21 more citing papers are in PubMed but not listed here.
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Authors and funding
25 authors at 11 institutions in 4 countries.
Agatha A van der KlaauwUniversity of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
Sophie CroizierThe Saban Research Institute, Developmental Neuroscience Program, Center for Endocrinology, Diabetes and Metabolism, Children's Hospital Los Angeles, University of Southern California, Los Angeles, CA 90027, USA; Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
Edson Mendes de OliveiraUniversity of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
Lukas K J StadlerUniversity of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
Soyoung ParkThe Saban Research Institute, Developmental Neuroscience Program, Center for Endocrinology, Diabetes and Metabolism, Children's Hospital Los Angeles, University of Southern California, Los Angeles, CA 90027, USA.
Youxin KongDivision of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK; Pathogenesis of Vascular Infections Unit, INSERM, Institut Pasteur, Paris, France.
Matthew C BantonUniversity of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK; School of Biological and Marine Sciences, University of Plymouth, Plymouth, UK.
Panna TandonCentre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, UK.
Audrey E HendricksWellcome Sanger Institute, Cambridge, UK; Department of Mathematical and Statistical Sciences, University of Colorado-Denver, Denver, CO 80204, USA.
Julia M KeoghUniversity of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
Susanna E RileyCentre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, UK.
Sofia PapadiaUniversity of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
Elana HenningUniversity of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
Rebecca BoundsUniversity of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
Elena G BochukovaUniversity of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK; The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Vanisha MistryUniversity of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
Stephen O'RahillyUniversity of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
Richard B SimerlyThe Saban Research Institute, Developmental Neuroscience Program, Center for Endocrinology, Diabetes and Metabolism, Children's Hospital Los Angeles, University of Southern California, Los Angeles, CA 90027, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, TN 37232-0615, USA.
INTERVAL
UK10K Consortium
James E N MinchinCentre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, UK.
Inês BarrosoUniversity of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK; Wellcome Sanger Institute, Cambridge, UK.
E Yvonne JonesDivision of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
Sebastien G BouretThe Saban Research Institute, Developmental Neuroscience Program, Center for Endocrinology, Diabetes and Metabolism, Children's Hospital Los Angeles, University of Southern California, Los Angeles, CA 90027, USA; INSERM U1172, Jean-Pierre Aubert Research Center, Lille, France. Electronic address: sbouret@chla.usc.edu.
I Sadaf FarooqiUniversity of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK. Electronic address: isf20@cam.ac.uk.
Addenbrooke's Hospital · GBEdinburgh College · GBUniversity of Cambridge · GBWellcome/MRC Institute of Metabolic Science · GBUniversity of Southern California · USCentre for Human Genetics · GBPathogenèse des infections vasculairesUniversité de Lille · FRUniversity of Colorado Denver · USVanderbilt University · USWellcome Sanger Institute · GB
Funding
Leptin and the Nutritional Programming of Obesity and DiabetesR01DK084142 · NIDDK · CHILDREN'S HOSPITAL OF LOS ANGELES · PI LEVITT, PAT · 2010 to 2022
$4.3MHypothalamic miRNAs in the Pathogenesis of ObesityR01DK102780 · NIDDK · CHILDREN'S HOSPITAL OF LOS ANGELES · PI BOURET, SEBASTIEN G · 2015 to 2017
$1.2MMolecular Mechanisms Underlying the Development of the Melanocortin SystemR01DK118401 · NIDDK · CHILDREN'S HOSPITAL OF LOS ANGELES · PI BOURET, SEBASTIEN G · 2018 to 2019
$848kBritish Heart Foundation RG/10/17/28553British Heart Foundation RG/13/13/30194British Heart Foundation RG/18/13/33946Cancer Research UK 17721Cancer Research UK C375/A17721Department of Health BTRU-2014-10024Medical Research Council G0900554Medical Research Council MC_UU_00014/1Medical Research Council MC_UU_12012/1Medical Research Council MC_UU_12012/5Medical Research Council MR/L003120/1Medical Research Council MR/M000141/1Medical Research Council MR/S025685/1NIDDK NIH HHS R01 DK084142NIDDK NIH HHS R01 DK102780NIDDK NIH HHS R01 DK118401Wellcome TrustWellcome Trust 098497/Z/12/ZWellcome Trust 099038/Z/12/ZWellcome Trust 100574/Z/12/ZWellcome Trust 203141/Z/16/ZWellcome Trust WT098051
Abstract
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.
Indexed as
AdolescentAdultAnimalsBody WeightCell LineChildChild, PreschoolDisease Models, AnimalEatingEnergy MetabolismFemaleGenetic VariationHomeostasisHumansHypothalamusLeptinLeptinMelanocortinsNerve Tissue ProteinsReceptors, Cell SurfaceSemaphorinsAgRPhypothalamusNeuropilinsobesityPlexinsPomcSemaphorin 3s
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