Your browser doesn't support javascript.
loading
Human Semaphorin 3 Variants Link Melanocortin Circuit Development and Energy Balance.
van der Klaauw, Agatha A; Croizier, Sophie; Mendes de Oliveira, Edson; Stadler, Lukas K J; Park, Soyoung; Kong, Youxin; Banton, Matthew C; Tandon, Panna; Hendricks, Audrey E; Keogh, Julia M; Riley, Susanna E; Papadia, Sofia; Henning, Elana; Bounds, Rebecca; Bochukova, Elena G; Mistry, Vanisha; O'Rahilly, Stephen; Simerly, Richard B; Minchin, James E N; Barroso, Inês; Jones, E Yvonne; Bouret, Sebastien G; Farooqi, I Sadaf.
Afiliación
  • van der Klaauw AA; University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
  • Croizier S; The 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.
  • Mendes de Oliveira E; University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
  • Stadler LKJ; University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
  • Park S; The 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.
  • Kong Y; Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK; Pathogenesis of Vascular Infections Unit, INSERM, Institut Pasteur, Paris, France.
  • Banton MC; University 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.
  • Tandon P; Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, UK.
  • Hendricks AE; Wellcome Sanger Institute, Cambridge, UK; Department of Mathematical and Statistical Sciences, University of Colorado-Denver, Denver, CO 80204, USA.
  • Keogh JM; University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
  • Riley SE; Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, UK.
  • Papadia S; University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
  • Henning E; University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
  • Bounds R; University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
  • Bochukova EG; University 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, Lo
  • Mistry V; University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
  • O'Rahilly S; University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
  • Simerly RB; The 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, Te
  • Minchin JEN; Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, UK.
  • Barroso I; University 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.
  • Jones EY; Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
  • Bouret SG; The 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: sb
  • Farooqi IS; University 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.
Cell ; 176(4): 729-742.e18, 2019 02 07.
Article en En | MEDLINE | ID: mdl-30661757
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.
Asunto(s)
Palabras clave
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Semaforinas / Metabolismo Energético / Melanocortinas Límite: Adolescent / Adult / Animals / Child / Child, preschool / Female / Humans / Male / Middle aged Idioma: En Revista: Cell Año: 2019 Tipo del documento: Article País de afiliación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Semaforinas / Metabolismo Energético / Melanocortinas Límite: Adolescent / Adult / Animals / Child / Child, preschool / Female / Humans / Male / Middle aged Idioma: En Revista: Cell Año: 2019 Tipo del documento: Article País de afiliación: Reino Unido