Human Semaphorin 3 Variants Link Melanocortin Circuit Development and Energy Balance

Agatha A van der Klaauw; Sophie Croizier; Edson Mendes de Oliveira; Lukas K J Stadler; Soyoung Park; Youxin Kong; Matthew C Banton; Panna Tandon; Audrey E Hendricks; Julia M Keogh; Susanna E Riley; Sofia Papadia; Elana Henning; Rebecca Bounds; Elena G Bochukova; Vanisha Mistry; Stephen O'Rahilly; Richard B Simerly; INTERVAL; UK10K Consortium; James E N Minchin; Inês Barroso; E Yvonne Jones; Sebastien G Bouret; I Sadaf Farooqi

doi:10.1016/j.cell.2018.12.009

Human Semaphorin 3 Variants Link Melanocortin Circuit Development and Energy Balance

Cell. 2019 Feb 7;176(4):729-742.e18. doi: 10.1016/j.cell.2018.12.009. Epub 2019 Jan 17.

Authors

Agatha A van der Klaauw¹, Sophie Croizier², Edson Mendes de Oliveira¹, Lukas K J Stadler¹, Soyoung Park³, Youxin Kong⁴, Matthew C Banton⁵, Panna Tandon⁶, Audrey E Hendricks⁷, Julia M Keogh¹, Susanna E Riley⁶, Sofia Papadia¹, Elana Henning¹, Rebecca Bounds¹, Elena G Bochukova⁸, Vanisha Mistry¹, Stephen O'Rahilly¹, Richard B Simerly⁹; INTERVAL; UK10K Consortium; James E N Minchin⁶, Inês Barroso¹⁰, E Yvonne Jones¹¹, Sebastien G Bouret¹², I Sadaf Farooqi¹³

Affiliations

¹ University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
² 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.
³ 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.
⁴ Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK; Pathogenesis of Vascular Infections Unit, INSERM, Institut Pasteur, Paris, France.
⁵ 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.
⁶ Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, UK.
⁷ Wellcome Sanger Institute, Cambridge, UK; Department of Mathematical and Statistical Sciences, University of Colorado-Denver, Denver, CO 80204, USA.
⁸ 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, London, UK.
⁹ 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, Tennessee, TN 37232-0615, USA.
¹⁰ 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.
¹¹ Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
¹² 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: sbouret@chla.usc.edu.
¹³ 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.

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.

Keywords: AgRP; Neuropilins; Plexins; Pomc; Semaphorin 3s; hypothalamus; obesity.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Animals
Body Weight
Cell Line
Child
Child, Preschool
Disease Models, Animal
Eating
Energy Metabolism / genetics*
Female
Genetic Variation / genetics
Homeostasis
Humans
Hypothalamus / metabolism
Leptin / metabolism
Male
Melanocortins / metabolism*
Mice
Mice, Inbred C57BL
Middle Aged
Nerve Tissue Proteins / metabolism
Neurons / metabolism
Obesity / genetics
Obesity / metabolism
Receptors, Cell Surface / metabolism
Semaphorins / genetics*
Semaphorins / metabolism
Young Adult
Zebrafish

Substances

Leptin
Melanocortins
Nerve Tissue Proteins
Receptors, Cell Surface
Semaphorins

Abstract

Publication types

MeSH terms

Substances

Grants and funding