Cell, 2019-02, Vol.176 (4), p.729-742.e18
- 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
2019
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- Autor(en) / Beteiligte
- 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
- Titel
- Human Semaphorin 3 Variants Link Melanocortin Circuit Development and Energy Balance
- Ist Teil von
- Cell, 2019-02, Vol.176 (4), p.729-742.e18
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2019
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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. [Display omitted] •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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0092-8674eISSN: 1097-4172DOI: 10.1016/j.cell.2018.12.009Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6370916
- Format
- –
- Schlagworte
- Adolescent, Adult, AgRP, Animals, Body Weight, Cell Line, Child, Child, Preschool, Disease Models, Animal, Eating, Energy Metabolism - genetics, Female, Genetic Variation - genetics, Homeostasis, Humans, hypothalamus, Hypothalamus - metabolism, Leptin - metabolism, Life Sciences, Male, Melanocortins - metabolism, Mice, Mice, Inbred C57BL, Middle Aged, Nerve Tissue Proteins - metabolism, Neurons - metabolism, Neuropilins, obesity, Obesity - genetics, Obesity - metabolism, Plexins, Pomc, Receptors, Cell Surface - metabolism, Semaphorin 3s, Semaphorins - genetics, Semaphorins - metabolism, Young Adult, Zebrafish