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.


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


  • Leptin
  • Melanocortins
  • Nerve Tissue Proteins
  • Receptors, Cell Surface
  • Semaphorins