EphrinB1 modulates glutamatergic inputs into POMC-expressing progenitors and controls glucose homeostasis

PLoS Biol. 2020 Nov 30;18(11):e3000680. doi: 10.1371/journal.pbio.3000680. eCollection 2020 Nov.


Proopiomelanocortin (POMC) neurons are major regulators of energy balance and glucose homeostasis. In addition to being regulated by hormones and nutrients, POMC neurons are controlled by glutamatergic input originating from multiple brain regions. However, the factors involved in the formation of glutamatergic inputs and how they contribute to bodily functions remain largely unknown. Here, we show that during the development of glutamatergic inputs, POMC neurons exhibit enriched expression of the Efnb1 (EphrinB1) and Efnb2 (EphrinB2) genes, which are known to control excitatory synapse formation. In vivo loss of Efnb1 in POMC-expressing progenitors decreases the amount of glutamatergic inputs, associated with a reduced number of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptor subunits and excitability of these cells. We found that mice lacking Efnb1 in POMC-expressing progenitors display impaired glucose tolerance due to blunted vagus nerve activity and decreased insulin secretion. However, despite reduced excitatory inputs, mice lacking Efnb2 in POMC-expressing progenitors showed no deregulation of insulin secretion and only mild alterations in feeding behavior and gluconeogenesis. Collectively, our data demonstrate the role of ephrins in controlling excitatory input amount into POMC-expressing progenitors and show an isotype-specific role of ephrins on the regulation of glucose homeostasis and feeding.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / metabolism
  • Energy Metabolism / physiology
  • Ephrin-B1 / metabolism*
  • Ephrin-B1 / physiology
  • Ephrin-B2 / metabolism
  • Ephrin-B2 / physiology
  • Excitatory Amino Acid Agents / metabolism
  • Glucose / metabolism*
  • Homeostasis / physiology
  • Male
  • Mice
  • Mice, Knockout
  • N-Methylaspartate / metabolism
  • Neurons / metabolism
  • Pro-Opiomelanocortin / metabolism*
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / metabolism


  • Ephrin-B1
  • Ephrin-B2
  • Excitatory Amino Acid Agents
  • Receptors, N-Methyl-D-Aspartate
  • N-Methylaspartate
  • Pro-Opiomelanocortin
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
  • Glucose

Grants and funding

This work was supported by the Swiss National Science Foundation grant (PZ00P3_167934/1) and Novartis grant (19B145) (to SC) and by an European Research Council Advanced Grant (INTEGRATE, No. 694798) and by a grant from the Swiss National Science Foundation (310030-182496) (to BT). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.