Enhanced AMPA Receptor Trafficking Mediates the Anorexigenic Effect of Endogenous Glucagon-like Peptide-1 in the Paraventricular Hypothalamus

Neuron. 2017 Nov 15;96(4):897-909.e5. doi: 10.1016/j.neuron.2017.09.042. Epub 2017 Oct 19.


Glucagon-like Peptide 1 (GLP-1)-expressing neurons in the hindbrain send robust projections to the paraventricular nucleus of the hypothalamus (PVN), which is involved in the regulation of food intake. Here, we describe that stimulation of GLP-1 afferent fibers within the PVN is sufficient to suppress food intake independent of glutamate release. We also show that GLP-1 receptor (GLP-1R) activation augments excitatory synaptic strength in PVN corticotropin-releasing hormone (CRH) neurons, with GLP-1R activation promoting a protein kinase A (PKA)-dependent signaling cascade leading to phosphorylation of serine S845 on GluA1 AMPA receptors and their trafficking to the plasma membrane. Finally, we show that postnatal depletion of GLP-1R in the PVN increases food intake and causes obesity. This study provides a comprehensive multi-level (circuit, synaptic, and molecular) explanation of how food intake behavior and body weight are regulated by endogenous central GLP-1. VIDEO ABSTRACT.

Keywords: AMPA receptor; GLP-1; electrophysiology; feeding; food intake behavior; membrane trafficking; obesity; paraventricular hypothalamus; phosphorylation; synaptic transmission.

MeSH terms

  • Animals
  • Cells, Cultured
  • Corticotropin-Releasing Hormone / physiology*
  • Cyclic AMP-Dependent Protein Kinases / physiology
  • Eating / physiology*
  • Glucagon-Like Peptide 1 / physiology*
  • Glucagon-Like Peptide-1 Receptor / physiology
  • Male
  • Mice
  • Mice, Transgenic
  • Neurons / physiology
  • Paraventricular Hypothalamic Nucleus / physiology*
  • Phosphorylation
  • Receptors, AMPA / metabolism
  • Receptors, AMPA / physiology*
  • Signal Transduction / physiology


  • Glucagon-Like Peptide-1 Receptor
  • Receptors, AMPA
  • Glucagon-Like Peptide 1
  • Corticotropin-Releasing Hormone
  • Cyclic AMP-Dependent Protein Kinases