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

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. [Display omitted] •NTS-to-PVN projecting GLP-1 signaling suppresses food intake•GLP-1 augments the excitatory synaptic strengths of CRH neurons via PKA pathway•GLP-1 signaling in PVN causes phosphorylation of S845 of GluA1 Liu et al. show that GLP-1 signaling in PVN suppresses food intake and may prevent obesity. The molecular mechanism underlying the GLP-1 function in the PVN is via AMPA receptor subunit-GluA1 phosphorylation and subsequent membrane trafficking in a PKA-dependent pathway.