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

Abstract

Glucagon Like Peptide 1 (GLP-1) positive neurons in the hindbrain Nucleus Tractus Solitarius (NTS) send robust projections to the paraventricular nucleus of the hypothalamus (PVN), which is involved in the regulation of food intake. However, it is unclear whether this pathway is sufficient and necessary to control feeding behavior, or how the GLP-1 neurons affect synaptic function to modulate food intake. Here, we found that specific stimulation of GLP-1 afferent fibers within the PVN is sufficient to suppress food intake independent of glutamate release. GLP-1 receptor (GLP-1R) activation augments excitatory synaptic strength in PVN corticotropin-releasing hormone (CRH) neurons. Moreover, a protein kinase A (PKA) dependent signaling cascade is initiated by GLP-1R activation, which results in the phosphorylation of serine S845 of GluA1 AMPA receptors and subsequently promotes GluA1 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.