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

Abstract

SUMMARY 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.

VIPergic neurons of the infralimbic and prelimbic cortices control palatable food intake through separate cognitive pathways

“…Our c-Fos expression data provide an explanation of how manipulations of IL and PL VIPergic neurons produce differential effects on food intake and novelty-driven behaviors. PL VIPergic stimulation was shown to reduce c-Fos expression in the ARC, while PVN c-Fos expression was increased, with both areas having been implicated in the control of food intake (36)(37)(38). Although direct activation of these target sites is unlikely, an indirect projection such as that from the PFC to the bed nucleus of the stria terminalis (BNST) (39) and subsequently from the BNST to the PVN could mediate the observed increase in c-Fos expression.…”

GLP‐1 neurons form a local synaptic circuit within the rodent nucleus of the solitary tract

“…Glutamatergic and GLP-1R signaling mechanisms interact in many brain regions (Gilman et al, 2003;Liu et al, 2017;Mietlicki-Baase et al, 2013, and GLP-1R signaling may modify excitatory synaptic transmission via cellular mechanisms involved in long-term synaptic plasticity ; similarly, clonal intestinal L-cells that secrete GLP-1 express VGLUT2 and co-release glutamate, hypothesized as important for intercellular signaling among intestinal L-cells (Uehara et al, 2006). The relatively low density of GLP-1+ fibers and terminals within the rat cNTS (see Figures 1 and 3) contrasts with the high density of GLP-1+ terminals within the rat hypothalamus and limbic forebrain (Gu et al, 2013).…”

Exercise, Obesity and CNS Control of Metabolic Homeostasis: A Review

“…Liu et al provided evidence in mice that glucagon-like peptide-1 (GLP-1) expressing neurons in the medulla send anorexigenic signals to the paraventricular nucleus (PVN) of the hypothalamus and that postnatal depletion of GLP-1 receptors in the PVN causes hyperphagic obesity (Liu et al, 2017 ). GLP-1 is a potent incretin, and regulates glucose independent of its anorexigenic effects (Näslund et al, 2004 ).…”