Activation of murine pre-proglucagon–producing neurons reduces food intake and body weight

Abstract

Statistics. All data were subjected to statistical analysis in GraphPad Prism 6. When WT and transgene GCG-Gq DREADD mice were compared, 2-tailed unpaired t tests were performed. Time course tests were analyzed with 2-way repeated measures ANOVA with treatment and time points as independent variables. When the same mice received alternating CNO and saline treatments, paired 2-tailed t tests were used to evaluate data for significance. Data from once-performed behavioral tests, such as the open field and elevated plus maze, were analyzed with unpaired 2-tailed t tests. Data are expressed as mean ± SEM. Statistical significance was considered with P < 0.05.Study approval. All animal procedures were approved by the Institutional Animal Care and Use Committee of the University of Virginia and conducted in accordance with its guidelines.

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

“…To investigate the function of endogenously released GLP-1 in the brain, we used Gcg-Cre (GLP-1 is a post-translational cleavage product of Gcg encoded preproglucagon protein) transgenic animals that we recently generated and carefully characterized (Gaykema et al, 2017). We first asked whether PVN neuronal activity is modulated by the activity of NTS GLP-1 producing GCG neurons.…”

“…Rather, it did significantly decrease the body weight of the obese mice which were fed by high fat food for 5 months (Gaykema et al, 2017). Chemogenetic inhibition of NTS GCG neurons for one week showed a slight increase in the daily food intake but with no obvious body weight gain when compared to control group (Figure S4, L–N).…”

“…The NTS GLP-1 producing neurons send robust projections to many forebrain regions, including the paraventricular nucleus of the hypothalamus (PVN) (Gaykema et al, 2017; Gu et al, 2013). The PVN is one of several brain centers implicated in food intake behavior (Betley et al, 2013), as lesioning of the PVN induces overeating and obesity (Shor-Posner et al, 1985; Sims and Lorden, 1986).…”

“…To address these outstanding questions described above, in the present study, we use a recently generated Gcg-Cre recombinase BAC transgenic mouse line (Gaykema et al, 2017), which provides a unique tool for specifically investigating functions of NTS GCG neurons using optogenetic and chemogenetic approaches. We address the functional anatomical impact of the NTS-to-PVN projecting neural pathway and show that GLP-1 signaling is sufficient to suppress feeding independent of glutamate co-release from GCG neurons.…”

DREADDing proglucagon neurons: a fresh look at metabolic regulation by the brain

“…Some of the findings of Gaykema et al (8) support their contention that targeting GCG + neurons might have distinct potential for therapeutic development. For example, it would be very advantageous if activation of these nerves can cause satiety without malaise or visceral illness, since nausea is currently the limiting side effect of GLP-1R agonists in clinical use.…”