Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, C058

Oral Communications

Potentiation of satiety by activation of glucagon-like peptide-1 producing preproglucagon neurons

D. Brierley1, F. Reimann2, F. Gribble2, S. Trapp1

1. Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom. 2. Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom.

Glucagon-like peptide-1 (GLP-1) analogues are anti-obesity treatments, however their clinical utility is compromised by nausea. Chemogenetic activation of GLP-1 producing preproglucagon (PPG) neurons in the caudal brainstem supresses food intake, however it is unclear whether this represents potentiation of satiety, or is secondary to induction of nausea/malaise. The extent to which PPGs are involved in physiological satiety further remains to be determined. To address this, transgenic mice expressing Cre recombinase in PPG neurons were anaesthetised with ketamine (75mg/kg, i.m.) + medetomidine (0.5mg/kg, i.m.) and stereotaxically injected with Cre-dependent AAVs encoding either hM3Dq or hM4Di DREADD receptors. Sex-matched cohorts (n=8) were used to investigate the effects of 2mg/kg (i.p.) CNO-induced neuronal activation (PPG-Gq) or inhibition (PPG-Gi) on feeding behaviours using within-subjects designs. Food intake was recorded using automated pellet dispensers and video coding of behavioural satiety sequences (BSS). Data are means ± SEM and analysed by ANOVA and post hoc Bonferroni or t-tests. In 3hr fasted PPG-Gq mice, CNO reduced dark phase intake (2.62g±0.15 to 1.47g±0.21; p=0.0027), in a sex-independent manner (Sex x CNO: F(1, 5)=0.23, p=0.65). Over 48hrs, intake was reduced during hour 1-5 (p<0.05-0.0001), and cumulative intake from hour 3-48 (p<0.001-0.0001), with no compensatory refeeding observed. cFos immunoreactivity revealed this anorectic effect was due to activation of 81.3%±6.8 of hM3Dq-transduced cells vs 0.8%±0.6 in saline controls (p<0.0001). To assess effects of PPG activation on satiety in the BSS paradigm, PPG-Gq mice were fasted for 18hrs prior to dark onset. PPG activation reduced 40min intake (0.31g±0.06 to 0.06g±0.01; p=0.016) and advanced the onset of satiety (15-20min to ≤5min), with the typical BSS maintained. Eating duration was decreased (3.1min±0.73 to 0.44min±0.10; p=0.012), and resting duration increased (11.5min±1.8 to 23.2min±2.6; p=0.016). In PPG-Gi mice, CNO-induced PPG inhibition had modest effects on food intake, only readily apparent during high-volume Ensure liquid diet intake. Following a 15min Ensure preload, hour 1 chow intake was increased (0.04g±0.02 to 0.08±0.03; p=0.039), driven by reduced latency to meal 1 (75.5min±13.1 to 53.0min±11.0; p=0.011). With 1hr Ensure access at dark onset, Ensure intake itself was increased by CNO (1.84g±0.19 to 2.09g±0.17; p=0.014), followed by a compensatory decrease in chow intake during hour 2 (0.09g±0.02 to 0.07g±0.02; p=0.016). These anorectic effects of chemogenetic PPG activation are consistent with potentiation of satiety, rather than induction of nausea/malaise. Given their apparently minor role in physiological satiety, PPG neurons thus have the capacity for supraphysiological stimulation to reduce food intake, which may represent an effective anti-obesity strategy.

Where applicable, experiments conform with Society ethical requirements