Introduction Administration of the glucagon-like peptide-1 receptor agonist (GLP-1RA) exenatide reduces food intake and induces weight loss. GLP-1 receptors are located throughout the body including the brain and vagal afferent neurones. Although exenatide slows gastric emptying (GE), it is believed the main mechanism behind exenatide-induced weight loss may be related to activation of central pathways that mediate satiety. However, research in humans is lacking. Brain activation can be indirectly measured by quantifying changes in the blood oxygen level dependent (BOLD) signal measured during functional magnetic resonance imaging (fMRI).
Methods To confirm a gastric inhibitory effect of exenatide, 12 healthy volunteers received a subcutaneous injection of 5 µg exenatide or placebo on separate occasions 60min prior to consumption of a 0.5 M carbohydrate test drink (500 mL). Over 45 min GE was non-invasively measured using breath tests. Then, to examine brain activation using fMRI, 15 healthy volunteers received 5 µg exenatide or placebo after ~10 h fast and underwent 70 min scanning (3T Philips scanner). Wholebrain analysis was conducted (data for the hypothalamus only are reported). For each volunteer the difference in mean%BOLD signal change from baseline between exenatide and placebo was extracted and analysed in 5min blocks using T-tests. Two volunteers were excluded due to excessive movement during scans.
Results Repeated measures ANOVA revealed that exenatide significantly slowed GE of the test drink with the area under the curve for exenatide being 31% lower than placebo (p < 0.005). fMRI analysis revealed bilateral increases in BOLD signal in the lower hypothalamus (p < 0.05), and a trend for increased BOLD (p < 0.075) in the right upper hypothalamus 45 min after exenatide. Conversely, BOLD signal was decreased in the left upper hypothalamus 40min after exenatide (p < 0.05).
Conclusion Our data confirms that a single dose of exenatide potently delays GE. Furthermore, most regions of the hypothalamus, a key appetite regulatory brain area, were progressively activated 45 min after exenatide administration. Those volunteers were fasted which suggests that the anorectic effects of exenatide in humans could be mediated via activation of central GLP-1 receptors, either directly or via vagal inputs. Further analysis will now be conducted to examine the effect of exenatide on areas in the brain associated with food reward such as the insula and orbitofrontal cortex.
Disclosure of Interest None Declared.
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