Understanding the anorectic effects of native glucagon-like peptide-1 (GLP-1) is challenging because it is rapidly inactivated by the enzyme dipeptidyl peptidase (DPP4) (1). GLP-1 receptors are located throughout the body including the brain and vagal afferent neurones. Exenatide is a long acting GLP-1 receptor agonist which, like GLP-1, reduces food intake, decreases body weight and delays gastric emptying (2), but crucially is resistant to the effects of DPP4. Exenatide may activate central pathways that mediate satiety, however research in humans is lacking. Changes in the blood oxygen level dependent (BOLD) signal measured during functional magnetic resonance imaging (fMRI) can be used as a surrogate correlate of changes in neural activity (3). To examine brain activation in humans after exenatide administration, 15 healthy adult volunteers received a subcutaneous injection of either 5µg exenatide or a placebo in a randomised cross over fashion during 70 minutes of fMRI (3T Philips scanner). For each volunteer, the difference in the mean % BOLD signal change from baseline between exenatide and placebo was extracted from 10 regions of interest covering the brainstem and hypothalamus. The extracted data were analysed in 5 minute blocks using T-tests. Due to excessive movement during scans, 2 volunteers were excluded from analysis. Bilateral increases in BOLD signal in the lower hypothalamus were evident 45 min after exenatide injection (P<0.05). The extent and time course of this increase is shown in Figure 1. In the bilateral midbrain there were trends for an increase in BOLD signal after 45 mins (P<0.075). This pattern of BOLD signal change was also observed in the right upper hypothalamus and pons. Conversely, BOLD signal was significantly decreased in the left upper hypothalamus 40 mins after exenatide injection (P<0.05); a similar trend was evident in the left pons and medulla. The overall pattern is that key appetite regulatory brain regions were progressively activated 45 min after exenatide administration. This suggests the anorectic effects of exenatide in humans may be mediated via activation of central GLP-1 receptors, either directly or via vagal inputs, rather than by a direct effect on delayed gastric emptying of meals since this study was undertaken in a fasting condition.