GLP-1 receptors exist in the parietal cortex, hypothalamus and medulla of human brains and the GLP-1 analogue liraglutide alters brain activity related to highly desirable food cues in individuals with diabetes: a crossover, randomised, placebo-controlled trial

Abstract

Aims/hypothesis: Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue that has been demonstrated to successfully treat diabetes and promote weight loss. The mechanisms by which liraglutide confers weight loss remain to be fully clarified. Thus, we investigated whether GLP-1 receptors are expressed in human brains and whether liraglutide administration affects neural responses to food cues in diabetic individuals (primary outcome).

Methods: In 22 consecutively studied human brains, expression of GLP-1 receptors in the hypothalamus, medulla oblongata and parietal cortex was examined using immunohistochemistry. In a randomised (assigned by the pharmacy using a randomisation enrolment table), placebo-controlled, double-blind, crossover trial, 21 individuals with type 2 diabetes (18 included in analysis due to lack or poor quality of data) were treated with placebo and liraglutide for a total of 17 days each (0.6 mg for 7 days, 1.2 mg for 7 days, and 1.8 mg for 3 days). Participants were eligible if they had type 2 diabetes and were currently being treated with lifestyle changes or metformin. Participants, caregivers, people doing measurements and/or examinations, and people assessing the outcomes were blinded to the medication assignment. We studied metabolic changes as well as neurocognitive and neuroimaging (functional MRI) of responses to food cues at the clinical research centre of Beth Israel Deaconess Medical Center.

Results: Immunohistochemical analysis revealed the presence of GLP-1 receptors on neurons in the human hypothalamus, medulla and parietal cortex. Liraglutide decreased activation of the parietal cortex in response to highly desirable (vs less desirable) food images (p < 0.001; effect size: placebo 0.53 ± 0.24, liraglutide -0.47 ± 0.18). No significant adverse effects were noted. In a secondary analysis, we observed decreased activation in the insula and putamen, areas involved in the reward system. Furthermore, we showed that increased ratings of hunger and appetite correlated with increased brain activation in response to highly desirable food cues while on liraglutide, while ratings of nausea correlated with decreased brain activation.

Conclusions/interpretation: For the first time, we demonstrate the presence of GLP-1 receptors in human brains. We also observe that liraglutide alters brain activity related to highly desirable food cues. Our data point to a central mechanism contributing to, or underlying, the effects of liraglutide on metabolism and weight loss. Future studies will be needed to confirm and extend these findings in larger samples of diabetic individuals and/or with the higher doses of liraglutide (3 mg) recently approved for obesity.

Trial registration: ClinicalTrials.gov NCT01562678 FUNDING : The study was funded by Novo Nordisk, NIH UL1 RR025758 and 5T32HD052961.

Keywords: Brain; Diabetes; GLP-1; Immunohistochemistry; Liraglutide; MRI; fMRI.

Figures

Fig. 1

Expression of GLP-1 receptors in human brain tissue. AP, area postrema; ARC, arcuate nucleus of the hypothalamus; DMNV, dorsal motor nucleus of the vagus; LPC, large pyramidal cells of the parietal cortex; NSol, nucleus solitarius; PmC, polymorphous cells of the parietal cortex; PVN, paraventricular nucleus of the hypothalamus; SPC, small pyramidal cells of the parietal cortex; VMH, ventromedial nucleus of the hypothalamus. White bars with grey border, no staining; light grey bars, weak staining; dark grey bars, mild staining; black bars, strong staining; diagonal stripe bars, very strong staining

Fig. 2

Staining for the GLP-1 receptor (magnification ×400) in the paraventricular nucleus of the hypothalamus (a), ventromedial hypothalamus (b), parietal cortex in small (c) and large pyramidal cells (d); staining in islets of Langerhans as a positive control (e) and glial and pyramidal cells without MAb 3F52 as a negative control (f). The arrow in (e) points to the non-neuroendocrine cells outside islets of Langerhans, which do not display immunopositivity, thus making them a valid positive control

Fig. 3

Brain activation in inferior parietal cortex in response to highly desirable compared with less desirable food images decreases with liraglutide treatment (whole-brain paired-samples t test). BOLD contrasts are superimposed on a T1 structural image in neurological orientation. The colour bar represents voxel T value

Fig. 4

In a secondary analysis, small volume corrections on images for insula and putamen; to be compared with results from van Bloemendaal et al (Fig. 3) [15]. The y-axis represents effect size of the activation (z scores). BOLD contrasts are superimposed on a T1 structural image in neurological orientation. The colour bar represents voxel T value. Lira, liraglutide

Fig. 5

Results from a whole-brain regression with VAS data during the liraglutide fMRI session for the contrast of highly desirable vs less desirable food images in the fasting state. Participants’ ratings of the VAS questions along a 10 cm line were regressed with whole-brain activations: ‘How hungry do you feel right now?’ (a); ‘How pleasant would it be to eat right now?’ (b); ‘How much do you think you could eat right now?’ (c) and ‘How nauseous do you feel right now?’ (d). Hot colours show positive correlations, cold colours show negative correlations. BOLD contrasts are superimposed on a T1 structural image in axial sections from z=−15 to z=60, in neurological orientation. The colour bars represent voxel T value