Endogenous GLP-1 alters postprandial functional connectivity between homeostatic and reward-related brain regions involved in regulation of appetite in healthy lean males: A pilotstudy

Aims: Peripheral infusion of glucagon-like peptide-1 (GLP-1) can affect brain activity in areas involved in the regulation of appetite, including hypothalamic and reward-related brain regions. In contrast, the physiological role of endogenous GLP-1 in the central regulation of appetite has hardly been investigated. Materials and Methods: This was a randomized, cross-over trial that involved 12 healthy volunteers who received an intragastric (ig) glucose (gluc) load, with or without intravenous (iv) exendin9-39 (ex9-39; specific GLP-1 receptor antagonist). Functional magnetic resonance imaging was used to investigate the effect of endogenous GLP-1 on resting state functional connectivity (rsFC) between homeostatic and reward-related brain regions. Visual analogue scales were used to rate appetite-related sensations. Blood samples were collected for GI hormone measurements. Results: Administration of iv-ex9-39/ig-gluc induced a significantly higher rsFC, relative to ig-gluc administration, between the hypothalamus and the left lateral orbitofrontal cortex (OFC) as well as the left amygdala (P ≤.001, respectively). Administration of iv-ex9-39/ig-gluc induced a significantly higher rsFC, relative to ig-gluc administration, between the right nucleus accumbens and the right lateral OFC (P <.001). Administration of iv-ex9-39/ig-gluc induced a significantly lower rsFC, relative to ig-gluc administration, between the midbrain and the right caudate nucleus (P =.001). Administration of ig-gluc significantly decreased prospective food consumption and increased sensations of fullness compared to pre-infusion baseline (P =.028 and P =.019, respectively); these effects were not present in the iv-ex9-39/ig-gluc condition. Conclusions: This pilot trial provides preliminary experimental evidence that glucose-induced endogenous GLP-1 affects central regulation of appetite by modulating rsFC in homeostatic and reward-related brain regions in healthy lean male participants in a GLP-1 receptor-mediated fashion.