A Snapshot seminar hosted by the School of Physiology, Pharmacology and Neuroscience
Abstract: The anorexigenic peptide glucagon-like peptide-1 (GLP-1) is secreted from gut enteroendocrine cells and brain preproglucagon (PPG) neurons, which respectively define the peripheral and central GLP-1 systems. PPG neurons in the nucleus tractus solitarii (NTS) have been assumed to link the peripheral and central GLP-1 systems in a unified gut-brain satiation circuit, in which GLP-1 released from the gut in response to meals acts via vagal and/or hormonal gut-brain pathways to trigger central release of GLP-1 from PPGNTS neurons to suppress further eating. However, direct evidence for this hypothesis is lacking, and the gut-brain connectivity necessary for this circuit has not been demonstrated.
We tested this hypothesis using complementary circuit mapping and behavioural approaches in transgenic mouse models which allowed selective manipulation of neuronal populations within the peripheral and central GLP-1 systems. Contrary to the unified GLP-1 circuit hypothesis, we determined that PPGNTS neurons are not a major target of either vagal or hormonal signalling pathways from the peripheral GLP-1 system. Furthermore, PPGNTS neurons are not activated by or required for the anorectic effects of the GLP-1RA drugs semaglutide or liraglutide. Consistent with the alternative hypothesis that peripheral and central GLP-1 systems are anatomically and functionally distinct entities, we demonstrated that chemogenetic activation of PPGNTS neurons, concurrent with peripheral semaglutide administration, suppressed eating more potently than either manipulation alone. Furthermore, this apparently additive effect could be replicated pharmacologically, as the 5-HT2CR agonist anti-obesity drug lorcaserin required PPGNTS neurons for its anorectic effect, and individually anorexigenic doses of lorcaserin and liraglutide suppressed eating to a greater extent when administered concurrently than either monotherapy alone.
We therefore conclude that central and peripheral GLP-1 systems suppress eating via apparently independent gut-brain circuits, providing a rationale for investigation of strategies for additive pharmacological manipulation of these systems for the treatment of obesity.