Central and peripheral GLP-1 systems independently and additively suppress eating

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. As peripheral satiation signals are integrated in the nucleus tractus solitarius (NTS), PPG neurons are assumed to link the peripheral and central GLP-1 systems, forming a unified GLP-1 gut-brain satiation circuit. This hypothesis, however, remains unsubstantiated. We report that PPG neurons encode satiation in mice, consistent with vagal gastrointestinal distension signalling. However, PPG neurons predominantly receive vagal input from oxytocin receptor-expressing vagal neurons, rather than those expressing GLP-1 receptors. Furthermore, PPG neurons are not necessary for eating suppression induced by the GLP-1 receptor agonists liraglutide or semaglutide, and semaglutide and PPG neuron activation additively suppress eating. Central and peripheral GLP-1 systems thus suppress eating via independent gut-brain circuits, hence PPG neurons represent a rational pharmacological target for anti-obesity combination therapy with GLP-1 receptor agonists.