Central and peripheral GLP-1 systems independently 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. PPG neurons in the nucleus tractus solitarii (NTS) are widely assumed to link the peripheral and central GLP-1 systems in a unified gut-brain satiation circuit. However, direct evidence for this hypothesis is lacking, and the necessary circuitry remains to be demonstrated. Here we show that PPG^NTS neurons encode satiation in mice, consistent with vagal signalling of gastrointestinal distension. However, PPG^NTS neurons predominantly receive vagal input from oxytocin-receptor-expressing vagal neurons, rather than those expressing GLP-1 receptors. PPG^NTS neurons are not necessary for eating suppression by GLP-1 receptor agonists, and concurrent PPG^NTS neuron activation suppresses eating more potently than semaglutide alone. We conclude that central and peripheral GLP-1 systems suppress eating via independent gut-brain circuits, providing a rationale for pharmacological activation of PPG^NTS neurons in combination with GLP-1 receptor agonists as an obesity treatment strategy.