Glucagon-like peptide-1 (GLP-1) acts as both an incretin hormone, and an anorexigenic neuropeptide, which has prompted the successful and ongoing development of GLP-1-based therapies for type 2 diabetes and obesity. Endogenous GLP-1 is produced by enteroendocrine cells in the gut, and preproglucagon (PPG) neurons in the brainstem, which are the defining populations of the peripheral and central GLP-1 systems, respectively. PPG neurons in the brainstem nucleus tractus solitarii (PPGNTS neurons) 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 has not been demonstrated. We used transgenic mice expressing Cre-recombinase under the glucagon (i.e. PPG) or GLP-1 receptor (Glp1r) promotors, coupled with viral targeting of Cre-dependent tracing and effector tools, to selectively map and interrogate gut-brain connectivity between the central and peripheral GLP-1 systems. This allowed us to test whether PPGNTS neurons have a role in physiological satiation, and whether endogenous or exogenous peripheral GLP-1 signalling drives central GLP-1-induced suppression of eating. We report that PPGNTS neurons encode satiation specifically during large meals, and have the capability for pharmacological activation to suppress eating without compensatory rebound hyperphagia or behavioural disruption. Activation of Glp1r vagal afferent neurons similarly suppressed intake, but conditioned a flavour avoidance, and circuit mapping approaches demonstrated that PPGNTS neurons are not a major synaptic target of this vagal population. PPGNTS neurons instead predominantly receive vagal input from oxytocin receptor-expressing vagal afferent neurons, and are necessary for peripheral oxytocin-induced eating suppression. Similarly, PPGNTS neurons are at most a minor synaptic target of Glp1r neurons in the area postrema, suggesting that endocrine GLP-1 signalling from the periphery by this route does not require PPGNTS neurons. Consistent with this observation, PPGNTS neurons are not activated by peripheral administration of the Glp1r agonist semaglutide, nor are they required for semaglutide-induced suppression of eating or bodyweight loss. Furthermore, chemogenetic activation of PPGNTS neurons concurrent with peripheral semaglutide administration suppresses eating more potently than semaglutide alone. We therefore conclude that the unified peripheral to central GLP-1 satiation circuit hypothesis is not supported, but that the peripheral and central GLP-1 systems are instead components of functionally and anatomically independent eating control circuits. These findings provide a rationale for pharmacological activation of PPGNTS neurons in combination with GLP-1 receptor agonists as an obesity treatment strategy.