Combinatorial therapies are under intense investigation for the development of more efficient anti-obesity drugs, however little is known about how they act in brain to produce enhanced anorexia and weight loss. Objectives: The goal of this study was to identify the brain sites and neuronal populations engaged during the co-administration of GLP-1R and CCK1R agonists, an efficient combination therapy in obese rodents. Methods: We measured acute and long-term feeding and body weight responses, and neuronal activation pattern throughout the neuraxis and in specific neuronal subsets in response to GLP-1R and CCK1R agonists administered alone or in combination in lean and high-fat fed mice. We used PhosphoTRAP to obtain unbiased molecular markers for neuronal populations selectively activated by the combination of the two agonists. Results: The initial anorectic response to GLP-1R and CCK1R co-agonism was mediated by a reduction in meal size but over a few hours, a reduction in meal number accounted for the sustained feeding suppressive effect. The nucleus of the solitary tract (NTS) is one of the few brain sites where GLP-1R and CCK1R signaling interact to produce enhanced neuronal activation. None of the previously categorized NTS neuronal subpopulations relevant to feeding behaviour were implicated in this increased activation. However, we identified NTS/AP Calcrl+ neurons as targets of this treatment. Conclusions: Collectively these studies indicate that circuit-level integration of GLP-1R and CCK1R coagonism in discrete brain nuclei including the NTS produces enhanced rapid and sustained appetite suppression and weight loss.