Collectively, we here show for the first time that GIPR signaling in cells that express the leptin receptor are not implicated in the regulation of body weight and food intake, but that lack of GIPR signaling in Lepr cells diminishes the glycemic beneficial effects of acyl-GIP and of GIPR:GLP-1R co-agonism under conditions of diet-induced obesity. Here, GLP1R is linked to obesity due to melanocortin 4 receptor deficiency.