By contrast, other studies have shown that global GIPR-KO mice are protected from both obesity and insulin resistance when fed a high-fat diet (31–35), and GIPR antagonism coupled with GLP-1R agonism leads to weight loss in early clinical trials and mouse models (36, 37), possibly by preventing leptin resistance (16, 38, 39). This evidence concerns the gene GLP1R and obesity due to melanocortin 4 receptor deficiency.