LEP and obesity due to melanocortin 4 receptor deficiency: 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).