Consequently, the observation that the eCB/CB1R system is overactive in humans with obesity and in genetic- and diet-induced obese animals [7,[11], [12], [13], [14], [15], [16],30,[38], [39], [40], [41]] led to preclinical developments and clinical efforts to test CB1R antagonists for the treatment of the metabolic syndrome. This evidence concerns the gene CNR1 and obesity due to melanocortin 4 receptor deficiency.