Moreover, our study demonstrates that (i) chronic blockade of CB1R in the periphery is as effective as globally acting CB1R antagonism in reversing obesity and its metabolic abnormalities in an established mouse model for PWS, and (ii) the disrupted body composition and energy balance in Magel2-null mice is associated with increased eCB ‘tone’ in the hypothalamus. Here, CNR1 is linked to obesity due to melanocortin 4 receptor deficiency.