Since activation of hypothalamic CB1R has been shown to modulate feeding, energy balance, and activity [42], [43], [44], [45], [46], our findings of upregulation of hypothalamic eCB ‘tone’ in Magel2-null mice fed either a STD or a HFD may further provide evidence that the eCB system plays a direct and critical role in developing hyperphagia and obesity as well as in altering the metabolic profile in PWS. Here, MAGEL2 is linked to Prader-Willi syndrome.