Instead, eCB signalling at CB2 receptors, on the one hand, and the activation of other eCBome receptors, such as peroxisome proliferator-activated receptors (PPAR)-α and -γ [22], orphan GPCRs including GPR18 [23], GPR55 [24], and GPR119 [25] and transient receptor vanilloid-type-1 (TRPV1) [26] channels by other NAEs [27], 2-MAGs [28] and NAAs [15], on the other hand, may counteract the obesity/T2D-worsening effects of excessive CB1 activation in peripheral organs, as well as its pro-addictive actions, without interfering with CB1 crucial functions in the brain. The gene discussed is CNR1; the disease is obesity due to melanocortin 4 receptor deficiency.