Coupled with the accentuated EC- and N/OFQ-induced presynaptic inhibition of glutamatergic input from SF-1 neurons onto POMC neurons, it stands to reason that the enhancement of this Gi/o-coupled metabotropic receptor-mediated response may represent a more global form of adaptive plasticity occurring with diet-induced obesity/insulin resistance at these synapses (see Fig. 15). Here, POMC is linked to obesity due to melanocortin 4 receptor deficiency.