The non-LepR subset may play a role similar to the known leptin-sensitive AgRP neurons, which, once activated, cause massive obesity.18,25 Related to this, ob/ob or db/db mice, both with functional leptin deficiency, associated with increased neuron activity in the Arc,22 presumably due to loss of inhibitory action by leptin on LepR neurons, are severely obese. The gene discussed is LEPR; the disease is obesity due to melanocortin 4 receptor deficiency.