Here, we consider 3 related questions raised by this paradox: (a) does AgRP neuron inhibition mediate leptin-induced anorexia; (b) does leptin act directly on AgRP neurons to inhibit them, or indirectly by activating inhibitory neurons lying upstream; and (c) are hyperphagia and obesity in leptin-deficient mice driven by activation of AgRP neurons, non-AgRP neurons, or both? This evidence concerns the gene LEP and Obesity.