Leptin-deficient (Lep(ob/ob)) mice are obese, diabetic, and infertile. Ablation of neurons that make agouti-related protein (AgRP) in moderately obese adult Lep(ob/ob) mice caused severe anorexia. The mice stopped eating for 2 wk and then gradually recovered. Their body weight fell to within a normal range for WT mice, at which point food intake and glucose tolerance were restored to that of WT mice. Remarkably, both male and female Lep(ob/ob) mice became fertile. Ablation of neurons that express melanin-concentrating hormone (MCH) in adult Lep(ob/ob) mice had no effect on food intake, body weight, or fertility, but resulted in improved glucose tolerance. We conclude that AgRP-expressing neurons play a critical role in mediating the metabolic syndrome and infertility of Lep(ob/ob) mice, whereas MCH-expressing neurons have only a minor role.