One of the most striking examples of dysfunctional hypothalamic signaling of energy homeostasis is observed in patients with hypothalamic lesions leading to hypothalamic obesity (HO). This drastic condition is frequently seen in patients with craniopharyngioma (CP), an embryological tumor located in the hypothalamic and/or pituitary region, frequently causing not only hypopituitarism, but also leading to damage of medial hypothalamic nuclei due to the tumor and its treatment. HO syndrome in CP patients is characterized by fatigue, decreased physical activity, uncontrolled appetite, and morbid obesity, and is associated with insulin and leptin resistance. Mechanisms leading to the profoundly disturbed energy homeostasis are complex. The Roth lab is currently utilizing a novel rat model of hypothalamic obesity, generated by targeting electrolytic lesions to the arcuate nucleus, ventromedial hypothalamic nucleus and dorsomedial hypothalamic nucleus of the brain, to identify potential therapies. These combined medial hypothalamic lesions induce hyperphagia, rapid weight gain, hyperinsulinemia, hyperleptinemia, and adiposity; the common characteristics of HO syndrome in CP patients.