Knowledge of how the brain contributes to the regulation of food intake in humans is limited. We used positron emission tomography and measures of regional cerebral blood flow (rCBF) (a marker of neuronal activity) to describe the functional anatomy of satiation (i.e., the response to a liquid meal) in the context of extreme hunger (36-h fast) in 11 obese (BMI ≥35 kg/m 2 , age 27 ± 5 years, weight 115 ± 11 kg, 38 ± 7% body fat; mean ± SD) and 11 lean (BMI ≤25 kg/m 2 , age 35 ± 8 years, weight 73 ± 9 kg, 19 ± 6% body fat) men. As in lean men, satiation in obese men produced significant increases in rCBF in the vicinity of the ventromedial and dorsolateral prefrontal cortex and significant decreases in rCBF in the vicinity of the limbic/paralimbic areas (i.e., hippocampal formation, temporal pole), striatum (i.e., caudate, putamen), precuneus, and cerebellum. However, rCBF increases in the prefrontal cortex were significantly greater in obese men than in lean men (P < 0.005). rCBF decreases in limbic/paralimbic areas, temporal and occipital cortex, and cerebellum were also significantly greater in obese men than in lean men (P < 0.005), whereas rCBF decreases in the hypothalamus and thalamus were attenuated in obese men compared with lean men (P < 0.05). This study raises the possibility that the brain responses to a meal in the prefrontal areas (which may be involved in the inhibition of inappropriate response tendencies) and limbic/paralimbic areas (commonly associated with the regulation of emotion) may be different in obese and lean men. Additional studies are required to investigate how these differential responses are related to the pathophysiology of obesity. Diabetes 49:838-846, 2000 O besity is a chronic relapsing disease with a prevalence reaching epidemic proportions in most industrialized countries (1,2). Whereas the exact pathophysiology of this disease remains unclear, studies in animals (3,4) and numerous reports in humans (5-10) indicate that eating behavior disorders (i.e., hyperphagia) and the resulting excessive energy intake play a major role in the development of obesity.The role of the brain (especially the hypothalamus) in the regulation of body weight is well established in animals (11). In humans, substantial molecular (12) and neuropharmacologic evidence (13) attest to the importance of the central nervous system in maintaining energy balance. However, the neuroanatomical correlates of human feeding behavior are largely unknown. Some information comes from pathological conditions associated with hyperphagia and obesity such as hypothalamic tumors (14) and Prader-Willi syndrome, the most common type of inherited human hypothalamic disorder (15). In addition, patients with frontal lobe dementia with computerized tomography documented prefrontal atrophy frequently present with hyperphagia (16). Furthermore, seizures of the opercula (including the insular cortex) induce mastication, salivation, swallowing, and gustatory hallucinations (17). Finally, in 1 study, 50% of patients with eating epi...