Obesity is a serious and growing public health problem in the United States and the world. The pathophysiological processes that underlie the increasing prevalence of obesity have not been clearly defined but likely involve faulty interactions between environmental factors, which favor positive energy balance, and weight regulatory systems in genetically susceptible individuals. Individuals who are genetically predisposed to thinness in the current environment may be able to sense and respond to excess energy intake more rapidly and accurately than those predisposed to obesity. The regulation of energy intake and therefore the potential adaptation to changes in energy balance is a complex process with interactions between homeostatic and non-homeostatic signals likely being critical. We have observed that thin (obese-resistant) individuals quickly sense changes in positive energy balance with not only changes in measures of appetite but also in brain regions important for the regulation of energy intake. This is in contrast to reduced-obese (obese-prone) individuals who do not appear to appropriately sense the changes in positive energy balance, suggesting that there is a differential sensitivity to positive energy balance between obese-resistant and obese-prone individuals. We have also found evidence for important interactions between external food cues and activation of brain regions important in the homeostatic regulation of energy balance. These findings emphasize the important role of environmental visual cues and suggest that there are important phenotypic differences in the interactions between external visual sensory inputs, energy balance status, and brain regions important in the regulation of energy intake.