Ghrelin was initially described a stomach hormone that regulates growth hormone release, appetite and adiposity. However recent studies highlight that ghrelin targets the brain to regulate a diverse number of processes including blood glucose, neuroprotection, learning and memory, stress and anxiety and reward. We consider ghrelin a signal of insufficient body energy stores and as such negative and positive energy balance increase and decrease plasma ghrelin respectively in animal models and in humans. This talk describes how metabolic status such as calorie restriction and diet-induced obesity affects the neuroendocrine ghrelin system. We show that diet-induced obesity affects the ability of ghrelin to induce appetite and regulate the reward pathways in the brain. In addition, we show that elevated ghrelin during calorie restriction mediates neuroprotection in models of Parkinson’s disease and helps to maintain blood glucose levels. We suggest the hypothesis that ghrelin has a positive effect on a diverse number of brain functions, in order to help promote food intake and shift an animal from negative to neutral energy balance.