The past 20 years witnessed an enormous leap in understanding of the central regulation of whole-body energy metabolism. Genetic tools have enabled identification of the region-specific expression of peripheral metabolic hormone receptors and have identified neuronal circuits that mediate the action of these hormones on behavior and peripheral tissue functions. One of the surprising findings of recent years is the observation that brain circuits involved in metabolism regulation remain plastic through adulthood. In this review, we discuss these findings and focus on the role of neurons and glial cells in the dynamic process of plasticity, which is fundamental to the regulation of physiological and pathological metabolic events.