A reciprocal rhythmic pattern of 2 afferent hormonal signals, anorexigenic leptin and orexigenic ghrelin, imparts rhythmicity to the neuropeptide Y (NPY) system, the final common pathway for appetite expression in the hypothalamus. We now show that leptin inhibits both the secretion of gastric ghrelin and the stimulation of feeding by ghrelin. We propose that this dual leptin restraint is the major regulatory arm of the feedback communication between the periphery and the hypothalamus for weight homeostasis, and disruption in the rhythmic communication at any locus in the leptin-ghrelin-NPY feedback loop impels loss of hypothalamic control, leading to abnormal weight gain and obesity.