Leptin regulates energy balance, in part, by modulating the activity of neuropeptide Y (NPY) and proopiomelanocortin (POMC) neurons in the hypothalamic arcuate nucleus. Leptin-deficient (ob/ob) mice differ from wild-type mice in the number of excitatory and inhibitory post-synaptic densities and currents onto NPY and POMC neurons. When leptin was delivered to ob/ob mice, the synaptic density rapidly normalized, an effect detectable within 6 hours, several hours before leptin's effect on food intake. Synaptic currents were also shifted toward wild-type values in leptin-replaced ob/ob mice. These data suggest that leptin-mediated plasticity in the ob/ob hypothalamus may underlie some of the hormone's behavioral effects. In an effort to determine whether the observed synaptic plasticity is leptin specific, we analyzed the effects of an orexigenic hormone, ghrelin, and anorexigenic hormone, estradiol. Ghrelin rearranged synapses in wild type animals to support suppressed POMC tone, whereas the estradiol triggered a robust increase in the number of excitatory, glutamate inputs of POMC neurons. The rearrangement of synapses by estradiol was leptin independent, because it was also evident in leptin- (ob/ob) and leptin receptor–deficient (db/db) mice and was paralleled with decreased food intake and increased energy expenditure in these mutant, obese animals. Such plasticity was also observed in other hypothalamic regions and extrahypothalamic sites. These observations raise the notion that synaptic plasticity is a major way through which peripheral metabolic hormones influence brain functions.