Leptin regulates energy homeostasis and reproduction. One key population of leptin receptors (Lepr) are found on proopiomelanocortin (POMC) neurons in the hypothalamic arcuate nucleus, and evidence links the action of gonadal estrogens to these same POMC neurons. To determine whether Lepr on POMC neurons are critical for reproductive capacity or for sex-specific energy and glucose homeostasis, we studied Cre/loxP mice lacking Lepr specifically on POMC neurons (Pomc-Cre, Lepr flox/flox mice) and their controls with normal Lepr (Lepr flox/flox mice). Pomc-Cre, Lepr flox/flox mice maintained normal reproductive capacity and accumulated more body fat than their same sex controls. Ovariectomy (OVX) was performed to investigate the effects of the estrogens and Lepr on POMC neurons on body fat accumulation and glucose tolerance. OVX Pomc-Cre, Lepr flox/flox females accumulated more fat than OVX Lepr flox/flox females did. Pomc-Cre, Lepr flox/flox males were glucose intolerant and insulin insensitive compared with control males. In contrast, control and Pomc-Cre, Lepr flox/flox females had similar glucose tolerance before and after OVX. Therefore leptin's action on POMC neurons reduces body fat accumulation, but is not critical for regulation of reproduction. The sex difference in leptin signaling on POMC neurons on glucose tolerance appears independent of ovarian hormones.