Leptin regulates energy balance by suppressing appetite and increasing energy expenditure through actions in the hypothalamus. Recently we demonstrated that the effects of leptin are, at least in part, mediated by the release of interleukin (IL)-1beta in the brain. Microglia constitute the major source of IL-1beta in the brain but it is not known whether these cells express leptin receptors, or respond to leptin to produce IL-1beta. Using RT-PCR and immunocytochemistry, we demonstrate that primary rat microglial cells express the short (non-signalling) and long (signalling) isoforms of the leptin receptors (Ob-R)s. Immunoassays performed on cell medium collected 24 h after leptin treatment (0.01-10 microg/mL) demonstrated a dose-dependent production and release of IL-1beta and its endogenously occurring receptor antagonist IL-1RA. In addition leptin-induced IL-1beta release occurs via a signal transducer and activator of transcription 3 (STAT3)-dependent mechanism. Western blot analysis demonstrated that leptin induced the synthesis of pro-IL-1beta in microglial cells and the release of mature 17 kDa isoform into the culture medium. Leptin-induced IL-1beta release was neither inhibited by the pan-caspase inhibitor BOC-D-FMK, nor by the caspase 1 inhibitor Ac-YVAD-CHO indicating that IL-1 cleavage is independent of caspase activity. These results confirm our earlier observations in vivo and demonstrate that microglia are an important source of IL-1beta in the brain in response to leptin.