Abstract The appetite suppressing hormone, leptin is now established as an important component of the immune response to pathogens partly via the induction of brain IL-1β. We have previously demonstrated that this hormone acts on microglia to induce the release of IL-1β through actions on its functional receptors. In the present study, we extended these findings by demonstrating that leptin’s action on microglia is that of a modulator rather than a direct trigger of inflammation. Using primary microglia cultures prepared from rat brain we show that pre-incubation of these cells with leptin for 24h prior to treatment with LPS increased the IL-1β output 2-fold. This effect was not limited to IL-1β but was also true for another cytokine, TNF-α and chemokines such as CINC-1 and MIP-2. The role of leptin in potentiating the microglial response to LPS appeared to be linked to morphological changes rendering the microglia more reactive. These results suggest that leptin has an important role in microglial function in inflammation and given that its circulating levels fluctuate across a number of conditions, these findings can have important implications for an individual’s ability to mount an efficient and complete response to invading pathogens.