Leptin is an adipocyte-derived hormone/cytokine that links nutritional status with neuroendocrine and immune functions. Lipid bodies (lipid droplets) are emerging as dynamic organelles with roles in lipid metabolism and inflammation. Here we investigated the roles of leptin in signaling pathways involved in cytoplasmic lipid body biogenesis and leukotriene (LT) B4 synthesis in macrophages. Our results demonstrated that leptin directly activated macrophages and induced the formation of ADRP-enriched lipid bodies. Newly formed lipid bodies were sites of 5-lipoxygenase localization, and correlated with an enhanced capacity of LTB4 production. We demonstrated that leptin-induced macrophage activation was dependent on PI3K activity, as the lipid body formation was inhibited by LY294002, and was absent in the PI3K knockout mice. Leptin induced phosphorylation of p70 S6K and 4EBP1 key downstream signaling intermediates of mTOR pathway in a rapamycin-sensitive mechanism The mTOR inhibitor, rapamycin, inhibited leptin-induced lipid body formation, both in vivo and in vitro. In addition, rapamycin inhibited leptin-induced ADRP accumulation in macrophages and lipid body-dependent leukotriene synthesis, demonstrating a key role for mTOR in lipid body biogenesis and function. Our results establish PI3K/mTOR as an important signaling pathway for leptin induced cytoplasmic lipid body biogenesis and ADRP accumulation. Furthermore, we demonstrate a previously unrecognized link between intracellular (mTOR) and systemic (leptin) nutrient sensors in macrophage lipid metabolism. Leptin-induced increased formation of cytoplasmic lipid bodies and enhanced inflammatory mediator production in macrophages may have implications to obesity-related cardiovascular diseases.