TI - Leptin induces macrophage lipid body formation by a phosphatidylinositol 3 - kinase - and mammalian target of rapamycin -dependent mechanism . AB - 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 B(4) synthesis in macrophages . Our results demonstrated that leptin directly activated macrophages and induced the formation of adipose differentiation-related protein -enriched lipid bodies . Newly formed lipid bodies were sites of 5-lipoxygenase localization and correlated with an enhanced capacity of leukotriene B(4) production . We demonstrated that leptin-induced macrophage activation was dependent on phosphatidylinositol 3-kinase ( PI3K ) activity , since the lipid body formation was inhibited by LY294002 and was absent in the PI3K knock-out mice . Leptin induces phosphorylation of p70 (S6K) and 4EBP1 key downstream signaling intermediates of the mammalian target of rapamycin ( 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 adipose differentiation-related protein 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 adipose differentiation-related protein 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 for obesity-related cardiovascular diseases .