Leptin Induces Macrophage Lipid Body Formation by a Phosphatidylinositol 3-Kinase- and Mammalian Target of Rapamycin-dependent Mechanism

Abstract

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 bodydependent 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.

Leptin and mTOR: Partners in metabolism and inflammation

“…66 Leptin-induced ADRP-enriched lipid bodies were blunted by rapamycin treatment. Taken together with the ability of leptin to induce the time-and dose-dependent P70S6K and 4EBP1 phosphorylation in a rapamycin-sensitive way, these data strongly suggest that leptin-induced increased cellular levels of ADRP depend on translational control through mTOR-dependent activation 14 (Fig. 2).…”

“…There is much interest on the regulation of ADRP as a key event in both adipocyte differentiation and macrophage foam cell formation. Interestingly, leptin-induced lipid body accumulation in macrophages in vivo or in vitro is accompanied by increased levels of ADRP, 14 demonstrating that leptin directly regulates the increase in ADRP cell content and accumulation of lipids within ADRP-enriched lipid bodies in macrophages and may have a role in foam cell formation. Increased ADRP expression by itself has been shown to be directly related to the enhanced capacity of neutral lipid storage, as ADRP promotes triglycerides and cholesterol storage and reduces cholesterol efflux.…”

“…43 This was also the case for leukemia cells, where rapamycin derivatives were able to inhibit both TORC1 and TORC2. 44 In both the hypothalamus and macrophages, leptin's effects on mTOR are sensitive to rapamycin, 14,39 thus indicating that these effects involve the activation of the TORC1 complex.…”

“…The macrophage shown is this figure was stained with Oil Red O evidencing lipid bodies in red, after leptin stimulation as described in. 14 Figure 2. Leptin activation of macrophages.…”

“…11 In macrophages, leptin acts as a potent chemoatractant and induces the production of inflammatory mediators including LTB 4 , TNFα and IL-6 among others. [12][13][14] Lymphocytes are also activated by leptin, which stimulates the proliferation of Th1 cells, leading to increased production of IL-1 and IFNγ. Such activation may play a role on the development of autoimmune diseases.…”