The proinflammatory cytokine macrophage migration inhibitory factor regulates glucose metabolism during systemic inflammation
The proinflammatory cytokine macrophage migration inhibitory factor regulates glucose metabolism during systemic inflammation
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DOI：
10.4049/jimmunol.179.8.5399
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发表时间：
2007-10-15
影响因子：
4.4
通讯作者：
Bucala, Richard
中科院分区：
文献类型：
--
作者：
Atsumi, Toshiya;Cho, You-Ree;Bucala, Richard
炎症引起宿主代谢的显著异常，这是由细胞因子的全身释放引起的。宿主的早期反应是高血糖症和对胰岛素作用的抵抗，其随时间发展为外周组织中葡萄糖摄取增加。尽管细胞因子TNF-α已显示出发挥某些分解代谢作用，但最近的研究表明TNF-α的代谢作用通过另外的介质（例如巨噬细胞迁移抑制因子（MIF））的下游调节而发生。我们研究了MIF基因缺陷的内毒素血症小鼠（MIF-/-）的血糖反应。与野生型小鼠相比，MIF-/-小鼠在给予内毒素或TNF-α后表现出正常的血糖和乳酸反应。在内毒素血症状态下，MIF-/-小鼠体内白色脂肪组织的葡萄糖摄入也显着增加。用MIF或抗MIF mAb处理脂肪细胞可调节胰岛素介导的葡萄糖转运和胰岛素受体信号转导;这些作用包括胰岛素受体底物-1的磷酸化、其与PI 3 K的p85调节亚基的结合以及Akt的下游磷酸化。遗传性MIF缺陷也促进脂肪形成，这与MIF在TNF-α作用中的下游作用雅阁。这些研究支持MIF在脓毒症期间在宿主葡萄糖代谢中的重要作用。
Inflammation provokes significant abnormalities in host metabolism that result from the systemic release of cytokines. An early response of the host is hyperglycemia and resistance to the action of insulin, which progresses over time to increased glucose uptake in peripheral tissue. Although the cytokine TNF-alpha has been shown to exert certain catabolic effects, recent studies suggest that the metabolic actions of TNF-a occur by the downstream regulation of additional mediators, such as macrophage migration inhibitory factor (MIF). We investigated the glycemic responses of endotoxemic mice genetically deficient in MIF (MIF-/-). In contrast to wild-type mice, MIF-/- mice exhibit normal blood glucose and lactate responses following the administration of endotoxin, or TNF-alpha. MIF-/- mice also show markedly increased glucose uptake into white adipose tissue in vivo in the endotoxemic state. Treatment of adipocytes with MIF, or anti-MIF mAb, modulates insulin-mediated glucose transport and insulin receptor signal transduction; these effects include the phosphorylation of insulin receptor substrate-1, its association with the p85 regulatory subunit of PI3K, and the downstream phosphorylation of Akt. Genetic MIF deficiency also promotes adipogenesis, which is in accord with a downstream role for MIF in the action of TNF-alpha. These studies support an important role for MIF in host glucose metabolism during sepsis.