Laboratory of Clinical Chemistry, School of Medicine, University of Crete, Heraklion, 71003 Crete, Greece.
Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology Hellas, Heraklion, 71110 Crete, Greece.
J Immunol. 2019 Mar 15;202(6):1786-1797. doi: 10.4049/jimmunol.1800065. Epub 2019 Feb 4.
Obesity and insulin resistance influences metabolic processes, but whether it affects macrophage metabolism is not known. In this study, we demonstrate that chronic exposure of macrophages to insulin either in culture or in vivo in diet-induced, glucose-intolerant mice rendered them resistant to insulin signals marked by failure to induce Akt2 phosphorylation. Similarly, macrophages lacking Akt2 or IGF1 receptor were also resistant to insulin signals. Insulin-resistant macrophages had increased basal mTORC1 activity, possessed an M2-like phenotype, and reduced LPS responses. Moreover, they exhibited increased glycolysis and increased expression of key glycolytic enzymes. Inhibition of mTORC1 reversed the M2-like phenotype and suppressed glycolysis in insulin-resistant macrophages. In the context of polymicrobial sepsis, mice harboring insulin-resistant macrophages exhibited reduced sepsis-induced lung injury. Thus, macrophages obtain resistance to insulin characterized by increased glycolysis and a unique M2-like phenotype, termed M-insulin resistant, which accounts for obesity-related changes in macrophage responses and a state of trained immunity.
肥胖和胰岛素抵抗会影响代谢过程，但尚不清楚它是否会影响巨噬细胞的代谢。在这项研究中，我们证明了巨噬细胞在培养中或在饮食诱导的葡萄糖不耐受小鼠体内的慢性胰岛素暴露使它们对胰岛素信号产生抗性，表现为 Akt2 磷酸化的诱导失败。同样，缺乏 Akt2 或 IGF1 受体的巨噬细胞也对胰岛素信号具有抗性。胰岛素抵抗的巨噬细胞具有更高的基础 mTORC1 活性，表现出 M2 样表型，并且 LPS 反应减少。此外，它们表现出增加的糖酵解和关键糖酵解酶的表达。抑制 mTORC1 可逆转 M2 样表型并抑制胰岛素抵抗的巨噬细胞中的糖酵解。在多微生物脓毒症的情况下，携带胰岛素抵抗的巨噬细胞的小鼠表现出减少的脓毒症诱导的肺损伤。因此，巨噬细胞获得了以增加的糖酵解和独特的 M2 样表型为特征的胰岛素抵抗，称为 M-胰岛素抵抗，这解释了肥胖相关的巨噬细胞反应变化和训练免疫状态。
