State Key Laboratory of Agrobiotechnology, College of Biological Science, China Agricultural University, Beijing, China.
Department of Surgery, Medical University of South Carolina, Charleston, South Carolina.
Am J Physiol Endocrinol Metab. 2020 Jun 1;318(6):E1004-E1013. doi: 10.1152/ajpendo.00542.2019. Epub 2020 Mar 24.
Macrophage polarization contributes to obesity-induced insulin resistance. Glucose-regulated protein 94 (GRP94) is an endoplasmic reticulum (ER) chaperone specialized for folding and quality control of secreted and membrane proteins. To determine the role of GRP94 in macrophage polarization and insulin resistance, macrophage-specific GRP94 conditional knockout (KO) mice were challenged with a high-fat diet (HFD). Glucose tolerance, insulin sensitivity, and macrophage composition were compared with control mice. KO mice showed better glucose tolerance and increased insulin sensitivity. Adipose tissues from HFD-KO mice contained lower numbers of M1 macrophages, with lower expression of M1 macrophage markers, than wild-type (WT) mice. In vitro, WT adipocytes cocultured with KO macrophages retained insulin sensitivity, whereas those cultured with WT macrophages did not. In addition, compared with WT bone marrow-derived macrophages (BMDMs), BMDMs from GRP94 KO mice exhibited lower expression of M1 macrophage marker genes following stimulation with LPS or IFN-γ, and exhibited partially increased expression of M2 macrophage marker genes following stimulation with interleukin-4. These findings identify GRP94 as a novel regulator of M1 macrophage polarization and insulin resistance and inflammation.
巨噬细胞极化导致肥胖引起的胰岛素抵抗。葡萄糖调节蛋白 94（GRP94）是内质网（ER）伴侣蛋白，专门用于折叠和分泌蛋白和膜蛋白的质量控制。为了确定 GRP94 在巨噬细胞极化和胰岛素抵抗中的作用，用高脂肪饮食（HFD）挑战巨噬细胞特异性 GRP94 条件性敲除（KO）小鼠。比较了 KO 小鼠与对照小鼠的葡萄糖耐量、胰岛素敏感性和巨噬细胞组成。KO 小鼠表现出更好的葡萄糖耐量和增加的胰岛素敏感性。HFD-KO 小鼠的脂肪组织中 M1 巨噬细胞数量较少，M1 巨噬细胞标志物的表达也低于野生型（WT）小鼠。在体外，WT 脂肪细胞与 KO 巨噬细胞共培养时保持胰岛素敏感性，而与 WT 巨噬细胞共培养时则没有。此外，与 WT 骨髓来源的巨噬细胞（BMDMs）相比，用 LPS 或 IFN-γ刺激时，来自 GRP94 KO 小鼠的 BMDMs 中 M1 巨噬细胞标记基因的表达较低，而在用白细胞介素-4 刺激时，M2 巨噬细胞标记基因的表达部分增加。这些发现确定了 GRP94 是 M1 巨噬细胞极化和胰岛素抵抗以及炎症的新型调节剂。
