Key Laboratory of Human Functional Genomics of Jiangsu Province, Biochemistry and Molecular Biology, Nanjing medical University, Nanjing, Jiangsu 211166, China.
Organ Transplant Center, Tianjin First Central Hospital, Nankai University, Tianjin 300192, China.
Cell Rep. 2021 Jan 5;34(1):108576. doi: 10.1016/j.celrep.2020.108576.
Type 2 diabetes mellitus (T2DM) is recognized as a chronic, low-grade inflammatory disease characterized by insulin resistance and pancreatic β cell dysfunction; however, the underlying molecular mechanism remains unclear. Here, we report a key β cell-macrophage crosstalk pathway mediated by the miRNA-29-TNF-receptor-associated factor 3 (TRAF3) axis. β cell-specific transgenic miR-29a/b/c mice are predisposed to develop glucose intolerance and insulin resistance when fed a high-fat diet (HFD). The metabolic effect of β cell miR-29 is largely mediated through macrophages because either depletion of macrophages or reconstitution with miR-29-signaling defective bone marrow improves metabolic parameters in the transgenic mice. Mechanistically, our data show that miR-29 promotes the recruitment and activation of circulating monocytes and macrophages and, hence, inflammation, via miR-29 exosomes in a TRAF3-dependent manner. Our results demonstrate the ability of β cells to modulate the systemic inflammatory tone and glucose homeostasis via miR-29 in response to nutrient overload.
2 型糖尿病（T2DM）被认为是一种慢性、低度炎症性疾病，其特征为胰岛素抵抗和胰岛β细胞功能障碍；然而，其潜在的分子机制尚不清楚。在这里，我们报告了一个由 miRNA-29-TNF 受体相关因子 3（TRAF3）轴介导的关键β细胞-巨噬细胞串扰途径。当喂食高脂肪饮食（HFD）时，β细胞特异性转基因 miR-29a/b/c 小鼠易发生葡萄糖不耐受和胰岛素抵抗。β 细胞 miR-29 的代谢作用主要是通过巨噬细胞介导的，因为巨噬细胞耗竭或用 miR-29 信号缺陷的骨髓重建均可改善转基因小鼠的代谢参数。从机制上讲，我们的数据表明，miR-29 通过 TRAF3 依赖性方式促进循环单核细胞和巨噬细胞的募集和激活，从而导致炎症。我们的结果表明，β 细胞能够通过 miR-29 响应营养过载来调节全身炎症状态和葡萄糖稳态。
