结肠促炎巨噬细胞通过肠道 Ccl2/Ccr2 依赖性途径引起胰岛素抵抗。
Colonic Pro-inflammatory Macrophages Cause Insulin Resistance in an Intestinal Ccl2/Ccr2-Dependent Manner.
机构信息
Division of Endocrinology, Metabolism, and Nephrology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan.
Division of Endocrinology, Metabolism, and Nephrology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan.
出版信息
Cell Metab. 2016 Aug 9;24(2):295-310. doi: 10.1016/j.cmet.2016.07.009.
High-fat diet (HFD) induces low-grade chronic inflammation and insulin resistance. However, little is known about the mechanism underlying HFD-induced chronic inflammation in peripheral insulin-responsive tissues. Here, we show that colonic pro-inflammatory macrophages regulate insulin sensitivity under HFD conditions. To investigate the pathophysiological role of colonic macrophages, we generated macrophage-specific chemokine (C-C Motif) receptor 2 (Ccr2) knockout (M-Ccr2KO) and intestinal epithelial cell-specific tamoxifen-inducible Ccl2 knockout (Vil-Ccl2KO) mice. Both strains exhibited similar body weight to control under HFD. However, they exhibited decreased infiltration of colonic pro-inflammatory macrophages, decreased intestinal permeability, and inactivation of the colonic inflammasome. Interestingly, they showed significantly improved glucose tolerance and insulin sensitivity with decreased chronic inflammation of adipose tissue. Therefore, inhibition of pro-inflammatory macrophage infiltration prevents HFD-induced insulin resistance and could be a novel therapeutic approach for type 2 diabetes.
高脂肪饮食（HFD）可引发低度慢性炎症和胰岛素抵抗。然而，人们对于 HFD 诱导外周胰岛素反应组织慢性炎症的机制知之甚少。在这里，我们发现结肠促炎巨噬细胞可调节 HFD 条件下的胰岛素敏感性。为了研究结肠巨噬细胞的病理生理作用，我们生成了巨噬细胞特异性趋化因子（C-C 基序）受体 2（Ccr2）敲除（M-Ccr2KO）和肠上皮细胞特异性他莫昔芬诱导型 Ccl2 敲除（Vil-Ccl2KO）小鼠。这两种品系在 HFD 下的体重与对照品系相似。然而，它们的结肠促炎巨噬细胞浸润减少，肠道通透性降低，结肠炎症小体失活。有趣的是，它们表现出明显改善的葡萄糖耐量和胰岛素敏感性，同时脂肪组织的慢性炎症减少。因此，抑制促炎巨噬细胞浸润可预防 HFD 诱导的胰岛素抵抗，可能成为 2 型糖尿病的一种新的治疗方法。
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