Kupffer cell activation is a causal factor for hepatic insulin resistance
Kupffer cell activation is a causal factor for hepatic insulin resistance
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DOI：
10.1152/ajpgi.00391.2009
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发表时间：
2010-01-01
影响因子：
4.5
通讯作者：
Leclercq, Isabelle A.
中科院分区：
文献类型：
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作者：
Lanthier, Nicolas;Molendi-Coste, Olivier;Leclercq, Isabelle A.
Lanthier N，Molendi-Coste O，Horsmans Y，货车Rooijen N，Cani PD，Leclercq IA.枯否细胞活化是肝脏胰岛素抵抗的一个致病因素。美国生理学胃肠和肝脏生理学杂志298：G107-G116，2010年。首次发表于2009年10月29日; doi：10.1152/ajpgi.00391.2009。招募的脂肪组织巨噬细胞有助于慢性和低度炎症，导致肥胖症的胰岛素抵抗。同样地，我们在此假设枯否细胞，肝内巨噬细胞，在高脂饮食诱导的肝胰岛素抵抗中起致病作用。给小鼠喂食正常饮食或高脂肪饮食3天。通过免疫组化和定量RT-PCR评价枯否细胞活化。通过高胰岛素-正葡萄糖钳夹技术在体内评估胰岛素敏感性，并通过蛋白质印迹法研究胰岛素激活的信号传导。在短期暴露于高脂饮食之前，静脉注射脂质体包封的氯膦酸盐以消耗巨噬细胞。在这里，我们在小鼠中描述了短期高脂饮食模型的特征，并证明了早期肝脏胰岛素抵抗和脂肪变性与枯否细胞活化同时发生。我们证明，在这种短期高脂饮食模型中，通过静脉注射氯膦酸二钠获得的选择性枯否细胞耗竭，在不影响脂肪组织巨噬细胞的情况下，足以增强胰岛素依赖性胰岛素信号传导，并显着改善体内肝脏胰岛素敏感性。我们的研究清楚地表明，肝脏巨噬细胞反应参与高脂饮食诱导的肝脏胰岛素抵抗的发生，因此可能是预防和治疗饮食和肥胖诱导的胰岛素抵抗的一个有吸引力的目标。
Lanthier N, Molendi-Coste O, Horsmans Y, van Rooijen N, Cani PD, Leclercq IA. Kupffer cell activation is a causal factor for hepatic insulin resistance. Am J Physiol Gastrointest Liver Physiol 298: G107-G116, 2010. First published October 29, 2009; doi:10.1152/ajpgi.00391.2009.-Recruited adipose tissue macrophages contribute to chronic and low-grade inflammation causing insulin resistance in obesity. Similarly, we hypothesized here that Kupffer cells, the hepatic resident macrophages, play a pathogenic role in hepatic insulin resistance induced by a high-fat diet. Mice were fed a normal diet or high-fat diet for 3 days. Kupffer cell activation was evaluated by immunohistochemistry and quantitative RT-PCR. Insulin sensitivity was assessed in vivo by hyperinsulinemic-euglycemic clamp and insulin-activated signaling was investigated by Western blot. Liposome-encapsulated clodronate was injected intravenously to deplete macrophages prior to a short-term exposure to high-fat diet. Here, we characterized a short-term high-fat diet model in mice and demonstrated early hepatic insulin resistance and steatosis concurrent with Kupffer cell activation. We demonstrated that selective Kupffer cell depletion obtained by intravenous clodronate, without affecting adipose tissue macrophages, was sufficient to enhance insulin-dependent insulin signaling and significantly improve hepatic insulin sensitivity in vivo in this short-term high-fat diet model. Our study clearly shows that hepatic macrophage response participates to the onset of high-fat diet-induced hepatic insulin resistance and may therefore represent an attractive target for prevention and treatment of diet-and obesity-induced insulin resistance.