Blockade of class IB phosphoinositide-3 kinase ameliorates obesity-induced inflammation and insulin resistance
Blockade of class IB phosphoinositide-3 kinase ameliorates obesity-induced inflammation and insulin resistance
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DOI：
10.1073/pnas.1016430108
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发表时间：
2011-04-05
影响因子：
11.1
通讯作者：
Kadowaki, Takashi
中科院分区：
文献类型：
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作者：
Kobayashi, Naoki;Ueki, Kohjiro;Kadowaki, Takashi
肥胖和胰岛素抵抗是代谢综合征的主要特征，与以异常巨噬细胞浸润脂肪组织为特征的慢性低度炎症状态密切相关。尽管有报道称，趋化因子通过在炎症状态下激活 IB 类磷酸肌醇 3 激酶 (PI3K γ) 来促进白细胞迁移，但人们对 PI3K γ 在肥胖诱导的巨噬细胞浸润组织、全身炎症和胰岛素抵抗中的作用知之甚少。在本研究中，我们使用饮食诱导和遗传诱导的肥胖小鼠模型来研究 PI3K γ 在组织巨噬细胞积累和肥胖诱导的胰岛素抵抗发展中的作用。缺乏p110γ（Pik3cg（-/-））（PI3Kγ的催化亚基）的小鼠表现出改善的全身胰岛素敏感性，并且肥胖动物组织中的胰岛素信号传导增强。在肥胖Pik3cg(-/-)小鼠的脂肪组织和肝脏中，浸润的促炎巨噬细胞的数量显着减少，导致这些组织中的炎症反应受到抑制。此外，骨髓特异性缺失和 PI3K γ 的药理学阻断也改善了肥胖诱导的巨噬细胞浸润和胰岛素抵抗。这些数据表明，PI3K γ 在肥胖引起的炎症和全身胰岛素抵抗的发展中发挥着至关重要的作用，并且 PI3K γ 可以成为 2 型糖尿病的治疗靶点。
Obesity and insulin resistance, the key features of metabolic syndrome, are closely associated with a state of chronic, low-grade inflammation characterized by abnormal macrophage infiltration into adipose tissues. Although it has been reported that chemokines promote leukocyte migration by activating class IB phosphoinositide-3 kinase (PI3K gamma) in inflammatory states, little is known about the role of PI3K gamma in obesity-induced macrophage infiltration into tissues, systemic inflammation, and the development of insulin resistance. In the present study, we used murine models of both diet-induced and genetically induced obesity to examine the role of PI3K gamma in the accumulation of tissue macrophages and the development of obesity-induced insulin resistance. Mice lacking p110 gamma (Pik3cg(-/-)), the catalytic subunit of PI3K gamma, exhibited improved systemic insulin sensitivity with enhanced insulin signaling in the tissues of obese animals. In adipose tissues and livers of obese Pik3cg(-/-) mice, the numbers of infiltrated proinflammatory macrophages were markedly reduced, leading to suppression of inflammatory reactions in these tissues. Furthermore, bone marrow-specific deletion and pharmacological blockade of PI3K gamma also ameliorated obesity-induced macrophage infiltration and insulin resistance. These data suggest that PI3K gamma plays a crucial role in the development of both obesity-induced inflammation and systemic insulin resistance and that PI3K gamma can be a therapeutic target for type 2 diabetes.