IKK-β links inflammation to obesity-induced insulin resistance
IKK-β links inflammation to obesity-induced insulin resistance
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DOI：
10.1038/nm1185
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发表时间：
2005-02-01
期刊：
影响因子：
82.9
通讯作者：
Karin, M
中科院分区：
文献类型：
--
作者：
Arkan, MC;Hevener, AL;Karin, M
炎症可能是胰岛素抵抗和2型糖尿病的代谢紊乱的基础。IkappaB激酶β （ikk - β，由Ikbkb编码）是通过NF-kappaB激活炎症反应的中心协调者。为了了解ikk - β在胰岛素抵抗中的作用，我们使用肝细胞（Ikbkb(Deltahep)）或髓细胞（Ikbkb(Deltamye)）缺乏这种酶的小鼠。Ikbkb（Deltahep）小鼠保持肝脏胰岛素反应，但在高脂肪饮食、肥胖或衰老的情况下，肌肉和脂肪会产生胰岛素抵抗。相比之下，Ikbkb（Deltamye）小鼠保留了整体胰岛素敏感性，并受到胰岛素抵抗的保护。因此，ikk - β局部作用于肝脏，系统性作用于髓细胞，其中NF-kappaB激活诱导炎症介质引起胰岛素抵抗。这些发现证明了肝细胞ikk - β在肝脏胰岛素抵抗中的重要性，以及髓细胞在全身性胰岛素抵抗发展中的核心作用。我们认为抑制ikk - β，特别是髓细胞，可能用于治疗胰岛素抵抗。
Inflammation may underlie the metabolic disorders of insulin resistance and type 2 diabetes. IkappaB kinase beta (IKK-beta, encoded by Ikbkb) is a central coordinator of inflammatory responses through activation of NF-kappaB. To understand the role of IKK-beta in insulin resistance, we used mice lacking this enzyme in hepatocytes (Ikbkb(Deltahep)) or myeloid cells (Ikbkb(Deltamye)). Ikbkb(Deltahep) mice retain liver insulin responsiveness, but develop insulin resistance in muscle and fat in response to high fat diet, obesity or aging. In contrast, Ikbkb(Deltamye) mice retain global insulin sensitivity and are protected from insulin resistance. Thus, IKK-beta acts locally in liver and systemically in myeloid cells, where NF-kappaB activation induces inflammatory mediators that cause insulin resistance. These findings demonstrate the importance of liver cell IKK-beta in hepatic insulin resistance and the central role of myeloid cells in development of systemic insulin resistance. We suggest that inhibition of IKK-beta, especially in myeloid cells, may be used to treat insulin resistance.