TNFα increases hypothalamic PTP1B activity via the NFκB pathway in rat hypothalamic organotypic cultures
TNFα increases hypothalamic PTP1B activity via the NFκB pathway in rat hypothalamic organotypic cultures
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DOI：
10.1016/j.regpep.2011.11.010
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发表时间：
2012-02-10
影响因子：
--
通讯作者：
Oiso, Yutaka
中科院分区：
文献类型：
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作者：
Ito, Yoshihiro;Banno, Ryoichi;Oiso, Yutaka
在肥胖症中，众所周知，脂肪组织或血清中肿瘤坏死因子α（TNF α）的水平升高，据报道，高脂饮食（HFD）可增加下丘脑中TNF α的表达。下丘脑蛋白酪氨酸磷酸酶18（PTP 1B）的表达水平，瘦素和胰岛素信号传导的负调节剂，也被HFD升高，几条证据支持TNF α和PTP 1B之间的关系。然而，TNF α如何在下丘脑局部作用以调节下丘脑PTP 1B表达和活性仍不清楚。在这项研究中，我们研究了TNF α是否可以调节PTP 1B的表达和活性，使用大鼠下丘脑器官型培养。与对照组相比，TNF α孵育导致PTP 1B的mRNA表达、蛋白水平和活性分别以剂量和时间依赖性方式增加。TNF α诱导的PTP 1B蛋白水平不受与钠通道阻断剂河豚毒素共孵育的影响，表明TNF α的作用不依赖于动作电位。TNF α还以剂量和时间依赖性方式增加核因子-κ B（NF κ B）亚单位p65的磷酸化。虽然与NF κ B抑制剂孵育不影响p65磷酸化或PTP 1 B表达的基础水平，但它显著抑制TNF α诱导的p65磷酸化和PTP 1 B表达至几乎基础水平。这些数据表明，TNF α作用于下丘脑，通过NF κ B通路增加下丘脑PTP 1 B表达和活性，并且TNF α介导的下丘脑NF κ B诱导可能通过增加下丘脑PTP 1 B活性导致下丘脑瘦素和胰岛素抵抗。(C)2011 Elsevier B. V.保留所有权利。
In obesity, levels of tumor necrosis-factor alpha (TNF alpha) are well known to be elevated in adipose tissues or serum, and a high-fat diet (HFD) reportedly increases TNF alpha expression in the hypothalamus. The expression levels of hypothalamic protein tyrosine phosphatase 18 (PTP1B), a negative regulator of leptin and insulin signaling, are also elevated by HFD, and several lines of evidence support a relationship between TNF alpha and PTP1B. It remains unclear however how TNF alpha acts locally in the hypothalamus to regulate hypothalamic PTP1B expression and activity. In this study, we examined whether TNF alpha can regulate PTP1B expression and activity using rat hypothalamic organotypic cultures. Incubation of cultures with TNF alpha resulted in increases in mRNA expression, protein levels and activity of PTP1B in a dose- and time-dependent manner, respectively compared with controls. TNF alpha-induced PTP1B protein levels were not influenced by co-incubation with the sodium channel blocker tetrodotoxin, indicating that the action of TNF alpha is independent of action potentials. TNF alpha also increased phosphorylation of p65, a subunit of nuclear factor-kappa B (NF kappa B), in a dose- and time-dependent manner. While incubation with inhibitors of NF kappa B did not affect basal levels of either p65 phosphorylation or PTP1B expression, it markedly suppressed both TNF alpha-induced p65 phosphorylation and PTP1B expression to almost basal levels. These data suggest that TNF alpha acts on the hypothalamus to increase hypothalamic PTP1B expression and activity via the NF kappa B pathway, and that TNF alpha-mediated induction of NF kappa B in the hypothalamus may cause leptin and insulin resistance in the hypothalamus by increasing hypothalamic PTP1B activity. (C) 2011 Elsevier B.V. All rights reserved.