Inhibition of hypothalamic inflammation reverses diet-induced insulin resistance in the liver.
Inhibition of hypothalamic inflammation reverses diet-induced insulin resistance in the liver.
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DOI：
10.2337/db11-0390
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发表时间：
2012-06
期刊：
影响因子：
7.7
通讯作者：
Velloso LA
中科院分区：
文献类型：
--
作者：
Milanski M;Arruda AP;Coope A;Ignacio-Souza LM;Nunez CE;Roman EA;Romanatto T;Pascoal LB;Caricilli AM;Torsoni MA;Prada PO;Saad MJ;Velloso LA
肝脏糖异生缺陷是导致2型糖尿病患者空腹高血糖的主要机制，并伴随脂肪变性，是肝脏胰岛素抵抗的标志。实验性肥胖至少部分是由下丘脑炎症引起的，下丘脑炎症导致瘦素抵抗和能量平衡调节缺陷。下丘脑炎症的药物或基因干扰可以恢复瘦素的敏感性，减少肥胖。在这里，我们评估了下丘脑抗炎方法调节肝脏对胰岛素反应的效果。用抗TLR4或肿瘤坏死因子α的免疫中和抗体侧脑室注射治疗肥胖大鼠，观察胰岛素信号转导、肝脏脂肪变性和糖异生。抑制TLR4或肿瘤坏死因子α可减轻下丘脑的炎症反应，同时降低下丘脑对瘦素的抵抗，改善肝脏的胰岛素信号转导。伴随而来的是肝脏脂肪变性的减轻和脂肪变性标志物在肝脏的表达减少。此外，抑制下丘脑炎症使受损的肝脏葡萄糖产生恢复。所有这些有益的作用都被迷走神经切断术所消除。因此，抑制肥胖患者的下丘脑炎症可以改善肝脏胰岛素信号转导，从而减少脂肪变性和减少糖异生。所有这些效应都是由迷走神经传递的副交感信号介导的。
Defective liver gluconeogenesis is the main mechanism leading to fasting hyperglycemia in type 2 diabetes, and, in concert with steatosis, it is the hallmark of hepatic insulin resistance. Experimental obesity results, at least in part, from hypothalamic inflammation, which leads to leptin resistance and defective regulation of energy homeostasis. Pharmacological or genetic disruption of hypothalamic inflammation restores leptin sensitivity and reduces adiposity. Here, we evaluate the effect of a hypothalamic anti-inflammatory approach to regulating hepatic responsiveness to insulin. Obese rodents were treated by intracerebroventricular injections, with immunoneutralizing antibodies against Toll-like receptor (TLR)4 or tumor necrosis factor (TNF)α, and insulin signal transduction, hepatic steatosis, and gluconeogenesis were evaluated. The inhibition of either TLR4 or TNFα reduced hypothalamic inflammation, which was accompanied by the reduction of hypothalamic resistance to leptin and improved insulin signal transduction in the liver. This was accompanied by reduced liver steatosis and reduced hepatic expression of markers of steatosis. Furthermore, the inhibition of hypothalamic inflammation restored defective liver glucose production. All these beneficial effects were abrogated by vagotomy. Thus, the inhibition of hypothalamic inflammation in obesity results in improved hepatic insulin signal transduction, leading to reduced steatosis and reduced gluconeogenesis. All these effects are mediated by parasympathetic signals delivered by the vagus nerve.
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影响因子：
105.7
作者：
MATTHEWS, JNS;ALTMAN, DG;ROYSTON, P
通讯作者：
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ISHIBASHI, S;BROWN, MS;HERZ, J
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Seppälä-Lindroos, A;Vehkavaara, S;Yki-Järvinen, H
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影响因子：
82.9
作者：
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通讯作者：
Flier, JS