Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity.
Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity.
复制标题
下丘脑Ikkbeta/nf-kappab以及ER应力的育儿与能量不平衡和肥胖。
DOI：
10.1016/j.cell.2008.07.043
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发表时间：
2008-10-03
期刊：
影响因子：
64.5
通讯作者：
Cai, Dongsheng
中科院分区：
文献类型：
--
作者：
Zhang, Xiaoqing;Zhang, Guo;Zhang, Hai;Karin, Michael;Bai, Hua;Cai, Dongsheng
营养过剩与代谢组织中的慢性炎症有关；然而，代谢炎症是否会损害神经调节系统，从而促进与营养过剩相关的疾病仍未被探索。我们的结果表明，代谢炎症介质IKKβ/NF-κB虽然在下丘脑神经元中丰富，但通常保持不活跃；然而，过度营养非典型地激活下丘脑IKKβ/NF-κB，至少通过增加下丘脑的内质网应激来实现。虽然强制激活下丘脑IKKβ/NF-κB可以阻断中枢胰岛素/瘦素信号和作用，但位置或细胞特异性抑制IKKβ可以广泛分布于整个大脑，或局部在下丘脑内侧基底区，或特别是在下丘脑AGRP神经元中，显著地保护肥胖和糖耐量减低。涉及的分子机制包括IKKβ/NF-κB对胰岛素和瘦素信号的核心抑制剂SOCS3的调控。总之，下丘脑IKKβ/NF-κB程序是导致肥胖的能量失衡的一般神经机制；抑制下丘脑IKKβ/NF-κB代表了对抗肥胖和相关疾病的新策略。
Overnutrition is associated with chronic inflammation in metabolic tissues; however, whether metabolic inflammation compromises the neural regulatory systems and therefore promotes overnutrition-associated diseases remains unexplored. Our results demonstrate that a mediator of metabolic inflammation, IKKβ/NF-κB, normally remains inactive although enriched in the hypothalamic neurons; however, overnutrition atypically activates hypothalamic IKKβ/NF-κB at least through elevated endoplasmic reticulum stress in the hypothalamus. While forced activation of hypothalamic IKKβ/NF-κB interrupts central insulin/leptin signaling and actions, site- or cell-specific suppression of IKKβ either broadly across the brain, or locally within the mediobasal hypothalamus, or specifically in hypothalamic AGRP neurons significantly protects against obesity and glucose intolerance. The involved molecular mechanisms include the control of IKKβ/NF-κB over SOCS3, a core inhibitor of insulin and leptin signaling. In conclusion, the hypothalamic IKKβ/NF-κB program is a general neural mechanism for energy imbalance underlying obesity; suppressing hypothalamic IKKβ/NF-κB represents a new strategy to combat obesity and related diseases.
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