近日來(lái)自美國(guó)愛(ài)因斯坦醫(yī)學(xué)院的研究人員在新研究中解析了下丘腦內(nèi)IKK/NF-κB信號(hào)通路對(duì)機(jī)體代謝性穩(wěn)態(tài)、肥胖及相關(guān)高血壓病的影響。這一研究為治療和預(yù)防人類(lèi)肥胖相關(guān)高血壓及心血管疾病指明了新方向,。相關(guān)研究論文在線(xiàn)發(fā)表在6月5日的《自然—醫(yī)學(xué)》（Nature medicine）雜志上,。
領(lǐng)導(dǎo)這一研究的是著名華人學(xué)者蔡?hào)|升博士,，其早年畢業(yè)于南京醫(yī)科大學(xué),，2000年于上海交通大學(xué)獲得博士學(xué)位，現(xiàn)為美國(guó)愛(ài)因斯坦醫(yī)學(xué)院分子藥理學(xué)系副教授,，主要的研究領(lǐng)域?yàn)榇x平衡和代謝失序中的炎癥及應(yīng)激研究,。
在早年的研究中，蔡?hào)|升博士發(fā)現(xiàn)代謝炎癥可以影響機(jī)體的高級(jí)中樞神經(jīng)細(xì)胞,，尤其是下丘腦（hypothalamus）,。這個(gè)大腦結(jié)構(gòu)是調(diào)控飲食和能量平衡的一個(gè)關(guān)鍵調(diào)控元素,，同時(shí)也掌控著周邊組織的代謝。然而一直以來(lái)研究人員對(duì)于下丘腦在包括肥胖及相關(guān)代謝疾病中所扮演的角色知之甚少,。
在去年蔡?hào)|升博士發(fā)表于Cell雜志上的一篇文章中，首次發(fā)現(xiàn)下丘腦的特異性神經(jīng)細(xì)胞中存在IKKbeta/NF-kappaB,，而且這一途徑在下丘腦中,，比周邊組織存在得更多，通常在大腦中保持非激活的狀態(tài),。研究人員發(fā)現(xiàn)通過(guò)高脂肪喂食發(fā)生營(yíng)養(yǎng)過(guò)剩會(huì)激發(fā)IKKbeta/NF-kappaB,，尤其是在下丘腦的神經(jīng)細(xì)胞。抑制這一信號(hào)通路則會(huì)降低動(dòng)物能量過(guò)度消耗,，肥胖增加的風(fēng)險(xiǎn),。
之后蔡?hào)|升研究小組將研究焦點(diǎn)放置了在探索IKKbeta/NF-kappaB信號(hào)通路與其他途徑的關(guān)系，以及調(diào)節(jié)IKK/NF-κB信號(hào)通路對(duì)機(jī)體代謝性穩(wěn)態(tài),、肥胖及相關(guān)疾病的影響上,。
高血壓病是目前全球最大的流行病之一，也是最常見(jiàn)的心血管疾病的主要風(fēng)險(xiǎn)因子,。高血壓指在靜息狀態(tài)下動(dòng)脈收縮壓和/或舒張壓增高(>=140/90mmHg),，常伴有脂肪和糖代謝紊亂以及心、腦,、腎和視網(wǎng)膜等器官功能性或器質(zhì)性改變,。目前臨床上有很多肥胖型高血壓病人且常伴有糖尿病。
在新文章中,，研究人員解析了下丘腦IKK/NF-κB信號(hào)通路對(duì)于肥胖相關(guān)性高血壓的影響,。研究人員證實(shí)快速激活內(nèi)側(cè)基底下丘腦IKK/NF-κB信號(hào)通路可導(dǎo)致實(shí)驗(yàn)小鼠的血壓快速增高。研究人員發(fā)現(xiàn)當(dāng)丘腦細(xì)胞中的NF-κB活性受到抑制時(shí)可抵消肥胖所致的高血壓,。此外,，研究人員證實(shí)促阿片黑皮蘇前體（POMC）神經(jīng)元在下丘腦IKK-β 和 NF-κB激活導(dǎo)致的高血壓效應(yīng)中起關(guān)鍵性的作用。研究結(jié)果表明內(nèi)側(cè)基底下丘腦尤其是下丘腦POMC 神經(jīng)元中IKK-β 和NF-κB激活是聯(lián)系肥胖與高血壓首要致病因素,。這一研究發(fā)現(xiàn)為預(yù)防及治療肥胖相關(guān)的高血壓和心血管疾病指明了新方向,。（生物谷Bioon.com）
生物谷推薦原文出處：
Nature Medicine DOI:10.1038/nm.2372
Uncoupling the mechanisms of obesity and hypertension by targeting hypothalamic IKK-[beta] and NF-[kappa]B
Sudarshana Purkayastha; Guo Zhang; Dongsheng Cai
Obesity-related hypertension has become an epidemic health problem and a major risk factor for the development of cardiovascular disease (CVD). Recent research on the pathophysiology of obesity has implicated a role for the hypothalamus in the pathogenesis of this condition1, 2, 3. However, it remains unknown whether the often-seen coupling of hypertension with obesity can also be explained by hypothalamic dysfunction, despite the emerging appreciation that many forms of hypertension are neurogenic in origin4, 5, 6, 7, 8, 9, 10, 11, 12, 13. Our studies here revealed that acute activation of the proinflammatory protein nuclear factor κB (NF-κB) and its upstream activator IκB kinase-β (IKK-β, encoded by Ikbkb) in the mediobasal hypothalamus rapidly elevated blood pressure in mice independently of obesity. This form of hypothalamic inflammation-induced hypertension involved the sympathetic upregulation of hemodynamics and was reversed by sympathetic suppression. Loss-of-function studies further showed that NF-κB inhibition in the mediobasal hypothalamus counteracted obesity-related hypertension in a manner that was dissociable from changes in body weight. In addition, we found that pro-opiomelanocortin (POMC) neurons were crucial for the hypertensive effects of the activation of hypothalamic IKK-β and NF-κB, which underlie obesity-related hypertension. In conclusion, obesity-associated activation of IKK-β and NF-κB in the mediobasal hypothalamus—particularly in the hypothalamic POMC neurons—is a primary pathogenic link between obesity and hypertension. Breaking this pathogenic link may represent an avenue for controlling obesity-related hypertension and CVD without requiring obesity control.
