近日，國(guó)際學(xué)術(shù)期刊Diabetes在線發(fā)表了上海生科院營(yíng)養(yǎng)所郭非凡研究組的研究論文 “ S6K1 in the CNS regulates energy expenditure via MC4R/CRH pathways in response to deprivation of an essential amino acid ”,。該研究首次發(fā)現(xiàn)下丘腦核糖體S6K蛋白激酶 (p70 S6K1)通過抑制黑素皮質(zhì)素受體4（MC4R）的表達(dá)進(jìn)而下調(diào)促腎上腺皮質(zhì)激素釋放激素(corticotropin-releasing hormone, CRH)水平,，參與機(jī)體能量代謝穩(wěn)態(tài)調(diào)控，揭示了亮氨酸缺乏時(shí)中樞神經(jīng)系統(tǒng)調(diào)節(jié)外周脂質(zhì)和能量代謝的新機(jī)制,。
中樞神經(jīng)系統(tǒng)的營(yíng)養(yǎng)感應(yīng)信號(hào)通路與外周組織的代謝分子調(diào)控網(wǎng)絡(luò)關(guān)系密切,，其功能紊亂是促發(fā)代謝性疾病的重要原因,。中樞神經(jīng)系統(tǒng),，特別是下丘腦，在營(yíng)養(yǎng)素感應(yīng)和調(diào)控代謝過程中扮演重要角色,。下丘腦兼有神經(jīng)和內(nèi)分泌系統(tǒng)的雙重功能,，能夠直接感受機(jī)體的營(yíng)養(yǎng)狀態(tài)，通過營(yíng)養(yǎng)感應(yīng)信號(hào)通路激活對(duì)外周組織的代謝調(diào)控。該研究組前期研究發(fā)現(xiàn)了中樞注射亮氨酸能夠改變白色脂肪組織激素敏感脂肪酶(hormone-sensitive lipase, HSL)的磷酸化水平和褐色脂肪組織解耦聯(lián)蛋白1 (uncoupling protein 1, UCP1)的表達(dá)水平,；并且亮氨酸缺乏導(dǎo)致下丘腦中室旁核中CRH表達(dá)增加,，進(jìn)而激活交感神經(jīng)系統(tǒng)，促進(jìn)外周脂質(zhì)和能量代謝,。但是,，亮氨酸缺乏如何激活CRH進(jìn)而調(diào)節(jié)外周能量代謝的分子機(jī)制尚不清楚。
在本研究中,，郭非凡研究組的博士生夏婷婷等人研究發(fā)現(xiàn),，亮氨酸缺乏引起小鼠下丘腦中核糖體S6K1蛋白激酶活性顯著下降；而第三腦室注射腺病毒介導(dǎo)的持續(xù)激活S6K1（CA-S6K1）能有效阻斷亮氨酸缺乏引起的下丘腦室旁核中CRH表達(dá)增加,、褐色脂肪組織UCP1 表達(dá)增加以及機(jī)體能量消耗的增加,；進(jìn)一步研究證實(shí)腦室注射CRH激素能夠逆轉(zhuǎn)S6K1持續(xù)激活對(duì)亮氨酸缺乏導(dǎo)致代謝變化的影響；從而證實(shí)亮氨酸缺乏引起下丘腦S6K1表達(dá)下調(diào),，進(jìn)而激活下丘腦室旁核中CRH表達(dá),，促進(jìn)了外周脂質(zhì)和能量代謝；通過下丘腦原代細(xì)胞培養(yǎng)實(shí)驗(yàn)進(jìn)一步揭示了S6K1對(duì)CRH的表達(dá)調(diào)控依賴于MC4R,。
該項(xiàng)研究首次證明了下丘腦CRH的表達(dá)受S6K1調(diào)控,，而S6K1是亮氨酸缺乏引起能量代謝變化的核心調(diào)節(jié)因子。該研究成果為進(jìn)一步研究中樞感應(yīng)氨基酸及調(diào)控外周能量代謝奠定了基礎(chǔ),，豐富了人們對(duì)中樞神經(jīng)系統(tǒng)調(diào)控外周代謝的認(rèn)識(shí),，有助于加深人們對(duì)肥胖及相關(guān)過代謝性疾病發(fā)生機(jī)制的理解。
該項(xiàng)工作得到科技部973計(jì)劃,、自然科學(xué)基金委,、上海市科委以及中科院等科研基金的支持。（生物谷Bioon.com）
doi:10.2337/db11-1278
PMC:
PMID:
S6K1 in the Central Nervous System Regulates Energy Expenditure via MC4R/Corticotropin-Releasing Hormone Pathways in Response to Deprivation of an Essential Amino Acid
Tingting Xia, Ying Cheng, Qian Zhang, Fei Xiao, Bin Liu, Shanghai Chen and Feifan Guo⇓
It is well established that the central nervous system (CNS), especially the hypothalamus, plays an important role in regulating energy homeostasis and lipid metabolism. We have previously shown that hypothalamic corticotropin-releasing hormone (CRH) is critical for stimulating fat loss in response to dietary leucine deprivation. The molecular mechanisms underlying the CNS regulation of leucine deprivation–stimulated fat loss are, however, still largely unknown. Here, we used intracerebroventricular injection of adenoviral vectors to identify a novel role for hypothalamic p70 S6 kinase 1 (S6K1), a major downstream effector of the kinase mammalian target of rapamycin, in leucine deprivation stimulation of energy expenditure. Furthermore, we show that the effect of hypothalamic S6K1 is mediated by modulation of Crh expression in a melanocortin-4 receptor–dependent manner. Taken together, our studies provide a new perspective for understanding the regulation of energy expenditure by the CNS and the importance of cross-talk between nutritional control and regulation of endocrine signals.
