近日中科院上海生命科學(xué)研究院營養(yǎng)科學(xué)研究所的研究人員在新研究中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)代謝的機(jī)制,，相關(guān)研究論文在線發(fā)表在國際內(nèi)分泌領(lǐng)域著名期刊《分子內(nèi)分泌學(xué)》（Molecular Endocrinology）上,。
領(lǐng)導(dǎo)這一研究的是營養(yǎng)研究所的郭非凡研究員,，其2001年獲得日本東京大學(xué)神經(jīng)生化學(xué)博士,，之后在美國從事博士后研究工作,，2007年被聘為中國科學(xué)院上海生命科學(xué)研究院營養(yǎng)科學(xué)研究所研究員,，入選百人計(jì)劃,。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,。
中樞神經(jīng)系統(tǒng)的營養(yǎng)感應(yīng)信號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)體的營養(yǎng)狀態(tài),，通過營養(yǎng)感應(yīng)信號通路激活對外周組織的代謝調(diào)控,。目前，氨基酸的中樞營養(yǎng)感應(yīng)及其對外周代謝調(diào)控尚無詳細(xì)報(bào)道,。
亮氨酸是機(jī)體的必需氨基酸之一,，也是重要的代謝調(diào)節(jié)因子。該研究組前期研究表明：亮氨酸缺乏能夠引起機(jī)體外周組織的廣泛代謝變化,，包括肝臟脂肪酸合成抑制,、胰島素敏感性增強(qiáng)、腹部脂肪快速丟失以及褐色脂肪組織產(chǎn)熱增加等,；研究還發(fā)現(xiàn)亮氨酸缺乏能夠引起下丘腦內(nèi)多個(gè)信號通路發(fā)生變化,，提示下丘腦能夠感應(yīng)亮氨酸缺乏這一營養(yǎng)狀態(tài)，并經(jīng)過系列信號整合后進(jìn)一步調(diào)控外周脂質(zhì)代謝,，但具體機(jī)制不清,。
在本研究中，郭非凡研究組的博士生成瀛和張倩等人發(fā)現(xiàn),，用亮氨酸缺乏飼料喂養(yǎng)的小鼠經(jīng)側(cè)腦室注射亮氨酸后,，能夠很快恢復(fù)下丘腦內(nèi)的亮氨酸水平；并能夠阻止亮氨酸缺乏導(dǎo)致的白色脂肪丟失和褐色脂肪產(chǎn)熱增加的表型變化,。研究表明,，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。進(jìn)一步的機(jī)制研究發(fā)現(xiàn),，亮氨酸缺乏導(dǎo)致下丘腦中室旁核中促腎上腺皮質(zhì)激素釋放激素 (corticotropin-releasing hormone, CRH)表達(dá)增加,，進(jìn)而激活交感神經(jīng)系統(tǒng)，一方面促進(jìn)其支配的白色脂肪組織內(nèi)脂增加,，表現(xiàn)為HSL磷酸化水平增加,；另一方面，促進(jìn)其支配的褐色脂肪組織內(nèi)能量消耗增加,，表現(xiàn)為UCP1表達(dá)升高,；兩者共同作用引起腹部脂肪快速丟失。在體外實(shí)驗(yàn)中通過使用各種特異性抑制劑,，發(fā)現(xiàn)亮氨酸缺乏激活下丘腦神經(jīng)元的Gs/cAMP/PKA/CREB信號通路,，CREB直接作用于CRH的啟動(dòng)子區(qū)域而調(diào)節(jié)CRH的表達(dá)。
該項(xiàng)研究首次闡明下丘腦CRH受亮氨酸水平調(diào)控，并且是亮氨酸缺乏引起外周脂質(zhì)和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)控外周脂質(zhì)代謝奠定了堅(jiān)實(shí)基礎(chǔ),，豐富了人們對中樞神經(jīng)系統(tǒng)調(diào)控外周代謝的認(rèn)識，有助于加深人們對肥胖及相關(guān)過代謝性疾病發(fā)生機(jī)制的理解,。(生物谷 Bioon.com)
doi:10.1126/science.1202529
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Leucine Deprivation Stimulates Fat Loss via Increasing CRH Expression in The Hypothalamus and Activating The Sympathetic Nervous System
Ying Cheng, Qian Zhang, Qingshu Meng, Tingting Xia, Zhiying Huang, Chunxia Wang, Bin Liu, Shanghai Chen, Fei Xiao, Ying Du and Feifan Guo
We previously showed that leucine deprivation decreases abdominal fat mass largely by increasing energy expenditure, as demonstrated by increased lipolysis in white adipose tissue (WAT) and uncoupling protein 1 (UCP1) expression in brown adipose tissue (BAT). The goal of the present study was to investigate the possible involvement of central nervous system (CNS) in this regulation and elucidate underlying molecular mechanisms. For this purpose, levels of genes and proteins related to lipolysis in WAT and UCP1 expression in BAT were analyzed in wild-type mice after intracerebroventricular administration of leucine or corticotrophin-releasing hormone antibodies, or in mice deleted for three β-adrenergic receptors, after being maintained on a leucine-deficient diet for 7 d. Here, we show that intracerebroventricular administration of leucine significantly attenuates abdominal fat loss and blocks activation of hormone sensitive lipase in WAT and induction of UCP1 in BAT in leucine-deprived mice. Furthermore, we provide evidence that leucine deprivation stimulates fat loss by increasing expression of corticotrophin-releasing hormone in the hypothalamus via activation of stimulatory G protein/cAMP/protein kinase A/cAMP response element-binding protein pathway. Finally, we show that the effect of leucine deprivation on fat loss is mediated by activation of the sympathetic nervous system. These results suggest that CNS plays an important role in regulating fat loss under leucine deprivation and thereby provide novel and important insights concerning the importance of CNS leucine in the regulation of energy homeostasis.
