產(chǎn)熱脂肪對(duì)代謝性疾病的治療潛能

黃海艷 湯其群

(1復(fù)旦大學(xué)基礎(chǔ)醫(yī)學(xué)院生物化學(xué)與分子生物學(xué)系 上海 200032; 2復(fù)旦大學(xué)代謝分子醫(yī)學(xué)教育部重點(diǎn)實(shí)驗(yàn)室 上海 200032)

專家簡(jiǎn)介湯其群,1966年出生,江蘇建湖人,長(zhǎng)江學(xué)者特聘教授,國家杰青,973首席科學(xué)家。

1990年畢業(yè)于上海醫(yī)科大學(xué)法醫(yī)學(xué)系,1995年獲得上海醫(yī)科大學(xué)生物化學(xué)與分子生物學(xué)博士學(xué)位,同年赴美國Johns Hopkins大學(xué)醫(yī)學(xué)院生物化學(xué)系做博士后。2002年受聘為Johns Hopkins大學(xué)醫(yī)學(xué)院兒科內(nèi)分泌系助理教授兼生化系助理教授。2005年6月辭去美國的職位,全職受聘于復(fù)旦大學(xué)?，F(xiàn)任復(fù)旦大學(xué)基礎(chǔ)醫(yī)學(xué)院院長(zhǎng),生物醫(yī)學(xué)研究院副院長(zhǎng),代謝分子醫(yī)學(xué)教育部重點(diǎn)實(shí)驗(yàn)室主任,中國生物化學(xué)與分子生物學(xué)學(xué)會(huì)副理事長(zhǎng),代謝專業(yè)委員會(huì)主任委員,JBiolChem雜志副主編。

主要研究方向?yàn)橹炯?xì)胞發(fā)育分化的機(jī)制和肥胖的成因,以及有效地控制肥胖的方法。在ProcNatlAcadSciUSA,GenesDev,MolCellBiol,MolCellProteomics,JBiolChem等SCI雜志上發(fā)表論文60余篇。曾獲上海市科技進(jìn)步一等獎(jiǎng),衛(wèi)生部科技進(jìn)步一等獎(jiǎng)、國家科技進(jìn)步二等獎(jiǎng),“霍英東優(yōu)秀青年教師”一等獎(jiǎng)(生物類)和談家楨生命科學(xué)創(chuàng)新獎(jiǎng)。

上海醫(yī)學(xué)院創(chuàng)建90周年寄語完善學(xué)科體系,創(chuàng)建世界一流醫(yī)學(xué)學(xué)科。

產(chǎn)熱脂肪對(duì)代謝性疾病的治療潛能

黃海艷1,2湯其群1,2△

(1復(fù)旦大學(xué)基礎(chǔ)醫(yī)學(xué)院生物化學(xué)與分子生物學(xué)系 上海 200032;2復(fù)旦大學(xué)代謝分子醫(yī)學(xué)教育部重點(diǎn)實(shí)驗(yàn)室 上海 200032)

脂肪組織對(duì)全身能量穩(wěn)態(tài)的調(diào)節(jié)發(fā)揮重要作用。人體有3種脂肪組織:白色脂肪(white adipose tissue,WAT),棕色脂肪(brown adipose tissue,BAT)和米色脂肪(beige adipose tissue)。棕色脂肪和米色脂肪通過產(chǎn)熱消耗能量,二者并稱為產(chǎn)熱性脂肪組織。本文將對(duì)產(chǎn)熱脂肪的調(diào)控加以介紹并討論其對(duì)代謝性疾病的治療潛能,同時(shí)也把本課題組在相關(guān)領(lǐng)域的貢獻(xiàn)加以介紹。

產(chǎn)熱脂肪; 能量代謝; 肥胖; 代謝疾病

脂肪組織的分類脂肪組織的功能對(duì)于代謝健康起著舉足輕重的作用,脂肪組織在肥胖的發(fā)生和進(jìn)展過程中處于核心位置。目前已知人體存在3種脂肪組織:白色脂肪(white adipose tissue,WAT),棕色脂肪(brown adipose tissue,BAT)和米色脂肪(beige adipose tissue)。白色脂肪組織以三酰甘油的形式儲(chǔ)存能量及為饑餓時(shí)提供能源,同時(shí)能以內(nèi)分泌、旁分泌、自分泌的方式分泌脂肪因子,參與調(diào)節(jié)機(jī)體穩(wěn)態(tài)[1-5]。棕色脂肪組織的主要功能是消耗能量和產(chǎn)熱。多種哺乳動(dòng)物在成年后體內(nèi)仍保留一定量的棕色脂肪組織,以更好地適應(yīng)低溫脅迫[6]。人在嬰兒期,棕色脂肪主要分布在腎周和背部,隨著年齡的增長(zhǎng),棕色脂肪發(fā)生退化。成人棕色脂肪存在于頸部、鎖骨上部和脊柱旁側(cè)[7-11]。棕色脂肪的產(chǎn)熱通過交感神經(jīng)系統(tǒng)作用于棕色脂肪細(xì)胞上的β3腎上腺素能受體,并最終由解偶聯(lián)蛋白1 (uncoupling protein,UCP1)完成。在白色脂肪和肌肉中存在誘導(dǎo)性棕色脂肪(inducible BAT),也被稱為米色脂肪(beige fat)[12-16]。米色脂肪細(xì)胞通常低表達(dá)UCP1,在某些因素誘導(dǎo)下UCP1高水平表達(dá)[17-19],進(jìn)而消耗能量、產(chǎn)熱,其產(chǎn)熱效率與經(jīng)典棕色脂肪細(xì)胞幾乎一樣[15-16,18],這個(gè)過程稱為米色化(beiging)。米色脂肪和棕色脂肪雖然所處部位不同,發(fā)育來源不同,但行使相同的產(chǎn)熱功能,并在消耗能量方面有同樣的潛力,二者并稱為產(chǎn)熱性脂肪組織[20]。產(chǎn)熱性脂肪組織的分化發(fā)育、功能調(diào)節(jié)和臨床應(yīng)用都是近幾年代謝領(lǐng)域的研究熱點(diǎn)。在生理?xiàng)l件下,有兩種激活產(chǎn)熱性脂肪組織的情況:冷暴露和飲食攝入(尤其是高熱量的食物)。在冷暴露時(shí),產(chǎn)熱性脂肪組織激活,起到保持體溫恒定的作用;飲食攝入時(shí),產(chǎn)熱脂肪活化,緩解一過性能量高峰,從而維持代謝穩(wěn)態(tài)[21]。

產(chǎn)熱脂肪組織的激活

產(chǎn)熱脂肪組織的來源 在嚙齒類,兩種產(chǎn)熱脂肪細(xì)胞起源于不同前體細(xì)胞[16,22-25],經(jīng)典的棕色脂肪細(xì)胞起源于來源myf5+的肌節(jié)前體細(xì)胞[22,25-26],與肌肉細(xì)胞相似,而米色脂肪細(xì)胞既可以起源于myf5+的細(xì)胞,也可以起源于myf5-的細(xì)胞[16,24,26]。最新研究結(jié)果顯示人的米色脂肪起源于脂肪組織血管網(wǎng)絡(luò),體外實(shí)驗(yàn)顯示脂肪組織塊發(fā)育而來的微血管可以在促血管生成因子(vascular endothelial growth factor,VEGF)和人成纖維細(xì)胞生長(zhǎng)因子(fibroblast growth factor B,hFGF-B)作用下發(fā)育成產(chǎn)熱的脂肪細(xì)胞[27]。 這些研究提示在人脂肪組織的毛細(xì)血管網(wǎng)存在可發(fā)育成米色脂肪細(xì)胞的前體細(xì)胞[15,28-29]。

產(chǎn)熱脂肪組織活化的誘導(dǎo)因素 棕色和米色脂肪的發(fā)育和產(chǎn)熱功能受到多種因素的觸發(fā)和調(diào)節(jié),例如冷暴露、運(yùn)動(dòng)、利鈉肽(natriuretic peptides)、格列酮類(thiazolidinediones,TZDs)、甲狀腺激素、骨形成蛋白7(bone morphogenetic protein 7,Bmp7)、骨形成蛋白8B (bone morphogenetic protein 8b,Bmp8b)、irisin、orexin和成纖維細(xì)胞生長(zhǎng)因子21(fibroblast growth factor 21,Fgf21)[23,30-31]等。本實(shí)驗(yàn)室一直研究BMP4對(duì)脂肪細(xì)胞發(fā)育和代謝的調(diào)節(jié)作用。我們發(fā)現(xiàn)BMP4主要通過激活Smad信號(hào)通路誘導(dǎo)多潛能C3H10T1/2細(xì)胞向前脂肪細(xì)胞定向,p38/MAPK信號(hào)通路也參與部分作用,賴氨酰氧化酶(lysyl oxidase,LOX)對(duì)該過程非常重要[32]。進(jìn)一步研究顯示,BMP4通過激活p38/MAPK信號(hào)通路激活A(yù)TF2及下游PGC1α調(diào)節(jié)脂肪細(xì)胞代謝和米色化[33]。具體表現(xiàn)在:脂肪組織特異性過表達(dá)BMP4后脂肪細(xì)胞內(nèi)脂滴變小,線粒體新生增加,Ucp1增加。BMP4轉(zhuǎn)基因小鼠代謝有所改善,胰島素敏感性增加,能抵御由高脂飲食誘導(dǎo)的肥胖和血脂升高[33]。在前脂肪細(xì)胞3T3-L1分化過程中加入BMP4,也可使細(xì)胞獲得米色脂肪細(xì)胞的表型。BMP4這種新功能的闡明可為臨床干預(yù)肥胖和改善胰島素敏感性提供新思路。另外,在誘導(dǎo)米色脂肪的新生過程中,BMP4促進(jìn)血管的生成,也下調(diào)血管周細(xì)胞內(nèi)PDGFRβ的蛋白水平,從而促進(jìn)干細(xì)胞的成脂分化[34],BMP4協(xié)調(diào)的兩種作用最終使皮下脂肪組織中米色脂肪細(xì)胞募集增加,代謝功能增強(qiáng) (圖1)。

BMP4 stimulates proliferation of stem cells,which exist around the vascular expressing PDGFRβ,as well as adipogenic differentiation and further beiging.

圖1BMP4在脂肪細(xì)胞招募及米色化中的作用
Fig1TheroleofBMP4inadipocyterecruitmentandbeiging

產(chǎn)熱脂肪組織的發(fā)育調(diào)控 產(chǎn)熱脂肪組織消耗能量和產(chǎn)熱是通過Ucp1完成的。Ucp1是棕色及米色脂肪細(xì)胞線粒體內(nèi)膜的一種易化的質(zhì)子通道,質(zhì)子通過該通道回流,從而破壞呼吸鏈電子傳遞過程中所建立的跨內(nèi)膜的質(zhì)子電化學(xué)梯度,不能驅(qū)動(dòng)ATP合酶合成ATP,而電化學(xué)梯度儲(chǔ)存的能量以熱能形式釋放,用于維持體溫。Ucp1的表達(dá)主要在轉(zhuǎn)錄水平進(jìn)行調(diào)節(jié)。在Ucp1基因5′側(cè)翼序列含有近端調(diào)節(jié)區(qū)域和遠(yuǎn)端增強(qiáng)子區(qū)域。近端調(diào)節(jié)區(qū)域含有C/EBP調(diào)節(jié)位點(diǎn)和cAMP調(diào)節(jié)元件(CRE,cAMP response element)[35-36]。遠(yuǎn)端增強(qiáng)子區(qū)域含有另外2個(gè)cAMP (cyclic adenosine monophosphate)調(diào)節(jié)元件和復(fù)雜的核受體結(jié)合位點(diǎn)組合,如PPAR (peroxisome proliferator-activated receptor)激活劑、維甲酸類及甲狀腺激素等的結(jié)合位點(diǎn)[37-39]。調(diào)控產(chǎn)熱脂肪發(fā)育的主要調(diào)控因子是PRDM16 (PRD1-BF1-RIZ1 homologous domain containing 16)[40]和過氧化物酶體增生物激活受體γ共激活因子1α (PPARγ-co-activator-1α,PGC-1α)[41-42]。許多誘導(dǎo)棕色脂肪細(xì)胞發(fā)育的因素也能誘導(dǎo)米色脂肪細(xì)胞的形成,例如β3腎上腺素能受體激動(dòng)劑,PPAR激動(dòng)劑、維甲酸、FGF21等,另外BMP家族的某些成員、飲食及運(yùn)動(dòng)等都能誘導(dǎo)米色脂肪的形成,具體調(diào)控機(jī)制我們?cè)凇缎律飳W(xué)年鑒2014》[43]中有詳細(xì)描述。以下重點(diǎn)介紹巨噬細(xì)胞對(duì)米色脂肪細(xì)胞的調(diào)控,我們課題組在其中做了大量工作。

巨噬細(xì)胞調(diào)節(jié)米色脂肪細(xì)胞功能 巨噬細(xì)胞具有抗炎性和致炎性兩種不同的狀態(tài):抗炎性巨噬細(xì)胞是M2型巨噬細(xì)胞或者替代激活巨噬細(xì)胞(Alternative activated macrophage,AAM);而炎性巨噬細(xì)胞又被稱為M1型巨噬細(xì)胞,或者經(jīng)典激活巨噬細(xì)胞(classical activated macrophage,CAM)[44]。正常情況下,M2型巨噬細(xì)胞(AAMs)是構(gòu)成機(jī)體脂肪組織中常駐巨噬細(xì)胞的主要成分,分泌抗炎因子IL-10,參與維持脂肪組織內(nèi)的代謝平衡;相反,肥胖狀態(tài)下體內(nèi)狀態(tài)傾向?qū)1型巨噬細(xì)胞(CAMs)的募集。值得注意的是,肥胖并沒有使脂肪組織內(nèi)的M2型巨噬細(xì)胞數(shù)目減少,有可能數(shù)目還會(huì)增加,但是M1/M2的比例發(fā)生了明顯改變使得機(jī)體處于促炎階段[45]。有研究發(fā)現(xiàn)冷暴露時(shí)脂肪細(xì)胞,或者鍛煉后的肌細(xì)胞可以分泌一種多肽Metrnl,激活嗜酸性粒細(xì)胞,后者通過分泌IL4激活M2巨噬細(xì)胞[46],M2巨噬細(xì)胞可以分泌包括去甲腎上腺素在內(nèi)的兒茶酚胺,通過激活β3腎上腺素能受體(β3AR),促進(jìn)WAT中脂肪細(xì)胞的脂解、線粒體的新生以及上調(diào)產(chǎn)熱基因PGC1α和UCP1的表達(dá)[47-50]。有研究發(fā)現(xiàn)FGF21通過自分泌作用于脂肪細(xì)胞促進(jìn)CCL11的表達(dá)和分泌,招募嗜酸性粒細(xì)胞進(jìn)入皮下脂肪組織,增加M2型巨噬細(xì)胞的聚集、脂肪前體細(xì)胞的增殖和定向成米色脂肪細(xì)胞[51]。

缺乏IL-4/IL-13,IL-4的受體IL-4Rα,或IL-4下游的關(guān)鍵轉(zhuǎn)錄因子STAT6的小鼠,M2型巨噬細(xì)胞的這一系列反應(yīng)都不能正常進(jìn)行,同時(shí)BAT中UCP1的表達(dá)也相對(duì)比正常小鼠有所減少[50]。急性暴露在寒冷的環(huán)境中超過6 h,這類小鼠維持核心體溫的能力也受損[47]。除此之外,用外源性IL-4處理的小鼠可以UCP1依賴的方式增加耗氧量,促進(jìn)米色化,改善高脂飲食誘導(dǎo)的肥胖[52]。Lee等[53]發(fā)現(xiàn)IL-4除了對(duì)M2型巨噬細(xì)胞發(fā)揮作用,還可以直接促進(jìn)前脂肪細(xì)胞分化成為米色細(xì)胞。這些研究成果提示,在短期的冷暴露階段,IL-4/IL-4Rα相關(guān)的M2型巨噬細(xì)胞的激活所產(chǎn)生的去甲腎上腺素對(duì)于棕色脂肪細(xì)胞的激活起到了十分關(guān)鍵的作用。

我們課題組發(fā)現(xiàn)冷暴露后脂肪組織BMP4表達(dá)升高,提示BMP4可以調(diào)控冷暴露誘導(dǎo)的米色脂肪的生成。那么BMP4是否調(diào)節(jié)脂肪組織中巨噬細(xì)胞的激活,從而在米色脂肪的生成中發(fā)揮作用呢？我們發(fā)現(xiàn)BMP4促進(jìn)M2型巨噬細(xì)胞的激活,而抑制M1型巨噬細(xì)胞的激活。BMP4通過激活p38/MAPK/STAT6/PI3K-AKT信號(hào)通路促進(jìn)了M2型巨噬細(xì)胞的增殖。BMP4除了通過M2型巨噬細(xì)胞分泌的兒茶酚胺類激素激活米色脂肪細(xì)胞的功能,也能促進(jìn)M2巨噬細(xì)胞分泌促血管生成因子,增加脂肪組織血管的新生,從而在米色脂肪的生成和功能發(fā)揮中起作用(待發(fā)表)。

產(chǎn)熱脂肪組織對(duì)代謝性疾病的治療潛能脂肪組織發(fā)育異常與許多疾病密切相關(guān),脂肪組織過多會(huì)引起肥胖。過多的脂質(zhì)沉積又是胰島素抵抗、2型糖尿病、高血壓等心血管疾病、非酒精性脂肪肝以及某些癌癥的主要危險(xiǎn)因素[54]。到目前還沒有有效的治療方法。而通過促進(jìn)棕色和米色脂肪發(fā)育或激活已成為治療肥胖的新研究方向。

人具有產(chǎn)熱性脂肪 嬰幼兒利用棕色脂肪維持正常體溫[6,23,29]。PET-CT (positron emission tomography and X-ray computed tomography)顯示成年人也含有UCP-1陽性的產(chǎn)熱脂肪細(xì)胞[7-10,55]。成人棕色脂肪主要是指“米色脂肪”,散落在成人體內(nèi)脊柱兩側(cè)以及鎖骨附近的皮膚[15]。體外實(shí)驗(yàn)顯示,人棕色和米色脂肪細(xì)胞可以由棕色和白色脂肪組織的SVF分化而來,在體移植研究表明,這些早期的產(chǎn)熱脂肪細(xì)胞前體能被激活并發(fā)揮燃燒脂肪的作用[27-28,55-56]。Min等[27]發(fā)現(xiàn),激活體外人SVF分化而來的米色細(xì)胞在體內(nèi)保留其產(chǎn)熱功能,而且將人原代的米色脂肪細(xì)胞移植能改善正常飲食和高脂飲食誘導(dǎo)的肥胖小鼠的代謝穩(wěn)態(tài)?；A(chǔ)脂肪細(xì)胞培養(yǎng)液中加入cAMP、 forskolin或去甲腎上腺素,能誘導(dǎo)和激活由成人脂肪塊前體細(xì)胞發(fā)育來的產(chǎn)熱脂肪細(xì)胞[28,55-56]。以上關(guān)于人原代脂肪細(xì)胞的激活和產(chǎn)熱功能提示米色脂肪細(xì)胞可用于體內(nèi)治療肥胖和相關(guān)代謝疾病。

人體內(nèi)產(chǎn)熱脂肪細(xì)胞可被冷暴露激活[7,9-10]。中等程度的冷暴露 (16 ℃)情況下,96%志愿者的BAT也被激活,瘦的個(gè)體BAT活性比肥胖個(gè)體更高[10]。選擇性β3-腎上腺素能受體激動(dòng)劑米拉貝隆(Mirabegron)能激活BAT,改善成人代謝穩(wěn)態(tài)[8]。冷暴露人血循環(huán)中irisin(鳶尾素)和FGF21水平增加,并進(jìn)一步激活人BAT的產(chǎn)熱功能[31]。有研究發(fā)現(xiàn)NAD+/sirtuin (SIRT) 通路能調(diào)控脂肪生成和產(chǎn)熱脂肪細(xì)胞[57-61]。2012年,Cantó等[57]發(fā)現(xiàn)煙酰胺核糖(nicotinamide riboside,NR) 能增加小鼠NAD+水平,激活 SIRT信號(hào)通路,提高棕色脂肪的氧化功能、能量消耗和減少飲食誘導(dǎo)的肥胖。2型糖尿病小鼠模型中,NR能提高小鼠葡萄糖耐量和減輕體重[62]。另外,Kahn等[61]也發(fā)現(xiàn)NR通過誘導(dǎo)線粒體功能促進(jìn)產(chǎn)熱。而NR臨床實(shí)驗(yàn)顯示,NR增加細(xì)胞能量產(chǎn)生,并且沒有任何嚴(yán)重的不良反應(yīng)[63]。以上結(jié)果表明激活BAT形成和活性的激活劑有可能被用于治療肥胖和超重。

產(chǎn)熱脂肪細(xì)胞的臨床應(yīng)用潛能

運(yùn)動(dòng)可誘導(dǎo)產(chǎn)熱脂肪形成 運(yùn)動(dòng)訓(xùn)練能提高全身葡萄糖穩(wěn)態(tài)和胰島素敏感性,在臨床上廣泛應(yīng)用于預(yù)防糖尿病和降低2型糖尿病患者血糖,主要負(fù)責(zé)消耗葡萄糖的骨骼肌的改變是這種作用的核心[64]。盡管骨骼肌對(duì)運(yùn)動(dòng)所致有利的代謝穩(wěn)態(tài)是最重要的,運(yùn)動(dòng)還會(huì)導(dǎo)致許多其他組織包括脂肪組織的改變。規(guī)律運(yùn)動(dòng)訓(xùn)練能引起脂肪組織脂肪細(xì)胞變小,脂含量降低[65-66],線粒體蛋白增加,導(dǎo)致皮下脂肪中米色脂肪細(xì)胞增加[67-71]。將小鼠暴露在含有轉(zhuǎn)輪的豐富環(huán)境中3～4周,米色脂肪細(xì)胞明顯增加,表現(xiàn)為UCP1、PRDM16和其他棕色或米色脂肪標(biāo)志基因增加[70-71]。小鼠短期轉(zhuǎn)輪運(yùn)動(dòng)訓(xùn)練就可導(dǎo)致棕色和米色脂肪標(biāo)志基因明顯上調(diào)[67]。大多數(shù)非運(yùn)動(dòng)誘導(dǎo)的米色化(冷暴露,許多藥物等),可能通過熱量散失和代償性的腎上腺素能激活,導(dǎo)致產(chǎn)熱需求增加,交感緊張度增加,進(jìn)而Ucp1增加以提高產(chǎn)熱[72]。然而運(yùn)動(dòng)訓(xùn)練導(dǎo)致米色化的功能目前尚不清楚。主要有以下幾種假說:運(yùn)動(dòng)訓(xùn)練使皮下脂肪細(xì)胞變小,脂含量降低會(huì)導(dǎo)致身體的絕緣效果下降,必需通過皮下脂肪米色化產(chǎn)熱[72-73];運(yùn)動(dòng)能增加皮下脂肪神經(jīng)支配可能與皮下脂肪米色化有關(guān)[72,74];運(yùn)動(dòng)通過其他組織的改變導(dǎo)致白色脂肪米色化,例如下丘腦來源的神經(jīng)營養(yǎng)因子分泌增加與運(yùn)動(dòng)誘導(dǎo)的米色化有關(guān)[70],骨骼肌釋放的運(yùn)動(dòng)因子對(duì)米色化有關(guān)[75],包括鳶尾素[70]、meteorin樣蛋白1[48]、肌肉生長(zhǎng)抑制素(myostatin,MSTN)[48]和 β-氨基異丁酸[76]等。運(yùn)動(dòng)誘導(dǎo)的皮下脂肪米色化機(jī)制還需進(jìn)一步闡明。無論通過哪種方式激活產(chǎn)熱脂肪,利用運(yùn)動(dòng)增加產(chǎn)熱脂肪生成已成為治療肥胖及相關(guān)代謝性疾病提供有效、經(jīng)濟(jì)的方法。

產(chǎn)熱脂肪激活的藥物開發(fā) 肥胖發(fā)生的根本原因是能量攝入長(zhǎng)期大于能量支出。預(yù)防或治療肥胖癥則要減少能量攝入,增加能量支出。肥胖癥的治療包括生活方式干預(yù),藥物治療和手術(shù)治療。當(dāng)生活方式干預(yù)不能有效降低體重,患者身體狀況又不適合手術(shù)時(shí),則需要考慮用藥物治療[77]。目前美國食品藥品監(jiān)督管理局(Food and Drug Administration,FDA)批準(zhǔn)的可以長(zhǎng)期使用的減肥藥有5種,分別為Orlistat,Lorcaserin,Phentermine/topiramate,Naltrexone/bupropion和Liraglutide,但是這些藥物具有不同程度的不良反應(yīng),極大地限制了它們?cè)谂R床上的應(yīng)用[78]。因此,減肥的藥物治療遠(yuǎn)遠(yuǎn)沒有達(dá)到理想的臨床效果。開發(fā)新藥迫在眉睫?？偟膩碚f,人體的產(chǎn)熱性脂肪組織具有良好的消耗多余能量的潛力,并且能在一定條件下激活;激活產(chǎn)熱性脂肪組織,不管是增強(qiáng)棕色脂肪的功能,還是促進(jìn)白色脂肪棕色化,都能有效地消耗多余能量,達(dá)到控制體重和改善代謝的目的。這使得產(chǎn)熱性脂肪組織成為治療肥胖癥的理想靶點(diǎn)[79]。目前,FDA批準(zhǔn)的減肥藥都是針對(duì)限制能量攝入開發(fā)的,通過促進(jìn)產(chǎn)熱性脂肪組織增加能量消耗發(fā)揮作用的減肥藥目前還沒有。已有研究發(fā)現(xiàn)可以激活產(chǎn)熱性脂肪組織的化合物,如辣椒素及其類似物[80],黃連素[81],紫鉚因[82],白藜蘆醇[83],水楊酰水楊酸[84]等(圖2)。進(jìn)一步說明了產(chǎn)熱性脂肪組織可通過藥物化學(xué)手段激活,具有作為治療靶點(diǎn)的可行性。但是以上化合物均不是針對(duì)產(chǎn)熱性脂肪組織開發(fā)的。迄今為止,沒有開展針對(duì)產(chǎn)熱性脂肪組織進(jìn)行的藥物篩選工作。

我們課題組發(fā)現(xiàn)青蒿素衍生物青蒿素甲醚能夠促進(jìn)白色脂肪米色化,同時(shí)增強(qiáng)米色脂肪的功能而預(yù)防肥胖,該研究發(fā)表在國際著名學(xué)術(shù)期刊CellResearch上[85]。青蒿素是古老中藥的一筆寶藏,幾十年來它為數(shù)以百萬計(jì)的瘧疾患者帶來了益處。我們篩選了3 000個(gè)化合物,并鑒定出了一個(gè)候選化合物青蒿素甲醚。暴露于青蒿素甲醚的3T3-L1細(xì)胞體積更小,并包含多個(gè)小脂滴,這是產(chǎn)熱脂肪細(xì)胞的典型特征。一步式qPCR顯示,在青蒿素甲醚處理后,米色脂肪相關(guān)基因(如PRDM16、PGC1a和UCP1)的相對(duì)mRNA水平有所升高。在C3H10T1/2細(xì)胞(一種間充質(zhì)干細(xì)胞系,可被誘導(dǎo)成脂肪細(xì)胞)也有類似結(jié)果,表現(xiàn)出產(chǎn)熱脂肪細(xì)胞的典型形態(tài)(體積更小,包含多室的脂滴)。青蒿素甲醚以劑量依賴性的方式上調(diào)米色相關(guān)基因(如UCP1、PGC1α和PRDM16)以及線粒體基因Cyto C的表達(dá)水平。為了進(jìn)一步驗(yàn)證青蒿素甲醚的促進(jìn)米色化的效應(yīng),我們從雄性C57BL6/J小鼠的腹股溝脂肪組織中分離出了包含脂肪前體細(xì)胞的基質(zhì)血管組分(stromal vasvular fraction cells,SVFs),暴露于青蒿素、甲醚的SVFs發(fā)育成為棕色樣脂肪細(xì)胞。而青蒿素甲醚誘導(dǎo)的C3H10T1/2 細(xì)胞棕色化過程中,p38 MAPK/ATF2軸被激活,Akt/mTOR通路去活化。這表明,在脂肪形成過程中,青蒿素衍生物可能通過調(diào)節(jié)兩個(gè)通路來調(diào)節(jié)脂肪棕色化,進(jìn)而預(yù)防肥胖。我們隨后通過皮下注射觀察青蒿素甲醚的體內(nèi)效果,并通過腹腔注射探索青蒿素甲醚的全身效應(yīng),發(fā)現(xiàn)青蒿素甲醚在嚙齒動(dòng)物模型上,同樣能促進(jìn)白色脂肪棕色化,抑制體重增長(zhǎng)及改善代謝,有良好的安全性和有效性。這是首次發(fā)現(xiàn)青蒿素甲醚類藥物有改善代謝的作用(圖2)。總之,青蒿素衍生物可在嚙齒類動(dòng)物模型中預(yù)防肥胖,并改善與肥胖相關(guān)的代謝性疾病,相信這種化合物及其衍生物在未來將有益于更多的人。

These compounds were found to elicit beneficial effects on metabolism and enhancing thermogenesis.

圖2已知可以激活米色脂肪的小分子化合物
Fig2Afewcompoundshavebeenreportedtoactivatebeiging

結(jié)語適量的脂肪組織為人體所必須,肥胖患者因含有過多的白色脂肪組織產(chǎn)生慢性炎癥而引起肥胖相關(guān)的代謝性疾病;人體具有產(chǎn)熱性的脂肪組織,產(chǎn)熱性脂肪組織具有良好的消耗多余能量的潛力,并且能在一定條件下激活;激活產(chǎn)熱性脂肪組織,不管是增強(qiáng)棕色脂肪的功能,還是促進(jìn)白色脂肪棕色化,都能有效地消耗多余能量,達(dá)到控制體重和改善代謝的目的。這使得產(chǎn)熱性脂肪組織成為治療肥胖癥及相關(guān)代謝性疾病的理想靶點(diǎn)。

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Therapeuticpotentialofthermogenicadiposetissue

HUANG Hai-yan1,2, TANG Qi-qun1,2△

(1DepeartmentofBiochemistryandMolecularBiology,SchoolofBasicMedicalSciences,FudanUniversity,Shanghai20032,China;2KeyLaboratoryofMetabolismandMolecularMedicine,MinistryofEducation,FudanUniversity,Shanghai200032,China)

Adipose tissue plays a critical role in regulating whole-body energy homeostasis.There are three types of adipose tissues in humans: white,brown and beige.Both beige and brown adipose burn lipid by dissipating energy in the form of heat and are uniformly referred to as thermogenic adipose tissue.In this review,we will summarize the recent findings in the activation of thermogenic adipose tissue and its therapeutic potential to counteract obesity and its related disorders.

thermogenic adipose tissue; energy metabolism; obesity; metabolic disorders

Q71,R589

A

10.3969/j.issn.1672-8467.2017.06.012

國家自然科學(xué)基金(31271489,81170781,31030048C120114)

△Corresponding author E-mail:qqtang@shmu.edu.cn

*ThisworkwassurpportedbytheNationalNaturalScienceFoundationofChina(31271489,81170781,31030048C120114).

2017-10-01;編輯:張秀峰)