神經(jīng)元穩(wěn)態(tài)失衡和飲食誘導(dǎo)肥胖癥的相關(guān)性研究進(jìn)展

黃智舜，鄭夢盈，馮慶君，洪燕女，盧鐘磊

神經(jīng)元穩(wěn)態(tài)失衡和飲食誘導(dǎo)肥胖癥的相關(guān)性研究進(jìn)展

黃智舜，鄭夢盈，馮慶君，洪燕女，盧鐘磊

福州大學(xué) 生物科學(xué)與工程學(xué)院，福建 福州 350108

近年來，因肥胖癥所造成的社會(huì)問題和醫(yī)療負(fù)擔(dān)越發(fā)嚴(yán)重。肥胖主要是由于機(jī)體能量的攝入與消耗不平衡所致，而中樞神經(jīng)系統(tǒng)以及相關(guān)神經(jīng)元在機(jī)體能量代謝平衡的調(diào)控中發(fā)揮著重要作用。下丘腦弓狀核含有抑食性阿黑皮素原(Proopiomelanocortin，POMC) 神經(jīng)元和促食性神經(jīng)肽Y (Neuropeptid Y，NPY)/刺鼠相關(guān)蛋白(Agouti-related protein，AgRP) 神經(jīng)元，是調(diào)控機(jī)體攝食行為的主要神經(jīng)元。研究顯示，高脂飲食會(huì)誘導(dǎo)POMC神經(jīng)元中的Rb蛋白發(fā)生磷酸化修飾并失活，導(dǎo)致POMC神經(jīng)元從靜息狀態(tài)重新進(jìn)入細(xì)胞周期循環(huán)，進(jìn)而迅速轉(zhuǎn)向細(xì)胞凋亡。高脂飲食也會(huì)引起神經(jīng)元再生抑制，并誘導(dǎo)炎癥發(fā)生和神經(jīng)元損傷，使神經(jīng)元穩(wěn)態(tài)失衡，引發(fā)瘦素抵抗，最終導(dǎo)致肥胖癥的發(fā)生。文中就神經(jīng)元穩(wěn)態(tài)失衡以及肥胖癥等疾病之間的關(guān)系進(jìn)行了綜述，希望能為飲食誘導(dǎo)肥胖癥等疾病的治療和預(yù)防提供新的方向和思路。

肥胖癥，神經(jīng)元穩(wěn)態(tài)失衡，高脂飲食

全球62%的肥胖人口集中在發(fā)展中國家，并且其肥胖增長率持續(xù)增加。2016年報(bào)告指出，全球男性肥胖率從1975年的3.2%增至10.8%，女性肥胖率從6.4%增至14.9%[1]，若以同樣的速度增長，2030年時(shí)全球?qū)⒂?1.2億人發(fā)展成肥胖，占世界人口的20%[2]。肥胖癥往往由多種因素相互影響而導(dǎo)致的，其中最主要的是能量調(diào)節(jié)神經(jīng)元和攝食行為控制中樞發(fā)生紊亂，機(jī)體能量代謝失衡，機(jī)體消耗的能量少于所攝入的，多余的能量轉(zhuǎn)變?yōu)橹?，最終引起肥胖[3]。瘦素能夠調(diào)節(jié)機(jī)體脂肪的儲(chǔ)存量并維持機(jī)體的能量平衡，瘦素功能異常是導(dǎo)致肥胖癥等主要原因之一。肥胖經(jīng)常與冠心病、高血壓以及胰島素抵抗等伴隨出現(xiàn)，不僅是心腦血管疾病、糖尿病、癌癥、痛風(fēng)等慢性病的重要誘因，還與神經(jīng)退行性疾病息息相關(guān)。內(nèi)側(cè)基底下丘腦是機(jī)體能量和攝食行為的神經(jīng)調(diào)節(jié)中樞，神經(jīng)元穩(wěn)態(tài)失衡會(huì)導(dǎo)致能量調(diào)節(jié)和攝食相關(guān)神經(jīng)元的減少，引發(fā)飲食誘導(dǎo)肥胖癥的形成[4]。文中主要論述中樞神經(jīng)系統(tǒng) (Central nervous system，CNS) 與機(jī)體能量調(diào)節(jié)、神經(jīng)元穩(wěn)態(tài)失衡和肥胖癥等疾病的關(guān)系，為肥胖癥等疾病的預(yù)防和治療提供參考。

1 中樞神經(jīng)系統(tǒng)與機(jī)體能量調(diào)節(jié)

1.1 能量調(diào)節(jié)中樞

內(nèi)側(cè)基底下丘腦 (Mediobasal hypothalamus，MBH) 是機(jī)體能量及攝食行為神經(jīng)調(diào)節(jié)中樞，位于大腦腹側(cè)，丘腦的下方，其可被劃分為弓狀核(Arcuate nucleus，ARC) 及腹內(nèi)側(cè)核 (Ventromedial nucleus，VMN)。位于內(nèi)側(cè)基底下丘腦的ARC與血腦屏障相對(duì)薄弱的正中隆起毗鄰，外周血液中的營養(yǎng)成分和激素可以通過毛細(xì)血管作用在ARC的神經(jīng)元，因此ARC被認(rèn)為是較早感知外周能量代謝變化的區(qū)域，并將信息傳遞到大腦其他部位[5]。ARC中主要包括兩類作用相反的神經(jīng)元，一類是分泌促進(jìn)食欲的神經(jīng)肽Y (Neuropeptid Y，NPY) 和刺鼠相關(guān)蛋白(Agouti-related protein，AgRP) 的神經(jīng)元；另一類是分泌抑制食欲的阿黑皮素原(Proopiomelanocortin，POMC) 及可卡因和安非他明調(diào)節(jié)轉(zhuǎn)錄肽(Cocaine-and amphetamine- regulated transcript，CART) 的神經(jīng)元[6]。這些神經(jīng)元是接收外周代謝信號(hào)的初級(jí)神經(jīng)元，如胰島素、胃促生長素和瘦素等信號(hào)，再由這些初級(jí)神經(jīng)元軸突投射至下丘腦室旁核、下丘腦外側(cè)區(qū)及腹內(nèi)側(cè)核的次級(jí)神經(jīng)元。

下丘腦室旁核和腹內(nèi)側(cè)核都接受著由弓狀核投射出的神經(jīng)纖維，室旁核會(huì)釋放具有厭食作用的神經(jīng)肽，如促腎上腺皮質(zhì)激素釋放激素，而腹內(nèi)側(cè)核可生成具有厭食性的腦源性神經(jīng)營養(yǎng)因子[7]。研究表明，下丘腦室旁核和腹內(nèi)側(cè)核被破壞后，均會(huì)導(dǎo)致動(dòng)物攝食增加、高血糖及肥胖癥的產(chǎn)生[8]。下丘腦室旁核和腹內(nèi)側(cè)核在能量調(diào)節(jié)中樞中起到抑制食物攝入和體質(zhì)量增加的作用。下丘腦外側(cè)區(qū)可合成并分泌具有促食性作用的神經(jīng)肽，包括增食欲素 (Orexin) 和黑色素濃集激素 (Melanin concentrating hormone，MCH)[9]。下丘腦外側(cè)核損傷會(huì)導(dǎo)致攝食量和體質(zhì)量的減少，被認(rèn)為是能量調(diào)節(jié)中樞的攝食中樞[10]。各個(gè)神經(jīng)通路相輔相成，通過CNS，維持著機(jī)體能量代謝平衡和攝食行為的調(diào)控。

1.2 能量調(diào)節(jié)神經(jīng)元

調(diào)控?cái)z食行為最為廣泛報(bào)道的兩類能量調(diào)節(jié)神經(jīng)元為抑食性的POMC神經(jīng)元和促食性的AgRP神經(jīng)元，兩者功能相互拮抗。機(jī)體通過相關(guān)激素來調(diào)控對(duì)應(yīng)的能量調(diào)節(jié)神經(jīng)元，從而控制機(jī)體的能量代謝。如瘦素可通過結(jié)合瘦素受體來激活瘦素靶神經(jīng)元，在多種細(xì)胞信號(hào)通路的作用下，發(fā)揮其抑制食欲、抑制脂肪合成以及增加機(jī)體能量消耗等功能[11-12]，參與對(duì)機(jī)體能量代謝平衡和穩(wěn)態(tài)的調(diào)控[13]。研究表明，瘦素靶神經(jīng)元功能異常往往和肥胖癥、心腦血管疾病和Ⅱ型糖尿病等息息相關(guān)，其中瘦素抵抗是主要的致病機(jī)制之一。瘦素抵抗是指體內(nèi)存在高瘦素水平，但對(duì)瘦素減少體重的信號(hào)反應(yīng)能力減弱，沒有發(fā)揮其減少攝食和增加能量消耗的功能，大多數(shù)肥胖者和嚙齒類動(dòng)物存在此現(xiàn)象[14]。

瘦素能促進(jìn)POMC神經(jīng)元合成并分泌具有厭食作用的α-促黑色素細(xì)胞刺激素(α-melanocyte- stimulating hormone，α-MSH)，α-MSH與其受體MC4R結(jié)合作用于其下游神經(jīng)元，發(fā)揮其抑制食欲和增加機(jī)體能量消耗的功能，并抑制肝細(xì)胞葡萄糖的釋放從而有效地降低了血糖濃度[15]。而AgRP神經(jīng)元能合成并釋放具有增強(qiáng)食欲的AgRP和NPY神經(jīng)肽，神經(jīng)肽AgRP與α-MSH競爭結(jié)合MCR4，從而拮抗α-MSH抑制攝食的作用，促食欲的NYP神經(jīng)肽能促進(jìn)攝食行為[16-17]。這兩條能量調(diào)節(jié)神經(jīng)通路互相配合，共同維持機(jī)體能量穩(wěn)態(tài)的平衡[18]。

Challis等[19]研究表明，敲除基因的小鼠，在正常的飲食條件下，其體重和攝食量明顯增加，且食欲會(huì)更加亢奮，導(dǎo)致更加明顯的肥胖。POMC神經(jīng)元對(duì)機(jī)體葡萄糖穩(wěn)態(tài)的維持也起著重要的作用。弓狀核區(qū)胰島素受體顯著下調(diào)的小鼠POMC神經(jīng)元會(huì)重新表達(dá)胰島素受體，瘦素受體缺失的小鼠POMC神經(jīng)元會(huì)重新表達(dá)瘦素受體，雖然其肥胖表型沒有得到明顯的改善，但其高血糖癥和高胰島素血癥得到了明顯的改善[20]。這些研究表明POMC神經(jīng)元通過胰島素和瘦素信號(hào)通路參與了肝臟葡萄糖代謝，但其具體機(jī)制仍不明確。

敲除基因的小鼠攝食量顯著減少[21]，相反，激活了AgRP神經(jīng)元，小鼠會(huì)出現(xiàn)食欲亢進(jìn)、體重增加等現(xiàn)象[22]。沉默AgRP神經(jīng)元后，正常喂飼條件下，小鼠的攝食量顯著減少，然而當(dāng)給予高脂高糖飲食，小鼠的攝食量恢復(fù)到正常水平，表明AgRP神經(jīng)元功能受損可能會(huì)增加食物誘發(fā)攝食行為的壓力[23]。

2 神經(jīng)元穩(wěn)態(tài)失衡與肥胖癥的關(guān)系

神經(jīng)元穩(wěn)態(tài)平衡涉及到神經(jīng)元的諸多細(xì)胞生物學(xué)過程，包括神經(jīng)元再生、細(xì)胞周轉(zhuǎn)以及保持神經(jīng)元有絲分裂靜息狀態(tài)等。能量調(diào)節(jié)神經(jīng)元可通過中樞神經(jīng)系統(tǒng)對(duì)機(jī)體的攝食行為和能量代謝平衡進(jìn)行調(diào)控，神經(jīng)元細(xì)胞分化成熟后不再分裂，過度損傷無法逆轉(zhuǎn)，所以更加需要維持能量調(diào)節(jié)神經(jīng)元的穩(wěn)態(tài)平衡。Lu等[24]相關(guān)研究表明，高脂飲食可引起小鼠下丘腦弓狀核POMC神經(jīng)元的Rb磷酸化，導(dǎo)致抑食性的POMC神經(jīng)元異常，最終造成小鼠肥胖。高脂飲食可抑制神經(jīng)元再生，誘導(dǎo)神經(jīng)元損傷、腦部炎癥的發(fā)生和神經(jīng)元細(xì)胞周期蛋白異常等，引起神經(jīng)元穩(wěn)態(tài)失衡，最終造成肥胖癥等疾病。

2.1 飲食誘導(dǎo)肥胖癥中的神經(jīng)元再生和損傷

研究表明，在飲食誘導(dǎo)肥胖癥模型中，神經(jīng)元再生受到抑制，神經(jīng)膠質(zhì)增多，并特異誘導(dǎo)下丘腦神經(jīng)元凋亡，導(dǎo)致神經(jīng)元損傷。神經(jīng)再生存在于成人下丘腦中，Mcnay等[25]研究發(fā)現(xiàn)，高脂飲食 (High-fat diet，HFD) 小鼠神經(jīng)元再生受到抑制，新生成的神經(jīng)元較少，這些神經(jīng)元周轉(zhuǎn)的抑制與新生神經(jīng)元凋亡的增加有關(guān)。成熟下丘腦神經(jīng)干細(xì)胞 (Adult hypothalamic NSCs，htNSCs) 存在于內(nèi)側(cè)基底下丘腦，高脂飲食可導(dǎo)致htNSCs損傷，顯著減少弓狀核區(qū)域BrdU陽性及Sox-2陽性神經(jīng)元數(shù)目，表明高脂飲食抑制了弓狀核區(qū)域神經(jīng)元的再生和存活，htNSCs神經(jīng)分化損傷最終會(huì)發(fā)展成肥胖癥和糖尿病等疾病[25-26]。Thaler等[27]研究發(fā)現(xiàn)，高脂喂飼一周后，在大鼠和小鼠的下丘腦弓狀核中，神經(jīng)元損傷的標(biāo)志物和反應(yīng)性膠質(zhì)的增生明顯增多。8個(gè)月的高脂喂飼導(dǎo)致小鼠下丘腦POMC神經(jīng)元相對(duì)于對(duì)照組減少25%。一項(xiàng)對(duì)34位病人大腦核磁共振成像的回顧性分析結(jié)果顯示，類似膠質(zhì)細(xì)胞活化增生的下丘腦損傷與患者的肥胖癥狀存在相關(guān)性。以上研究表明，高脂飲食使能量調(diào)節(jié)神經(jīng)元異常，抑制其神經(jīng)元再生，誘導(dǎo)其凋亡，導(dǎo)致神經(jīng)膠質(zhì)增多，損傷能量調(diào)節(jié)中樞，引起能量代謝平衡失調(diào)，最終發(fā)展成飲食誘導(dǎo)肥胖癥。

2.2 飲食誘導(dǎo)肥胖癥中的下丘腦炎癥

飲食誘導(dǎo)嚙齒類動(dòng)物肥胖模型中，其外周組織和下丘腦區(qū)域發(fā)生炎癥反應(yīng)。在大鼠和小鼠高脂喂飼1–3 d后，下丘腦炎癥信號(hào)明顯。高脂飲食通過一種依賴于炎癥原位激活的機(jī)制來鈍化下丘腦中瘦素和胰島素的厭食信號(hào)[28]。作為代謝炎癥的介質(zhì)，促炎蛋白核因子κB (Nuclear factor κB，NF-κB) 及其上游激活因子IκB激酶β (IκB kinase β，IKKβ) 廣泛存在于下丘腦神經(jīng)元，通常保持無活性狀態(tài)，高脂飲食通過提高下丘腦內(nèi)質(zhì)網(wǎng)應(yīng)激來激活下丘腦IKKβ/NF-κB。強(qiáng)制激活下丘腦IKKβ/NF-κB會(huì)中斷中樞胰島素/瘦素信號(hào)傳導(dǎo)，并中斷了IKKβ的作用或細(xì)胞特異性抑制[29]。Purkayastha等[30]發(fā)現(xiàn)，下丘腦炎癥反應(yīng)能夠誘發(fā)高血壓。腫瘤壞死因子-α (Tumor necrosis factor-α，TNF-α) 可誘導(dǎo)IKKβ的磷酸化而激活I(lǐng)KKβ/NF-κB，在小鼠內(nèi)側(cè)基底下丘腦急性激活I(lǐng)KKβ/NF-κB會(huì)迅速升高小鼠血壓，TNF-α主要激活POMC神經(jīng)元中的IKKβ/NF-κB，而不是NPY/AgRP神經(jīng)元，而抑制內(nèi)側(cè)基底下丘腦POMC神經(jīng)元的NF-κB活性，能夠抵抗飲食性誘導(dǎo)肥胖癥相關(guān)的高血壓。所以POMC神經(jīng)元對(duì)于下丘腦IKKβ和NF-κB激活高血壓效應(yīng)是至關(guān)重要的[31]，下丘腦炎癥相關(guān)信號(hào)通路IKKβ和NF-κB的激活是飲食誘導(dǎo)肥胖與高血壓之間主要的致病因素。由于下丘腦炎癥信號(hào)轉(zhuǎn)導(dǎo)可以導(dǎo)致細(xì)胞凋亡信號(hào)的激活，Moraes等[28]評(píng)估了高脂飲食對(duì)誘導(dǎo)下丘腦細(xì)胞凋亡的影響，結(jié)果表明高脂飲食可在下丘腦弓狀核和外側(cè)區(qū)誘導(dǎo)神經(jīng)元凋亡和減少突觸輸入。飲食誘導(dǎo)肥胖癥的下丘腦炎癥與多種中樞神經(jīng)系統(tǒng)的信號(hào)通路息息相關(guān)，會(huì)造成神經(jīng)膠質(zhì)增生和神經(jīng)元損傷，從而引發(fā)進(jìn)一步的能量調(diào)節(jié)神經(jīng)元穩(wěn)態(tài)失衡，破壞能量代謝平衡。

2.3 飲食誘導(dǎo)肥胖癥下的神經(jīng)元細(xì)胞周期異常與穩(wěn)態(tài)失衡

神經(jīng)元細(xì)胞分化成熟，處于有絲分裂后狀態(tài) (Post-mitotic state)，不再進(jìn)入細(xì)胞周期循環(huán)和增殖[32]。Rb蛋白是基因 (Retinoblastoma gene，RB) 的編碼產(chǎn)物，是重要的細(xì)胞周期調(diào)節(jié)因子，結(jié)合并抑制下游轉(zhuǎn)錄因子E2Fs的活性，使細(xì)胞周期停滯[33]，Rb蛋白的活性缺失將使細(xì)胞進(jìn)入S期并增殖[34]。因此，神經(jīng)元的穩(wěn)態(tài)平衡和有絲分裂后狀態(tài)的維持或許與Rb蛋白的作用緊密相關(guān)。研究表明，Rb除了在腫瘤細(xì)胞中以基因突變失活外，還可通過磷酸化失活，而其上游可能存在的激酶有細(xì)胞周期蛋白依賴性激酶(Cyclin-dependent kinases，CDKs) 和AMP活化蛋白激酶 (AMP-activated protein kinase，AMPK)[35-36]。一些病理狀態(tài)的局部微環(huán)境有可能通過上調(diào)改變Rb上游激酶的活性來增加Rb蛋白的磷酸化水平，使得Rb功能失活，進(jìn)而影響到神經(jīng)元有絲分裂后狀態(tài)的維持，破壞神經(jīng)元穩(wěn)態(tài)平衡。

筆者課題組相關(guān)研究表明，高脂喂飼導(dǎo)致小鼠下丘腦弓狀核POMC神經(jīng)元Rb蛋白磷酸化。在小鼠POMC神經(jīng)元和AgRP神經(jīng)元中特異性敲除，發(fā)現(xiàn)Rb蛋白缺失可導(dǎo)致POMC神經(jīng)元從靜息狀態(tài)重新進(jìn)入細(xì)胞周期循環(huán)，進(jìn)而迅速轉(zhuǎn)向細(xì)胞凋亡，抑食性POMC神經(jīng)元數(shù)目急劇減少，小鼠攝食明顯增加進(jìn)而發(fā)展成肥胖癥；而當(dāng)在促食性的AgRP神經(jīng)元中被特異性敲除后，沒有發(fā)現(xiàn)任何細(xì)胞水平及小鼠表型的變化，表明Rb蛋白的功能具有神經(jīng)元細(xì)胞特異性[24]。以上研究表明，高脂喂飼可導(dǎo)致Rb蛋白磷酸化異常，Rb功能失活使下游E2F通路激活，從而導(dǎo)致下丘腦能量調(diào)節(jié)神經(jīng)元穩(wěn)態(tài)失衡，與能量調(diào)節(jié)、攝食行為密切相關(guān)的神經(jīng)元減少，并引起瘦素抵抗，最終發(fā)展成飲食誘導(dǎo)肥胖癥。

3 飲食誘導(dǎo)肥胖癥潛在的治療策略

Lu等[24]相關(guān)研究表明，高脂飲食導(dǎo)致小鼠下丘腦弓狀核POMC神經(jīng)元Rb蛋白磷酸化，Rb蛋白功能失活使下游E2F通路激活，還可能引發(fā)下丘腦炎癥的發(fā)生和神經(jīng)元細(xì)胞損傷，從而導(dǎo)致下丘腦神經(jīng)元穩(wěn)態(tài)失衡和能量調(diào)節(jié)神經(jīng)元的減少，最終發(fā)展成飲食誘導(dǎo)肥胖癥。所以，抑制下丘腦弓狀核POMC神經(jīng)元中Rb蛋白的磷酸化，有望成為一種治療飲食誘導(dǎo)肥胖癥的新方法。細(xì)胞周期蛋白D (Cyclin D) 能結(jié)合并激活CDK4和CDK6，形成CDK4/6-Cyclin D復(fù)合物，磷酸化Rb蛋白而釋放轉(zhuǎn)錄因子E2Fs，進(jìn)一步激活下游相關(guān)通路[37]。筆者課題組未發(fā)表的數(shù)據(jù)顯示，通過慢病毒介導(dǎo)，在小鼠基底下丘腦表達(dá)Rb不可磷酸化的突變體，在下丘腦局部形成了抑制Rb磷酸化的生理?xiàng)l件，從而抑制了小鼠肥胖癥表型。該結(jié)果提供了一種治療飲食誘導(dǎo)肥胖癥的新思路。Abemaciclib是一種高度特異的口服小分子CDK4/6抑制劑，能抑制Rb磷酸化，導(dǎo)致G1期阻滯，從而抑制細(xì)胞增殖，已經(jīng)被FDA批準(zhǔn)用于臨床治療。Abemaciclib具有抑制POMC神經(jīng)元中Rb磷酸化的作用，因而有望被進(jìn)一步開發(fā)用于治療飲食誘導(dǎo)肥胖癥，具有良好的應(yīng)用前景，但是關(guān)于藥物的靶向性和給藥方式，仍然需要進(jìn)一步的研究和探索。

NAD依賴性脫乙酰酶Sirtuin-1 (NAD-dependent deacetylase sirtuin-1，SIRT1) 是一種代謝傳感器蛋白質(zhì)，通過氧化煙酰胺腺嘌呤二核苷酸 (NAD+) 去乙?；irt1在下丘腦中表達(dá)，禁食后其表達(dá)增加[38]。急性抑制下丘腦Sirt1的水平會(huì)降低大鼠禁食誘導(dǎo)的食欲過盛[39-40]。Ramadori等[41]研究證實(shí)，POMC神經(jīng)元中的Sirt1，對(duì)長期控制體重穩(wěn)態(tài)有著重要作用。在POMC神經(jīng)元中，缺乏脫乙酰酶Sirt1會(huì)導(dǎo)致能量消耗減少，從而引起對(duì)飲食誘導(dǎo)肥胖的超敏反應(yīng)。在敲除的突變小鼠中，POMC神經(jīng)元中瘦素參與磷酸肌醇3-激酶信號(hào)的能力與周圍白色脂肪組織重塑的能力嚴(yán)重受損，說明POMC神經(jīng)元中的Sirt1對(duì)抵抗飲食誘導(dǎo)肥胖的正常自主適應(yīng)是必不可少的[42]，維持POMC神經(jīng)元中的Sirt1，可作為治療肥胖癥的潛在策略之一。

IKKβ/NF-κB在下丘腦中介導(dǎo)胰島素和瘦素抵抗，有可能是導(dǎo)致肥胖癥和Ⅱ型糖尿病的核心致病機(jī)制之一。細(xì)胞因子信號(hào)轉(zhuǎn)導(dǎo)抑制劑3(Suppressor of cytokine signaling3，SOCS3) 是一種常見的瘦素和胰島素信號(hào)傳導(dǎo)抑制劑[43]，選擇性地消融下丘腦神經(jīng)元中的基因可以增強(qiáng)下丘腦瘦素信號(hào)，并且IKKβ/NF-κB的抑制能夠減弱SOCS3對(duì)瘦素和胰島素信號(hào)傳導(dǎo)的阻遏，SOCS3可能是下丘腦IKKβ/NF-κB引起中樞瘦素和胰島素抵抗的重要中介[31]。星形膠質(zhì)細(xì)胞富含于CNS，且參與許多基本過程，包括突觸傳導(dǎo)、神經(jīng)血管耦合、血腦屏障維護(hù)和免疫反應(yīng)等。在肥胖的嚙齒動(dòng)物和人類中，基底下丘腦的星形膠質(zhì)細(xì)胞被激活，星形膠質(zhì)細(xì)胞具有影響能量穩(wěn)態(tài)的潛力。Douglass等[44]研究表明，減少星形膠質(zhì)細(xì)胞炎癥信號(hào)可以保護(hù)小鼠免受HFD誘導(dǎo)下丘腦炎癥并降低對(duì)飲食誘導(dǎo)肥胖癥的易感性和葡萄糖不耐受。HFD誘導(dǎo)下，星形膠質(zhì)細(xì)胞中基因敲除的小鼠食物攝入減少，能量消耗增加，肥胖情況明顯減少。表明IKKβ/NF-κB炎癥反應(yīng)參與多種神經(jīng)元信號(hào)通路轉(zhuǎn)導(dǎo)，能調(diào)節(jié)機(jī)體能量平衡的多個(gè)方面。IKKβ/NF-κB通常在CNS中沒有活性，抑制下丘腦中的IKKβ/NF-κB信號(hào)通路可能是一種治療飲食誘導(dǎo)肥胖癥安全的方法。然而，仍然有許多問題需要進(jìn)一步的探索，例如尋找在CNS中選擇性抑制這種途徑的方法，可能會(huì)是未來的研究熱點(diǎn)。

4 總結(jié)與展望

近年來，針對(duì)肥胖癥形成機(jī)制的研究越發(fā)深入，而能量調(diào)節(jié)神經(jīng)元對(duì)肥胖癥的作用一直是研究的熱點(diǎn)。本文論述了神經(jīng)元穩(wěn)態(tài)失衡與肥胖癥等疾病之間可能的關(guān)系，探討了高脂飲食可造成神經(jīng)元損傷和神經(jīng)元穩(wěn)態(tài)失衡，從而引起與能量調(diào)節(jié)相關(guān)神經(jīng)元數(shù)目的減少及瘦素抵抗，最終導(dǎo)致飲食誘導(dǎo)肥胖癥等疾病的潛在分子機(jī)理和治療策略。

除肥胖癥外，神經(jīng)元穩(wěn)態(tài)失衡也存在于某些神經(jīng)退行性疾病。在阿爾茲海默癥患者中，神經(jīng)元胞內(nèi)鈣離子穩(wěn)態(tài)失衡會(huì)激活鈣離子依賴的核酸內(nèi)切酶，通過信號(hào)傳導(dǎo)[45]，誘發(fā)神經(jīng)元穩(wěn)態(tài)失衡和突觸損傷，最終導(dǎo)致認(rèn)知功能障礙[46]；帕金森病患者的神經(jīng)元存在線粒體功能障礙，不僅無法提供充足的能量，還會(huì)引發(fā)氧化應(yīng)激損傷，破壞神經(jīng)元穩(wěn)態(tài)平衡，導(dǎo)致神經(jīng)元凋亡[47]。

神經(jīng)元穩(wěn)態(tài)失衡相關(guān)疾病的發(fā)病原因往往不是單因素的，具有復(fù)雜性和多樣性。為了能取得更好的治療效果，多靶點(diǎn)和多條神經(jīng)通路的聯(lián)合治療將會(huì)成為未來的研究和治療趨勢。通過本文的論述希望能為預(yù)防和治療“飲食誘導(dǎo)肥胖癥”和某些神經(jīng)退行性疾病提供新的策略。

[1] Lin S, Naseri T, Linhart C, et al. Trends in diabetes and obesity in Samoa over 35 years, 1978–2013. Diabet Med, 2017, 34(5): 654–661.

[2] Hou XH, Liu Y, Lu HJ, et al. Ten-year changes in the prevalence of overweight, obesity and central obesity among the Chinese adults in urban shanghai, 1998–2007—comparison of two cross-sectional surveys. BMC Publ Health, 2013, 13: 1064.

[3] Lee DJ, Gjb E, Lozano AM. Neuromodulation for the treatment of eating disorders and obesity. Ther Adv Psychopharmacol, 2018, 8(2): 73–92.

[4] Caron A, Labbé SM, Lanfray D, et al. Mediobasal hypothalamic overexpression of deptor protects against high-fat diet-induced obesity. Mol Metabol, 2016, 5(2): 102–112.

[5] Ciofi P. The arcuate nucleus as a circumventricular organ in the mouse. Neurosci Lett, 2011, 487(2): 187–190.

[6] Huang MF, Hu F. Hypothalamic melanocortin system in the control of energy metabolism. J Clin Pathol Res, 2016, 36(6): 852–858 (in Chinese). 黃梅鳳, 胡芳. 下丘腦黑皮質(zhì)素系統(tǒng)對(duì)機(jī)體能量代謝的調(diào)控. 臨床與病理雜志, 2016, 36(6): 852–858.

[7] Marchelek-My?liwiec M, Cichocka E, Dziedziejko V, et al. Insulin resistance and brain-derived neurotrophic factor levels in chronic kidney disease. Ann Clin Biochem, 2015, 52(2): 213–219.

[8] Zhu YX, Wang Q, Wang S, et al. Obesity and mechanisms of appetite regulation. J Jilin Univ: Med Ed, 2013, 39(5): 1067–1071 (in Chinese). 朱永香, 王倩, 王爽, 等. 肥胖與食欲調(diào)控機(jī)制. 吉林大學(xué)學(xué)報(bào): 醫(yī)學(xué)版, 2013, 39(5): 1067–1071.

[9] Hopkins M, Blundell JE. Energy balance, body composition, sedentariness and appetite regulation: Pathways to obesity. Clin Sci, 2016, 130(18): 1615–1628.

[10] Yang DD, Xu L, Guo FF, et al. Orexin-a and endocannabinoid signaling regulate glucose-responsive arcuate nucleus neurons and feeding behavior in obese rats. Neuropeptides, 2018, 69: 26–38.

[11] Pan WW, Myers GM Jr. Leptin and the maintenance of elevated body weight. Nat Rev Neurosci, 2018, 19(2): 95–105.

[12] Gao YQ, Vidal-Itriago A, Milanova I, et al. Deficiency of leptin receptor in myeloid cells disrupts hypothalamic metabolic circuits and causes body weight increase. Mol Metab, 2018, 7: 155–160.

[13] Yang XN, Zhang CY, Wang BW, et al. Leptin signalings and leptin resistance. Prog Physiol Sci, 2015, 46(5): 327–333 (in Chinese). 楊曉寧, 張辰雨, 王炳蔚, 等. 瘦素信號(hào)與瘦素抵抗機(jī)制研究進(jìn)展. 生理科學(xué)進(jìn)展, 2015, 46(5): 327–333.

[14] Buonfiglio D, Parthimos R, Dantas R, et al. Melatonin absence leads to long-term leptin resistance and overweight in rats. Front Endocrinol, 2018, 9: 122.

[15] Myers GM Jr, Olson DP. Snapshot: Neural pathways that control feeding. Cell Metabol, 2014, 19(4): 732–732.e1.

[16] Morton GJ, Meek TH, Schwartz MW. Neurobiology of food intake in health and disease. Nat Rev Neurosci, 2014, 15(6): 367–378.

[17] Varela L, Horvath TL. Leptin and insulin pathways in POMC and AgRP neurons that modulate energy balance and glucose homeostasis. EMBO Rep, 2012, 13(12): 1079–1086.

[18] Lee N, Kim SG, Kim J, et al. Brain-specific homeobox factor as a target selector for glucocorticoid receptor in energy balance. Mol Cellul Biol, 2013, 33(14): 2650–2658.

[19] Malhotra R, Warne JP, Salas E, et al. Loss of atg12, but not atg5, in pro-opiomelanocortin neurons exacerbates diet-induced obesity. Autophagy, 2015, 11(1): 145–154.

[20] Sominsky L, Ziko I, Nguyen TX, et al. Hypothalamic effects of neonatal diet: Reversible and only partially leptin dependent. J Endocrinol, 2017, 234(1): 41–56.

[21] Egan OK, Inglis MA, Anderson GM. Leptin signaling in AgRP neurons modulates puberty onset and adult fertility in mice. J Neurosci, 2017, 37(14): 3875–3886.

[22] Aponte Y, Atasoy D, Sternson SM. AgRP neurons are sufficient to orchestrate feeding behavior rapidly and without training. Nat Neurosci, 2011, 14(3): 351–355.

[23] Denis RGP, Joly-Amado A, Webber E, et al. Palatability can drive feeding independent of agrp neurons. Cell Metabol, 2015, 22(4): 646–657.

[24] Lu ZL, Marcelin G, Bauzon F, et al. pRb is an obesity suppressor in hypothalamus and high-fat diet inhibits prb in this location. EMBO J, 2013, 32(6): 844–857.

[25] McNay DEG, Brian?on NB, Kokoeva MV, et al. Remodeling of the arcuate nucleus energy-balance circuit is inhibited in obese mice. J Clin Invest, 2012, 122(1): 142–152.

[26] Li JX, Tang YZ, Cai DS. Ikkβ/nf-κb disrupts adult hypothalamic neural stem cells to mediate a neurodegenerative mechanism of dietary obesity and pre-diabetes. Nat Cell Biol, 2012, 14(10): 999–1012.

[27] Thaler JP, Yi CX, Schur EA, et al. Obesity is associated with hypothalamic injury in rodents and humans. J Clin Invest 2012, 122(1): 153–162.

[28] Moraes JC, Coope A, Morari J, et al. High-fat diet induces apoptosis of hypothalamic neurons. PLoS ONE, 2009, 4(4): e5045.

[29] Zhang XQ, Zhang G, Zhang H, et al. Hypothalamic IKKβ/nf-κB and ER stress link overnutrition to energy imbalance and obesity. Cell, 2008, 135(1): 61–73.

[30] Purkayastha S, Zhang G, Cai DS. Uncoupling the mechanisms of obesity and hypertension by targeting hypothalamic IKK-β and NF-κB. Nat Med, 2011, 17(7): 883–887.

[31] Jiang P, Ma DF, Wang X, et al. Astragaloside iv prevents obesity-associated hypertension by improving pro-inflammatory reaction and leptin resistance. Mol Cells, 2018, 41(3): 244–255.

[32] Deneris ES, Hobert O. Maintenance of postmitotic neuronal cell identity. Nat Neurosci, 2014, 17(7): 899–907.

[33] Ianari A, Natale T, Calo E, et al. Proapoptotic function of the retinoblastoma tumor suppressor protein. Cancer Cell, 2009, 15(3): 184–194.

[34] Malumbres M, Pevarello P, Barbacid M, et al. CDK inhibitors in cancer therapy: What is next? Trends Pharmacol Sci, 2008, 29(1): 16–21.

[35] Kim KY, Wang DH, Campbell M, et al. PRMT4-mediated arginine methylation negatively regulates retinoblastoma tumor suppressor protein and promotes E2f-1 dissociation. Mol Cell Biol, 2015, 35(1): 238–248.

[36] Santiago-Cardona PG, Pérez-Morales J, González-Flores J. Detection of retinoblastoma protein phosphorylation by immunoblot analysis//Santiago-Cardona P, Ed. The Retinoblastoma Protein. New York, NY: Humana Press, 2018.

[37] Wang R, Da LT, Wulaniqige. Research progress in the role of CDK6 and E2F-1 in pRb pathway in cell cycle regulation. J Mod Oncol, 2015, 23(3): 423–426 (in Chinese). 王瑞, 達(dá)林泰, 烏蘭其其格. Cdk6及e2f-1參與細(xì)胞周期調(diào)控pRb通路的研究進(jìn)展. 現(xiàn)代腫瘤醫(yī)學(xué), 2015, 23(3): 423–426.

[38] Kim D, Nguyen MD, Dobbin MM, et al. Sirt1 deacetylase protects against neurodegeneration in models for alzheimer’s disease and amyotrophic lateral sclerosis. EMBO J, 2014, 26(13): 3169–3179.

[39] Li XL, Zhang SW, Blander G, et al. Sirt1 deacetylates and positively regulates the nuclear receptor LXR. Mol Cell, 2007, 28(1): 91–106.

[40] Purushotham A, Schug TT, Xu Q, et al. Hepatocyte-specific deletion of sirt1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. Cell Metabol, 2009, 9(4): 327–338.

[41] Ramadori G, Lee CE, Bookout AL, et al. Brain sirt1: Anatomical distribution and regulation by energy availability. J Neurosci, 2008, 28(40): 9989–9996.

[42] Ramadori G, Fujikawa T, Fukuda M, et al. Sirt1 deacetylase in POMC neurons is required for homeostatic defenses against diet-induced obesity. Cell Metabol, 2010, 12(1): 78–87.

[43] Benzler J, Ganjam GK, Pretz D, et al. Central inhibition of IKKβ/NF-κB signaling attenuates high-fat diet-induced obesity and glucose intolerance. Diabetes, 2015, 64(6): 2015–2027.

[44] Douglass JD, Dorfman MD, Fasnacht R, et al. Astrocyte IKKβ/NF-κB signaling is required for diet-induced obesity and hypothalamic inflammation. Mol Metabol, 2017, 6(4): 366–373.

[45] Ugan Y, Naz?ro?lu M, ?ahin M, et al. Anti-tumor necrosis factor alpha (infliximab) attenuates apoptosis, oxidative stress, and calcium ion entry through modulation of cation channels in neutrophils of patients with ankylosing spondylitis. J Membr Biol, 2016, 249(4): 437–447.

[46] Popugaeva E, Pchitskaya E, Bezprozvanny I. Dysregulation of neuronal calcium homeostasis in alzheimer’s disease – a therapeutic opportunity? Biochem Biophys Res Commun, 2016, 483(4): 998–1004.

[47] Liu L, Zhang K, Sandoval H, et al. Glial lipid droplets and ROS induced by mitochondrial defects promote neurodegeneration. Cell, 2015, 160(1/2): 177–190.

Advances in the correlation between loss of neural homeostasis and diet-induced obesity

Zhishun Huang, Mengying Zheng, Qingjun Feng, Yannü Hong, and Zhonglei Lu

College of Biological Sciences and Engineering, Fuzhou University, Fuzhou 350108, Fujian, China

The social problems and medical burdens caused by obesity have become more serious in recent years. Obesity is mainly caused by the imbalance of energy intake and consumption in the body. The central nervous system and related neurons regulate the balance of energy metabolism. The hypothalamic arcuate nucleus (ARC) contains anorexigenic proopiomelanocortin (POMC) neurons and orexigenic neuropeptid Y(NPY)/agouti-related protein (AgRP) neurons that regulate the feeding behavior of body. High-fat diet induces phosphorylation of Rb protein in POMC neurons, and inactivation of Rb phosphorylation leads to re-entry of POMC neurons from the resting-state into the cell cycle, which rapidly shifts to apoptosis. High-fat diet also causes the inhibition of neuronal regeneration, induces inflammation and neuronal damage, loss of neuronal homeostasis, leptin resistance, and ultimately leads to obesity. This review discusses the relationship between loss of neuronal homeostasis and dietary obesity, as well as the underlying mechanisms, which might provide the evidence for prevention and treatment of these diseases.

obesity, loss of neuronal homeostasis, high-fat diet

January 8, 2019;

March 13, 2019

Supported by: National Natural Science Foundation of China (Nos. 81600662, 81772759), School Talents Foundation of Fuzhou University (No. XRC-1625).

Zhonglei Lu. Tel/Fax: +86-591-22866278; E-mail: zhonglei.lu@fzu.edu.cn

國家自然科學(xué)基金 (Nos. 81600662, 81772759)，福州大學(xué)校人才基金 (No. XRC-1625) 資助。

2019-03-28

http://kns.cnki.net/kcms/detail/11.1998.Q.20190327.1029.002.html

黃智舜, 鄭夢盈, 馮慶君, 等. 神經(jīng)元穩(wěn)態(tài)失衡和飲食誘導(dǎo)肥胖癥的相關(guān)性研究進(jìn)展.生物工程學(xué)報(bào), 2019, 35(8): 1433–1440.Huang ZS, Zheng MY, Feng QJ, et al. Advances in the correlation between loss of neural homeostasis and diet-induced obesity. Chin J Biotech, 2019, 35(8): 1433–1440.

(本文責(zé)編 陳宏宇)