鄧秋紅 賈 剛 趙 華 陳小玲 劉光芒 蔡景義 湯加勇

(四川農(nóng)業(yè)大學(xué)動(dòng)物營(yíng)養(yǎng)研究所，成都611130)

?

新型厭食神經(jīng)肽nesfatin-1的分布和生物學(xué)功能

鄧秋紅 賈 剛*趙 華 陳小玲 劉光芒 蔡景義 湯加勇

(四川農(nóng)業(yè)大學(xué)動(dòng)物營(yíng)養(yǎng)研究所，成都611130)

nesfatin-1是新近發(fā)現(xiàn)的一種厭食神經(jīng)肽，在中樞主要位于下丘腦和腦干，在外周主要分布于胃、腸、胰島和性腺，其表達(dá)受到營(yíng)養(yǎng)、生理、病理和其他攝食激素的調(diào)節(jié)。nesfatin-1在中樞神經(jīng)元和外周細(xì)胞中與多種激素協(xié)同參與攝食和血糖穩(wěn)衡等能量代謝過程，并激活下丘腦-垂體-腎上腺軸(HPA)參與應(yīng)激反應(yīng)，還能作用于HPA影響發(fā)育期的啟動(dòng)。本文重點(diǎn)對(duì)nesfatin-1在中樞和外周的分布、影響其表達(dá)的因素以及生物學(xué)功能進(jìn)行了綜述。

nesfatin-1；分布；表達(dá)；厭食作用；生物學(xué)功能

外周和中樞神經(jīng)系統(tǒng)依靠復(fù)雜的神經(jīng)元網(wǎng)絡(luò)和激素系統(tǒng)調(diào)節(jié)動(dòng)物的采食，實(shí)現(xiàn)對(duì)能量平衡的調(diào)控。已經(jīng)發(fā)現(xiàn)參與維持采食和能量平衡的激素有許多，包括瘦素(leptin)、饑餓激素(ghrelin)、食欲素、胰島素、刺鼠相關(guān)肽、締脂素和可卡因-苯丙胺調(diào)節(jié)轉(zhuǎn)錄肽等。2006年，nesfatin-1被鑒定為一種新型的參與調(diào)節(jié)攝食行為的下丘腦和腦干肽。腦室內(nèi)(intracerebroventricular，icv)注射nesfatin-1可抑制動(dòng)物采食，長(zhǎng)期使用nesfatin-1則引起動(dòng)物體脂肪和體重?fù)p失[1]。nesfatin-1的發(fā)現(xiàn)引起了學(xué)者們的廣泛關(guān)注和研究。目前，對(duì)nesfatin-1的研究主要集中于其在體內(nèi)的分布、影響其表達(dá)的因素、生物學(xué)功能及其作用機(jī)制等方面。因此，本文將針對(duì)以上4個(gè)方面的內(nèi)容對(duì)nesfatin-1在近年來的研究進(jìn)展作一詳細(xì)綜述。

1 nesfatin-1的結(jié)構(gòu)、分布與表達(dá)

1.1 結(jié)構(gòu)

nesfatin-1是核連蛋白-2(nucleobindin 2，NUCB2)的3種產(chǎn)物之一，它是由82個(gè)氨基酸(AA)組成的神經(jīng)肽，分子質(zhì)量為9.8ku，擁有NUCB2的厭食活性[2]。nesfatin-1中間片段從第24至第53個(gè)AA殘基被稱為M30。M30的AA序列在不同物種上高度保守，在大鼠和小鼠上完全一致，與人類相比有2個(gè)AA殘基不同(圖1)；M30以劑量依賴的方式抑制動(dòng)物采食，其半抑制濃度(IC50)與nesfatin-1(0.36nmol/g體重)相同[3]。

圖1 nesfatin-1的分子結(jié)構(gòu)以及人類、大鼠和小鼠nesfatin-1的AA序列對(duì)照?qǐng)DFig.1 Molecular structure of nesfatin-1and comparison of amino acids sequence of human, rat and mouse nesfatin-1[3]

1.2 分布及與其他激素的共同定位

nesfatin-1廣泛存在于中樞神經(jīng)系統(tǒng)，包括下丘腦室旁核(paraventricular nucleus，PVN)、弓形核(arcuate nucleus，Arc)、視上核(supraoptic nucleus，SON)、外側(cè)區(qū)(lateral hypothalamic area，LHA)、未定帶[1]、背內(nèi)側(cè)核、腹內(nèi)側(cè)核[4]、腦干的Edinger-Westphal核、迷走神經(jīng)運(yùn)動(dòng)背核(dorsal motor nucleus of the vagus，DMNV)、中縫核(raphe pallidus，Rpa)、孤束核(nucleus of solitary tract，NTS)[4]和藍(lán)斑(locus coeruleus，LC)、垂體的前葉和中葉[5]、延髓腹外側(cè)髓質(zhì)(entrolateral medulla，VLM)、小腦浦肯野細(xì)胞[6]、脊髓交感和副交感節(jié)前神經(jīng)元以及海馬椎體細(xì)胞層[7]。nesfatin-1在中樞的免疫陽性以下丘腦的表達(dá)強(qiáng)度最高[6]。雙標(biāo)記免疫熒光染色發(fā)現(xiàn)中樞nesfatin-1與加壓素、催產(chǎn)素(oxytocin，OXT)、促甲狀腺激素釋放激素(thyrotropin-releasing hormone，TRH)、促腎上腺皮質(zhì)激素釋放激素(corticotropin releasing hormone，CRH)共同定位于PVN和SON[4-5]，與酪氨酸羥化酶(tyrosine hydroxylase，TH)共同定位于Arc和NTS，與5-羥色胺(5-HT)共同定位于Rpa。神經(jīng)肽-Y(NPY)神經(jīng)元與nesfatin-1神經(jīng)元緊密相鄰地共同定位于Arc和LHA中[4]。nesfatin-1還與促性腺激素釋放激素(GnRH)共同定位于金魚下丘腦前結(jié)節(jié)核和后結(jié)節(jié)外側(cè)核[8]。

NUCB2在外周廣泛存在于金魚的肝臟、脂肪、卵巢、睪丸、肌肉、直腸、前腸和腮中，其中肝臟的表達(dá)量遠(yuǎn)高于其他組織[2]。對(duì)小鼠而言，NUCB2/nesfatin-1廣泛分布于外周組織，包括脾臟、胸腺、心臟、睪丸、卵巢和子宮。與金魚不同的是，nesfatin-1在肝臟和肌肉中的表達(dá)量最低，提示nesfatin-1在嚙齒動(dòng)物和水生動(dòng)物上可能存在某些功能的差異。雙標(biāo)記免疫熒光染色顯示nesfatin-1和ghrelin共同定位于胃泌酸腺中部的X/A樣內(nèi)分泌細(xì)胞[9]，以及金魚的前腸內(nèi)分泌細(xì)胞[10]。NUCB2和胰島素共同定位于胰腺β細(xì)胞[11]，與促胰泌素包括胰高血糖素樣肽-1(GLP-1)和葡萄糖依賴的胰島素營(yíng)養(yǎng)多肽(glucose dependent insulinotropic polypeptide，GIP)共同定位于小鼠腸上皮細(xì)胞[12]。

1.3 不同因素對(duì)NUCB2/nesfatin-1表達(dá)的調(diào)節(jié)

1.3.1 營(yíng)養(yǎng)狀態(tài)

禁食顯著降低大鼠下丘腦PVN和SON中活化的nesfatin-1神經(jīng)元和血漿nesfatin-1水平；禁食后再飼顯著增加PVN和SON中活化的nesfatin-1神經(jīng)元，提示nesfatin-1受到營(yíng)養(yǎng)狀態(tài)的負(fù)反饋調(diào)節(jié)[13]。有趣的是，在金魚上短期和長(zhǎng)期禁食降低下丘腦NUCB2表達(dá)的同時(shí)，顯著提高了肝臟NUCB2的表達(dá)，提示在食物剝奪后NUCB2/nesfatin-1在水生動(dòng)物肝臟中可能起到一個(gè)特殊的作用實(shí)現(xiàn)對(duì)能量代謝的調(diào)控[2]。nesfatin-1在中樞與哺乳動(dòng)物雷帕霉素靶蛋白(mTOR)共同定位于Arc神經(jīng)元[14]，在外周與mTOR的下游靶標(biāo)pS6K1共同定位于胃X/A樣內(nèi)分泌細(xì)胞[15]。mTOR作為細(xì)胞能量感受器[16]，可能通過感受營(yíng)養(yǎng)狀態(tài)的改變調(diào)節(jié)nesfatin-1的表達(dá)。

1.3.2 生理病理狀態(tài)

年長(zhǎng)者禁食后血漿nesfatin-1水平顯著高于年幼者[17]。限制型神經(jīng)性厭食癥患者血漿nesfatin-1水平顯著低于正常人[18]。2型糖尿病患者血漿nesfatin-1水平顯著低于正常個(gè)體和1型糖尿病病患[17]。嘔吐毒素能激活豬VLM、迷走神經(jīng)背核簇、PVN、Arc和SON的nesfatin-1神經(jīng)元[19]。在高脂飼糧誘導(dǎo)的肥胖小鼠上，脂肪組織nesfatin-1蛋白表達(dá)和循環(huán)nesfatin-1水平顯著提高[15]。

1.3.3 其他攝食相關(guān)激素的調(diào)節(jié)

抑制食欲的膽囊收縮素劑量依賴地活化大鼠PVN和NTS中nesfatin-1神經(jīng)元[13,20]。胞內(nèi)鈣離子濃度([Ca2+]i)的提高是反映神經(jīng)元活性的標(biāo)記[21]。10mmol/L高糖和10-13mol/L胰島素顯著提高PVN nesfatin-1神經(jīng)元的[Ca2+]i，活化nesfatin-1神經(jīng)元[22]。icv注射50pmol leptin顯著提高PVNNUCB2mRNA的表達(dá)[23]。抑制食欲5-HT的受體激動(dòng)劑氯苯哌嗪顯著提高下丘腦NUCB2mRNA的表達(dá)[24]。icv注射1ng/g促食欲的ghrelin抑制前腦NUCB2mRNA的表達(dá)[10]。

2 nesfatin-1的生物學(xué)功能

2.1 厭食作用及其作用機(jī)理

2.1.1 中樞和外周nesfatin-1對(duì)采食的抑制作用

短期icv注射nesfatin-1劑量依賴地降低大鼠和小鼠的采食量[1,13,25]。注射nesfatin-1的抗體Ab24免疫球蛋白G(IgG)顯著提高了采食量[1]；長(zhǎng)期將nesfatin-1灌注進(jìn)第3腦室，采食量和體增重顯著降低；長(zhǎng)期持續(xù)icv注射NUCB2的反義嗎啉代寡核苷酸抑制下丘腦內(nèi)源NUCB2，采食量和體增重顯著增加。在金魚腹膜內(nèi)(intraperitoneal，ip)注射nesfatin-1顯著減少了采食量[2]。在小鼠上，皮下(subcutaneous，sc)注射nesfatin-1和M30也抑制了采食；連續(xù)6d ip注射nesfatin-1持續(xù)降低了體增重[3]。

2.1.2 中樞和外周nesfatin-1抑制采食的作用機(jī)制

2.1.2.1 外周nesfatin-1信號(hào)的傳遞

值得注意的是，小鼠上即使ip和sc注射nesfatin-1的劑量達(dá)到中樞注射劑量的23倍也不能抑制采食[25]，而在金魚上抑制采食的ip注射劑量是icv劑量的100倍[2]，提示nesfatin-1的厭食作用主要位于中樞部位[25]。那么外周nesfatin-1發(fā)揮抑制采食的作用是如何實(shí)現(xiàn)的呢？一方面，血腦屏障(blood-brain barrier，BBB)在nesfatin-1從大腦到血液和從血液到大腦的流動(dòng)中作為限制滲透性屏障發(fā)揮作用。Pan等[26]和Price等[27]研究發(fā)現(xiàn)，nesfatin-1以不飽和的易化擴(kuò)散方式穿越BBB，到達(dá)大腦實(shí)質(zhì)[27]，且主要結(jié)合于下丘腦[26]。nesfatin-1從大腦回血的速率因腦脊液的重吸收而受到限制[27]。另一方面，外周nesfatin-1通過N-型鈣通道引起傳入迷走神經(jīng)元Ca2+內(nèi)流，興奮傳入迷走神經(jīng)，由煙堿膽堿能受體神經(jīng)元將信號(hào)傳至NTS[3, 28- 29]，兒茶酚胺能的NTS神經(jīng)元可能投影到PVN中激活nesfatin-1神經(jīng)元[20]。

2.1.2.2 影響攝食神經(jīng)元的興奮性

Price等[30]首次證明PVN中大部分神經(jīng)元能響應(yīng)nesfatin-1的刺激發(fā)生超極化或去極化。Price等[31]研究發(fā)現(xiàn)，Arc中高達(dá)82%的NPY神經(jīng)元響應(yīng)nesfatin-1的刺激發(fā)生超極化。那么，nesfatin-1是如何影響神經(jīng)元的膜電位的呢？一方面，Price等[31]采用ATP敏感的鉀通道(KATP)的拮抗劑格列本脲(glibenclamide)使nesfatin-1引起的NPY神經(jīng)元的超極化膜電位回復(fù)至基礎(chǔ)水平，提示nesfatin-1可能活化KATP引起Arc中NPY神經(jīng)元的超極化，抑制促食欲的NPY神經(jīng)元。另一方面，G蛋白受體抑制劑百日咳毒素、無Ca2+溶液、蛋白激酶A(PKA)抑制劑KT 5720或L-型和P/Q-型Ca2+門控通道阻斷劑維拉帕米(verapamil)和ω-芋螺毒素(ω-conotoxin)MVIIC抑制了nesfatin-1引起的下丘腦神經(jīng)元[Ca2+]i的增加，提示下丘腦nesfatin-1可能與G蛋白偶聯(lián)受體相互作用，開放L-型和P/Q-型Ca2+門控通道或激活PKA信號(hào)途徑引起Ca2+內(nèi)流，興奮神經(jīng)元[4]。

2.1.2.3 leptin獨(dú)立的其他激素的介導(dǎo)

icv注射nesfatin-1顯著降低了leptin受體缺乏的肥胖型Zucker大鼠的采食量，并且nesfatin-1的抗體Ab24IgG并不影響注射leptin降低的采食量；然而，黑皮質(zhì)素MC3/4受體拮抗劑SHU9119的預(yù)處理廢除了nesfatin-1的厭食作用，表明nesfatin-1信號(hào)可能獨(dú)立于leptin由黑皮質(zhì)素信號(hào)系統(tǒng)進(jìn)行介導(dǎo)[1]。PVN中nesfatin-1可能經(jīng)L-型Ca2+門控通道引起Ca2+內(nèi)流活化PVN中OXT能神經(jīng)元，同時(shí)投影到NTS由OXT受體介導(dǎo)發(fā)揮厭食作用[32]。CRH1/CRH2拮抗劑astressin-B或CRH2拮抗劑astressin2-B廢除了icv注射nesfatin-1的厭食效應(yīng)[13]。PVN中nesfatin-1也可直接作用于CRH和TRH神經(jīng)元，釋放出CRH和TRH與組胺神經(jīng)元上相應(yīng)受體結(jié)合促進(jìn)組胺的分泌抑制采食[33]。

2.1.2.4 胃動(dòng)力減弱

中樞注射nesfatin-1會(huì)引起胃動(dòng)力的減弱[13,34]。icv注射nesfatin-1CRH獨(dú)立地抑制胃排空[13]。分析前腦中nesfatin-1抑制胃排空的可能原因發(fā)現(xiàn)，nesfatin-1神經(jīng)元在PVN、Arc和前腦邊緣系統(tǒng)的基底內(nèi)側(cè)杏仁核(basomedial amygdala，BMA)之間投影，內(nèi)源nesfatin-1部分經(jīng)由黑皮質(zhì)素旁路影響胃擴(kuò)張敏感性神經(jīng)元的放電活動(dòng)降低胃動(dòng)力[35-36]。此外，第4腦室或小腦延髓池注射nesfatin-1也CRH獨(dú)立地抑制采食[13]。進(jìn)一步研究發(fā)現(xiàn)，后腦注射nesfatin-1可能經(jīng)T-型Ca2+通道引起DMNV神經(jīng)元Ca2+內(nèi)流興奮體內(nèi)傳出迷走神經(jīng)，抑制胃酸分泌[34]。

綜上所述，nesfatin-1發(fā)揮其抑制采食的作用主要通過以下6條途徑(圖2)：1)外周nesfatin-1經(jīng)血液循環(huán)以易化擴(kuò)散的方式穿越BBB進(jìn)入下丘腦；2)外周nesfatin-1厭食信號(hào)經(jīng)迷走傳入神經(jīng)由NTS傳至下丘腦；3)下丘腦nesfatin-1直接作用于神經(jīng)元通過KATP門控通道引起Arc中NPY神經(jīng)元的超極化，抑制促食欲的NPY神經(jīng)元；4)開放L-型、P/Q-型Ca2+門控通道引起Ca2+內(nèi)流激活下丘腦神經(jīng)元，由OXT、CRH、TRH、組胺和黑皮質(zhì)素系統(tǒng)介導(dǎo)nesfatin-1的厭食作用；5)nesfatin-1在前腦中經(jīng)黑皮質(zhì)素旁路影響胃擴(kuò)張敏感性神經(jīng)元的興奮性減弱胃動(dòng)力；6)nesfatin-1在后腦經(jīng)T-型鈣門控通道引起Ca2+內(nèi)流激活DMNW神經(jīng)元，興奮體內(nèi)傳出迷走神經(jīng)抑制胃酸分泌。

圖2 推定的中樞和外周nesfatin-1發(fā)揮其采食抑制作用的主要路徑Fig.2 Potential pathways by which nesfatin-1induces a reduction of food intake[37]

2.2 對(duì)血糖穩(wěn)態(tài)和胰島素的作用

在1型糖尿病小鼠上，靜脈內(nèi)注射nesfatin-1胰島素依賴地降低血糖水平[38]。nesfatin-1可刺激腸促胰島素GLP-1和GIP的分泌[12]；亦可直接作用于胰島β內(nèi)分泌細(xì)胞經(jīng)L-型鈣通道引起Ca2+內(nèi)流促進(jìn)胰島素分泌[39]。在產(chǎn)生胰島素抵抗的肥胖小鼠上，中樞nesfatin-1通過激活胰島素受體(INSR)/胰島素受體底物-1(IRS-1)/AMP依賴的蛋白激酶(AMPK)以及mTOR/蛋白激酶B(Akt)，抑制肝臟中糖異生限速酶——葡萄糖-6-磷酸酯酶和磷酸烯醇式丙酮酸羧激酶的表達(dá)，降低肝臟葡萄糖生成，促進(jìn)肌肉吸收葡萄糖的能力，從而提高機(jī)體對(duì)胰島素的敏感性[40- 41]。

2.3 參與應(yīng)激反應(yīng)

中樞nesfatin-1的表達(dá)能響應(yīng)應(yīng)激的發(fā)生。急性束縛應(yīng)激和避水應(yīng)激均顯著增加PVN、SON、PVN、LC、NTS、RPa和VLM中活化的nesfatin-1神經(jīng)元[7,42-43]。中樞nesfatin-1能誘導(dǎo)活化色氨酸羥化酶(TPH，5-HT合成限速酶)、酪氨酸羥化酶(TH，兒茶酚胺合成限速酶)和PVN中的CRH神經(jīng)元，提高血漿促腎上腺皮質(zhì)激素和皮質(zhì)酮的水平激活下丘腦-垂體-腎上腺軸(hypothalamic-pituitary-adrenal axis，HPA)參與應(yīng)激反應(yīng)[42-43]。外周注射nesfatin-1可降低應(yīng)激的損害。ip注射nesfatin-1能降低caspase-3介導(dǎo)的神經(jīng)元細(xì)胞凋亡，抑制核轉(zhuǎn)錄因子kappa B(NF-κB)依賴的炎性反應(yīng)，緩解蛛網(wǎng)膜下出血誘導(dǎo)的神經(jīng)損傷和氧化腦損傷[44]。在缺血/再灌注損傷的急性期，外周nesfatin-1注射能降低血漿內(nèi)皮型一氧化氮合酶(eNOS)水平和氧化應(yīng)激指數(shù)[45]。

2.4 對(duì)繁殖的作用

nesfatin-1對(duì)繁殖的影響主要表現(xiàn)在對(duì)發(fā)育期的啟動(dòng)上。在嚙齒動(dòng)物上nesfatin-1甚至能對(duì)抗不良代謝條件最大限度地恢復(fù)促黃體生成素(LH)的分泌[46]。然而，在金魚上nesfatin-1卻顯著降低金魚下丘腦cGnRH-Ⅱ和sGnRH及垂體促黃體激素(LH-β)和促卵泡激素(FSH-β)的表達(dá)，以及血清LH的水平，并顯著降低體外培養(yǎng)的斑馬魚初級(jí)卵泡基礎(chǔ)的和成熟誘導(dǎo)激素增加的卵母細(xì)胞生發(fā)泡破裂率，降低卵細(xì)胞的成熟率[8]。由此可知，與嚙齒動(dòng)物不同，nesfatin-1對(duì)魚類的繁殖具有抑制作用，其中的原因有待進(jìn)一步研究。

3 小 結(jié)

nesfatin-1在體內(nèi)廣泛分布，主要參與能量代謝調(diào)節(jié)，其生物學(xué)功能涉及采食抑制、降血糖、增加胰島素敏感性、響應(yīng)應(yīng)激，對(duì)繁殖的作用主要是參與發(fā)育期的啟動(dòng)。其作用機(jī)理涉及到神經(jīng)元的興奮和抑制，然而目前對(duì)于nesfatin-1的研究還處在初級(jí)階段，關(guān)于它如何作用于胞膜選擇性引起離子通道開放興奮或抑制神經(jīng)元的機(jī)理尚不清楚；并且nesfatin-1的受體尚未被鑒定出來，這大大限制了對(duì)其作用機(jī)理的研究。nesfatin-1的發(fā)現(xiàn)進(jìn)一步豐富了機(jī)體能量調(diào)節(jié)的神經(jīng)激素網(wǎng)，弄清nesfatin-1的作用機(jī)理可以為臨床上用于治療肥胖癥和糖尿病，為動(dòng)物生產(chǎn)中用于調(diào)節(jié)攝食、應(yīng)激及繁殖等生理過程提供理論依據(jù)。

[1] OH I S,SHIMIZU H,SATOH T,et al.Identification of nesfatin-1as a satiety molecule in the hypothalamus[J].Nature,2006,443(7112):709-712.

[2] GONZALEZ R,KERBEL B,CHUN A,et al.Molecular,cellular and physiological evidences for the anorexigenic actions of nesfatin-1in goldfish[J].PLoS One,2010,5(12):e15201.

[3] SHIMIZU H,OH-I S,HASHIMOTO K,et al.Peripheral administration of nesfatin-1reduces food intake in mice:the leptin-independent mechanism[J].Endocrinology,2009,150(2):662-671.

[4] CRISTINA BRAILOIU G,DUN S L,BRAILOIU E,et al.nesfatin-1:distribution and interaction with a G protein-coupled receptor in the rat brain[J].Endocrinology,2007,148(10):5088-5094.

[5] FOO K S,BRISMAR H,BROBERGER C.Distribution and neuropeptide coexistence of nucleobindin-2mRNA/nesfatin-like immunoreactivity in the rat CNS[J].Neuroscience,2008,156(3):563-579.

[6] GOEBEL M,STENGEL A,WANG L X,et al.nesfatin-1immunoreactivity in rat brain and spinal cord autonomic nuclei[J].Neuroscience Letters,2009,452(3):241-246.

[7] GOEBEL-STENGEL M,WANG L X,STENGEL A,et al.Localization of nesfatin-1neurons in the mouse brain and functional implication[J].Brain Research,2011,1396:20-34.

[8] GONZALEZ R,SHEPPERD E,THIRUPPUGAZH V,et al.nesfatin-1regulates the hypothalamo-pituitary-ovarian axis of fish[J].Biology of Reproduction,2012,87(4):84.

[9] STENGEL A,GOEBEL M,WANG L X,et al.Ghrelin,des-acyl ghrelin and nesfatin-1in gastric X/A-like cells:role as regulators of food intake and body weight[J].Peptides,2010,31(2):357-369.

[10] KERBEL B,UNNIAPPAN S.nesfatin-1suppresses energy intake,co-localises ghrelin in the brain and gut,and alters ghrelin,cholecystokinin and orexin mRNA expression in goldfish[J].Journal of Neuroendocrinology,2012,24(2):366-377.

[11] FOO K S,BRAUNER H,?STENSON C G,et al.Nucleobindin-2/nesfatin in the endocrine pancreas:distribution and relationship to glycaemic state[J].Journal of Endocrinology,2010,204(3):255-263.

[12] RAMESH N,MORTAZAVI S,UNNIAPPAN S.Nesfatin-1stimulates glucagon-like peptide-1and glucose-dependent insulinotropic polypeptide secretion from STC-1cellsinvitro[J].Biochemical and Biophysical Research Communications,2015,462(2):124-130.

[13] STENGEL A,GOEBEL M,WANG L X,et al.Central nesfatin-1reduces dark-phase food intake and gastric emptying in rats:differential role of corticotropin-releasing factor2receptor[J].Endocrinology,2009,150(11):4911-4919.

[14] INHOFF T,STENGEL A,PETER L,et al.Novel insight in distribution of nesfatin-1and phospho-mTOR in the arcuate nucleus of the hypothalamus of rats[J].Peptides,2010,31(2):257-262.

[15] LI Z,XU G,LI Y,et al.mTOR-dependent modulation of gastric nesfatin-1/NUCB2[J].Cellular Physiology and Biochemistry,2012,29(3/4):493-500.

[16] COTA D,PROULX K,SMITH BLAKE K A,et al.Hypothalamic mTOR signaling regulates food intake[J].Science,2006,312(5775):927-930.

[17] LI Q C,WANG H Y,CHEN X,et al.Fasting plasma levels of nesfatin-1in patients with type 1and type 2diabetes mellitus and the nutrient-related fluctuation of nesfatin-1level in normal humans[J].Regulatory Peptides,2010,159(1/2/3):72-77.

[18] OGISO K,ASAKAWA A,AMITANI H,et al.Plasma nesfatin-1concentrations in restricting-type anorexia nervosa[J].Peptides,2011,32(1):150-153.

[19] GAIGé S,BONNET M S,TARDIVEL C,et al.c-Fos immunoreactivity in the pig brain following deoxynivalenol intoxication:focus on NUCB2/nesfatin-1expressing neurons[J].NeuroToxicology,2013,34:135-149.

[20] NOETZEL S,STENGEL A,INHOFF T,et al.CCK-8S activates c-Fos in a dose-dependent manner in nesfatin-1immunoreactive neurons in the paraventricular nucleus of the hypothalamus and in the nucleus of the solitary tract of the brainstem[J].Regulatory Peptides,2009,157(1/2/3):84-91.

[21] GRIENBERGER C,KONNERTH A.Imaging calcium in neurons[J].Neuron,2012,73(5):862-885.

[22] GANTULGA D,MAEJIMA Y,NAKATA M,et al.Glucose and insulin induce Ca2+signaling in nesfatin-1neurons in the hypothalamic paraventricular nucleus[J].Biochemical and Biophysical Research Communications,2012,420(4):811-815.

[23] DARAMBAZAR G,NAKATA M,OKADA T,et al.Paraventricular NUCB2/nesfatin-1is directly targeted by leptin and mediates its anorexigenic effect[J].Biochemical and Biophysical Research Communications,2015,456(4):913-918.

[24] NONOGAKI K,OHBA Y,SUMII M,et al.Serotonin systems upregulate the expression of hypothalamic NUCB2via 5-HT2C receptors and induce anorexia via a leptin-independent pathway in mice[J].Biochemical and Biophysical Research Communications,2008,372(1):186-190.

[25] GOEBEL M,STENGEL A,WANG LX,et al.Central nesfatin-1reduces the nocturnal food intake in mice by reducing meal size and increasing inter-meal intervals[J].Peptides,2011,32(1):36-43.

[26] PAN W H,HSUCHOU H,KASTIN A J.Nesfatin-1crosses the blood-brain barrier without saturation[J].Peptides,2007,28(11):2223-2228.

[27] PRICE T O,SAMSON W K,NIEHOFF M L,et al.Permeability of the blood-brain barrier to a novel satiety molecule nesfatin-1[J].Peptides,2007,28(12):2372-2381.

[28] SHIMIZU H,OHSAKI A,OH-I S,et al.A new anorexigenic protein,nesfatin-1[J].Peptides,2009,30(5):995-998.

[29] IWASAKI Y,NAKABAYASHI H,KAKEI M,et al.Nesfatin-1evokes Ca2+signaling in isolated vagal afferent neurons via Ca2+influx through N-type channels[J].Biochemical and Biophysical Research Communications,2009,390(3):958-962.

[30] PRICE C J,HOYDA T D,SAMSON W K,et al.Nesfatin-1influences the excitability of paraventricular nucleus neurones[J].Journal of Neuroendocrinology,2008,20(2):245-250.

[31] PRICE C J,SAMSON W K,FERGUSON A V.nesfatin-1inhibits NPY neurons in the arcuate nucleus[J].Brain Research,2008,1230:99-106.

[32] MAEJIMA Y,SEDBAZAR U,SUYAMA S,et al.Nesfatin-1-regulated oxytocinergic signaling in the paraventricular nucleus causes anorexia through a leptin-independent melanocortin pathway[J].Cell Metabolism,2009,10(5):355-365.

[33] GOTOH K,MASAKI T,CHIBA S,et al.Nesfatin-1,corticotropin-releasing hormone,thyrotropin-releasing hormone,and neuronal histamine interact in the hypothalamus to regulate feeding behavior[J].Journal of Neurochemistry,2013,124(1):90-99.

[34] XIA Z F,FRITZE D M,LI J Y,et al.Nesfatin-1inhibits gastric acid secretion via a central vagal mechanism in rats[J].American Journal of Physiology:Gastrointestinal and Liver Physiology,2012,303(5):G570-G577.

[35] XU L,WANG Q L,GUO F F,et al.Nesfatin-1signaling in the basom edial amygdala modulates the gastric distension-sensitive neurons discharge and decreases gastric motility via melanocortin 3/4receptors and modified by the arcuate nucleus[J].European Journal of Pharmacology,2015,764:164-172.

[36] LI Z L,XU L,SUN X R,et al.Central nesfatin-1influences the excitability of ghrelin-responsive gastric distension neurons in the arcuate nucleus and reduces gastric motility in rats[J].European Journal of Neuroscience,2013,38(11):3636-3643.

[37] STENGEL A,GOEBEL M,TACHé Y.Nesfatin-1:a novel inhibitory regulator of food intake and body weight[J].Obesity Reviews,2011,12(4):261-271.

[38] SU Y J,ZHANG J,TANG Y C,et al.The novel function of nesfatin-1:anti-hyperglycemia[J].Biochemical and Biophysical Research Communications,2010,391(1):1039-1042.

[39] NAKATA M,MANAKA K,YAMAMOTO S,et al.Nesfatin-1enhances glucose-induced insulin secretion by promoting Ca2+influx throughL-type channels in mouse islet β-cells[J].Endocrine Journal,2011,58(4):305-313.

[40] YANG M L,ZHANG Z H,WANG C,et al.Nesfatin-1action in the brain increases insulin sensitivity through Akt/AMPK/TORC2pathway in diet-induced insulin resistance[J].Diabetes,2012,61(8):1959-1968.

[41] WU D D,YANG M L,CHEN Y,et al.Hypothalamic nesfatin-1/NUCB2knockdown augments hepatic gluconeogenesis that is correlated with inhibition of mTOR-STAT3signaling pathway in rats[J].Diabetes,2014,63(4):1234-1247.

[42] K?NCZ?L K,BODNR I,ZELENA D,et al.Nesfatin-1/NUCB2may participate in the activation of the hypothalamic-pituitary-adrenal axis in rats[J].Neurochemistry International,2010,57(3):189-197.

[43] YOSHIDA N,MAEJIMA Y,SEDBAZAR U,et al.Stressor-responsive central nesfatin-1activates corticotropin-releasing hormone,noradrenaline and serotonin neurons and evokes hypothalamic-pituitary-adrenal axis[J].Aging,2010,2(11):775-784.

[45] AYADA C,TORU ü,GEN? O,et al.Balanced oxidative status by nesfatin-1in intestinal ischemia-reperfusion[J].International Journal of Clinical and Experimental Medicine,2015,8(3):3318-3324.

(責(zé)任編輯 武海龍)

Distribution and Biological Functions of a Novel Anorexigenic Neuropeptide Nesfatin-1

DENG Qiuhong JIA Gang*ZHAO Hua CHEN Xiaoling LIU Guangmang CAI Jingyi TANG Jiayong

(InstituteofAnimalNutrition,SichuanAgriculturalUniversity,Chengdu611130,China)

Nesfatin-1is a newly discovered anorexia neuropeptides. nesfatin-1is found to be prominently expressed in hypothalamic and brainstem nuclei and especially in peripheral gastrointestinal and pancreatic endocrine cells and gonads. Its expression is influenced by nutrition, physiology, pathology and other feeding related hormones. The centrally and peripherally intracellular co-localization of nesfatin-1immunore activity with several hormones points towards differential regulation and consequently functions in the control of food intake and glucose homeostasis, and the physiological process of stress response and puberty onset by hypothalamic-pituitary-adrenal axis (HPA) and hypothalamic-pituitary-gonadal axis activation, respectively. This review focuses on the central and peripheral distribution, the factors affecting the expression, and the biological functions ofnesfatin-1.[ChineseJournalofAnimalNutrition, 2016, 28(4)：1004-1010]

nesfatin-1; distribution; expression; anorexia; biological function

10.3969/j.issn.1006-267x.2016.04.006

2015-10-22

四川省科技支撐計(jì)劃(2013NZ0054)

鄧秋紅(1985—)，女，四川德陽人，博士研究生，研究方向?yàn)轱暳腺Y源開發(fā)及高效利用。E-mail： dqiuhong818@163.com

*通信作者：賈 剛，教授，博士生導(dǎo)師，E-mail： jiagang700510@163.com

S811.3

A

1006-267X(2016)04-1004-07

*Corresponding author, professor, E-mail: jiagang700510@163.com