魚類leptin的生物學(xué)特性及功能

盧榮華孫君君梁旭方聶國興楊 峰

(1. 河南師范大學(xué)水產(chǎn)學(xué)院, 新鄉(xiāng) 453007; 2. 華中農(nóng)業(yè)大學(xué)水產(chǎn)學(xué)院, 武漢 430070)

魚類leptin的生物學(xué)特性及功能

盧榮華1孫君君1梁旭方2聶國興1楊 峰1

(1. 河南師范大學(xué)水產(chǎn)學(xué)院, 新鄉(xiāng) 453007; 2. 華中農(nóng)業(yè)大學(xué)水產(chǎn)學(xué)院, 武漢 430070)

瘦素(Leptin)是肥胖基因(Obese gene)的產(chǎn)物, 屬于I型細胞因子。在哺乳動物中, leptin主要由脂肪細胞合成與分泌, 是調(diào)控攝食、能量代謝、骨骼發(fā)育、甲狀腺功能以及繁殖等生理過程的重要激素。目前, 多種硬骨魚類的leptin基因已被克隆, 其功能也已得到初步研究。研究認為, 魚類leptin的主要合成部位在肝臟, 其在氨基酸序列上與哺乳動物存在很大差異, 但蛋白質(zhì)結(jié)構(gòu)高度保守; 功能方面, leptin可調(diào)節(jié)魚類的攝食、葡萄糖和脂肪代謝以及繁殖等生命活動過程。本文就魚類leptin及其受體的特征結(jié)構(gòu)、組織分布、表達調(diào)控及功能研究進展進行簡要綜述。

Leptin; 魚類; 生物學(xué)特性; 食欲調(diào)節(jié); 能量代謝

1994年, Zhang等[1]首次分離出哺乳動物的肥胖基因(Obese gene), 瘦素(Leptin)即是肥胖基因的產(chǎn)物, 該名字起源于希臘語leptos意為“瘦的”, 其得名是由于研究發(fā)現(xiàn)缺失leptin會造成哺乳動物的肥胖。哺乳動物leptin由脂肪組織分泌, 已證明其在糖脂代謝[2,3]、生殖[4,5]、免疫[6]、能量消耗[7]以及攝食中發(fā)揮重要作用, 被認為是機體的一種飽食因子[8—10]。與對陸生動物leptin的深入研究相比, 魚類leptin雖然也已引起學(xué)者們的關(guān)注, 但相關(guān)功能研究尚開展的不多。

1 Leptin及Leptin受體的結(jié)構(gòu)與同源性分析

1.1 Leptin的結(jié)構(gòu), 拷貝數(shù)及同源性分析

Johnson等[11]首次通過鼠leptin抗體在藍綠鱗鰓太陽魚(Lepomis macrochirus)、虹鱒(Oncorhynchus mykiss)、大口黑鱸(Pomonix annularis)和斑點叉尾鲴(Ictalurus punctatus)中檢測到其血液、腦、心、肝中均存在leptin。日本學(xué)者Kurokawa等[12]通過基因組同線性方法從紅鰭東方鲀(Takifugu rubripes)等變溫動物中首次鑒定并分離出肥胖基因。隨后, 包括日本青 鳉(Oryzias latipes)[12,13]、鯉(Cyprinus carpio)[14]、斑馬魚(Danio rerio)[15]、大麻哈魚(Oncorhynchus keta)[16]、虹鱒[16]、草魚(Ctenopharyngodon idella)[17]、北極鮭(Salvelinus alpinus)[18]、大西洋鮭(Salmo salar)[19]、 鱸 (Morone saxatilis)[20]、 黃 顙 魚(Pelteobagrus fulvidraco)[21]和大黃魚[22]等魚類以及非洲爪蟾(Xenopus laevis)[23]、熱帶爪蟾(Xenopus tropicalis)[12,23]、寬虎紋鈍口螈(Ambystoma tigrinum)[24]等兩棲動物的leptin基因也被先后分離, 并在鯉[14]、草魚[17]、虹鱒[16,25]和 青 鳉(Oryzias latipes)[26]等部分物種中進行了相對深入的研究。

在非洲爪蟾和目前已知的多數(shù)魚類中, 肥胖基因由3個外顯子和2個內(nèi)含子組成, 與人類的肥胖基因結(jié)構(gòu)相似[1], 且內(nèi)含子的相對位置高度保守[12,16,17,23,27]。然而, 寬虎紋鈍口螈[24]、鯉[14]和鱖(Siniperca chuatsi)的肥胖基因只含有 2個外顯子和 1個內(nèi)含子(第 2個內(nèi)含子), 它們的第1個內(nèi)含子在進化過程中已丟失[13,15,23,24,27—29]?；蚪M同線性分析表明, 人、小鼠、熱帶爪蟾、河鲀 和斑馬魚等的leptin基因在基因組中的線性排列非常相似[12,14,16,17,23,24,27], 表明它們起源相同。

在人和小鼠等哺乳動物以及非洲爪蟾的基因組中, 肥胖基因僅有一個拷貝, 編碼一種蛋白產(chǎn)物。然而最近的研究發(fā)現(xiàn), 在斑馬魚、日本青 鳉和石斑魚(Epinephelus coioides)的基因組中存在2個肥胖基因拷貝, 編碼兩種不同的產(chǎn)物(分別命名為leptin-A型和leptin-B型)[13,15,30]。斑馬魚的leptin-A和leptin-B僅含有24%的氨基酸同源性, 表明它們屬于兩種不同的leptin亞型。因此魚類可能普遍存在兩種leptin亞型[13,15]。盡管先前的研究發(fā)現(xiàn)鯉中也存在兩種leptin轉(zhuǎn)錄本, 然而它們之間的氨基酸同源性高達84%,系統(tǒng)樹分析發(fā)現(xiàn)它們同聚于leptin-A進化分枝, 表明它們很可能同屬于leptin-A型, 這可能是由鯉(四倍體)在～16Mya發(fā)生的基因組加倍引起。系統(tǒng)樹分析和氨基酸同源性分析顯示, 目前分離得到的魚類leptin絕大部分屬于leptin-A型, 包括綠河豚(Tetraodon nigroviridis)[12]、虹鱒[16]、北極紅點鮭(Salvelinus alpinus)[18]、鰱(Hypophthalmichthys molitrix)和草魚[17]等, 在鯉及其他大部分魚類中很可能還存在leptin-B型[15]。兩種leptin亞型在魚類中的出現(xiàn)以及它們組織表達的差異, 可能賦予leptin新的功能。最新的研究發(fā)現(xiàn), 某些種類如大西洋鮭的leptin甚至出現(xiàn)了多達四個亞型同源物(LepA1, LepA2, LepB1/B2)[31]。

Leptin的蛋白序列在哺乳動物中高度保守, 魚類及其他變溫動物leptin與哺乳動物leptin的氨基酸同源性卻很低(如河 鲀 、斑馬魚、虹鱒和非洲爪蟾 leptin等與人leptin的氨基酸同源性分別為13.2%、22%、21.4%和35.0%)[12,14,16,17,23,24,27], 此外, 不同種屬魚類leptin之間的氨基酸同源性同樣很低(如 河鲀 與斑馬魚、虹鱒leptin的氨基酸同源性為19%和20.9%, 鯉和虹鱒leptin的氨基酸同源性為26.8%)[12—17,23,24,27]。分析發(fā)現(xiàn), 它們用于形成二硫鍵的半胱氨酸卻高度保守, 蛋白二級結(jié)構(gòu)(4個α螺旋)也同樣高度保守, 而且三級結(jié)構(gòu)預(yù)測表明它們之間的空間結(jié)構(gòu)十分相似[12—17,23,24,27]。

1.2 Leptin受體的基因結(jié)構(gòu)

人等哺乳動物的leptin受體(Leptin receptor, leptin-R)為單一拷貝, 但其可通過不同的剪接方式產(chǎn)生多達6種長度不同的轉(zhuǎn)錄本[32]。其中, 長型leptin-R在介導(dǎo)leptin的調(diào)控功能中起重要作用[32]。人的leptin-R含有20個外顯子, 非洲爪蟾的外顯子則多達26個[23]。目前, 已在海洋青鳉魚(Oryzias melastigma)[33]、 日本青 鳉[13]、 河 鲀[34]和草魚[35]等魚類中分離了leptin-R基因, 日本青鳉leptin-R基因含有20個外顯子[13], 河 鲀leptin-R基因則含有21個外顯子[34]。目前在非洲爪蟾中僅發(fā)現(xiàn)長型leptin-R一種類型,其他在哺乳動物中出現(xiàn)的5種類型至今未見報道。

2 Leptin及l(fā)eptin受體的組織差異表達

2.1 Leptin的組織分布及分泌濃度

Leptin在多種組織中均有表達, 在人等哺乳動物中, 脂肪組織是leptin的主要合成位點[1,36]。此外, 其在胎盤等多種組織中也可以合成[36]。與哺乳動物不同, 非洲爪蟾leptin在腦和心臟中大量表達[23], 寬虎紋鈍口螈 leptin主要在皮膚和卵巢中表達[24], 而魚類的leptin雖然在包括腸道、脂肪、大腦等不同組織中都有少量表達, 但主要表達部位是肝臟[11—17,19,27,34]。此外, 不同亞型leptin的組織表達情況也有差異。在日本青 鳉中, leptin-A主要表達在鰓、肝臟、腦垂腺、脾、腸、心臟等組織中, leptin-B在卵巢、腦垂腺、鰓和心臟中表達水平較高。在斑馬魚中, leptin-A 主要在肝臟中表達, 而leptin-B在腦和眼中大量表達[15]。leptin亞型組織分布的不同, 提示其可能有各自獨特的功能。如leptin-B在卵巢的大量表達暗示其可能在調(diào)控生殖功能中起重要作用[13]。

在正常生理狀態(tài)下, 人的血漿leptin濃度為0.2—0.3 nmol/L[28,29], 鼠類的血漿leptin濃度為0.09—0.3 nmol/L[37,38]。而Kling等[39]測定了多種魚類的血漿leptin濃度, 結(jié)果表明魚類的血漿leptin濃度為1.1—5 nmol/L, 比哺乳動物的血漿leptin濃度高。哺乳動物能依據(jù)血漿中的leptin濃度傳達體內(nèi)脂肪含量信息給大腦, 進而指導(dǎo)攝食行為、代謝及生理內(nèi)分泌, 使其與機體的營養(yǎng)狀況相一致[40]。上述leptin組織表達及分泌濃度的差異, 暗示魚類的leptin在功能及調(diào)節(jié)通路上可能與哺乳動物有較大差異。

2.2 Leptin受體的組織分布

不論在哺乳動物還是魚類中, leptin均通過其受體發(fā)揮調(diào)控攝食及能量平衡等功能[41—47]。哺乳動物長型leptin-R主要在下丘腦中表達[1,32,36], 小鼠缺乏leptin-R會因食欲過強導(dǎo)致肥胖[48]。海洋青鳉的leptin-R主要在鰓、脾臟、腎臟和肌肉中表達, 且雌性海洋青鳉leptin-R的表達量要高于雄性的[33]。薛俊蓮等[49]通過RT-PCR方法獲得鯽魚的leptin受體序列,并制備了鯽魚2個瘦素受體的多克隆抗體; 檢測了鯽魚組織和血清中的受體, 初步確定了鯽魚血清中存在可溶瘦素受體。

3 Leptin的功能

3.1 Leptin在調(diào)控攝食中的作用

用哺乳動物的 leptin在金魚體內(nèi)通過腹腔和側(cè)腦室注射后顯示其攝食減少、體重下降以及調(diào)控攝食和能量代謝相關(guān)基因表達水平發(fā)生改變[50,51]。在鱸腹腔內(nèi)注射人leptin也可抑制其攝食[20]。然而, 以哺乳動物 leptin處理銀大馬哈魚(Oncorhynchus kisutch)[52]、鯰(Ictalurus punctatus)[53]和綠海魴(Lepomis cyanellus)[54], 卻并不能改變它們的攝食行為或能量代謝。這可能與特異性的魚類 leptin的功能有關(guān)。目前在絕大多數(shù)魚類研究中發(fā)現(xiàn) leptin具有抑制攝食的作用[16,17,25]。Murashita等[16]用重組虹鱒 leptin處理后發(fā)現(xiàn)可顯著抑制虹鱒的攝食行為、刺激抑制食欲因子阿片促黑色素原 A1/A2 (proopiomelanocorein- A1/A2, POMC-A1/A2)基因表達并降低促食欲因子神經(jīng)肽Y(neuropeptide Y, NPY)基因的表達水平。進一步研究發(fā)現(xiàn)重組鮭 leptin也可顯著抑制大西洋鮭的生長, 分析原因認為 leptin可能通過顯著提高 POMC-A1轉(zhuǎn)錄, 抑制食物攝入而導(dǎo)致生長減慢[55]。Li等[17]制備了草魚leptin蛋白,通過短期(1 d)和長期(13 d)腹腔注射實驗, 發(fā)現(xiàn)leptin短期處理可明顯抑制草魚的攝食、抑制 NPY等攝食相關(guān)基因的表達。在石斑魚中, 饑餓和再投喂實驗表明, Leptin-A在調(diào)節(jié)攝食和能量代謝中發(fā)揮重要作用[30]。

3.2 Leptin在調(diào)控糖脂代謝中的作用

在哺乳動物中l(wèi)eptin可抑制脂肪的沉積, 促進脂肪的水解[56—58]等, 還可通過影響動物下丘腦和后腦的葡萄糖感受性神經(jīng)元的活性, 抑制促食欲肽(NPY, AgRP, Orexin)和激活厭食欲肽(POMC, CART, CCK)的表達[59—61]進而來調(diào)控其攝食行為, 并促進能量消耗。因此, leptin調(diào)節(jié)攝食的作用也與對葡萄糖的代謝調(diào)控交織在一起; 除中樞神經(jīng)系統(tǒng)外, leptin還可直接調(diào)節(jié)外周組織器官, 促進肝臟葡萄糖生成, 調(diào)控肝臟磷酸烯醇丙酮酸羧激酶(Phosphoenolpyruvate carboxykinase, PEPCK)基因表達和糖異生效率[62], 通過乳酸攝取增加直接刺激肝糖原產(chǎn)生。leptin對PEPCK及糖異生的影響限制了甘油三酯的合成, 因而哺乳類leptin主要通過調(diào)控糖和脂代謝與攝食的偶聯(lián)來維持其體脂蓄積及機體能量代謝的穩(wěn)定。

目前, 已有一些關(guān)于魚類 leptin對脂類代謝的研究, 如 leptin能增加太陽魚細胞內(nèi)脂肪酸結(jié)合蛋白的量[54]; 重組草魚 leptin蛋白通過腹腔注射后,可促進脂代謝基因或能量代謝基因解偶聯(lián)蛋白2(Uncoupling protein 2, UCP2)、膽鹽活化的胰脂肪酶(Bile salt-activated lipase, BSAL)和脂肪酸延長酶(Fatty acid elongase, ELO)的基因表達, 這與虹鱒實驗中所得結(jié)果相似, 也與非洲爪蟾和哺乳動物的結(jié)果一致[17]; 筆者在草魚營養(yǎng)性肝細胞脂變模型中的研究結(jié)果也表明, leptin劑量依賴性促進甘油的釋放,并可影響9個脂肪代謝關(guān)鍵基因在轉(zhuǎn)錄和翻譯水平的表達, 且其誘導(dǎo)脂肪分解的作用是由 JAK-STAT信號通路來介導(dǎo)的[3]。

迄今為止, 已有研究發(fā)現(xiàn)魚類leptin和糖代謝(血糖變化)、饑餓及再投喂條件關(guān)系密切。在金魚腹腔內(nèi)注射leptin后, 可引起肝糖原、肌糖原以及循環(huán)激素水平的變化[51,52]; 在虹鱒腦室注射leptin后可提高糖合成和分解過程中相關(guān)酶的含量, GK活性以及與糖代謝反應(yīng)有關(guān)基因的mRNA水平, 研究還發(fā)現(xiàn)leptin作用后會引起血糖濃度升高[25]。Huising等[14]以鯉為模型, 研究發(fā)現(xiàn)攝食后其肝臟leptin mRNA表達量上升, 其峰值出現(xiàn)在血糖含量的升高和血漿游離脂肪酸下降之后, 這可能是因為其leptin表達量由攝食后血糖含量變化所控制。Gorissen等[15]證實斑馬魚在禁食一周后, 其肝臟leptin-B的mRNA水平顯著降低, 而leptin-A的mRNA水平則升高, 這與leptin的不同亞型有關(guān)。虹鱒在長期饑餓(3周)中, leptin的表達水平顯著升高[39]。在鱸中, 饑餓3周其肝中l(wèi)eptin的mRNA水平顯著減少, 再投喂3周后leptin mRNA水平則回升[20]; 上述這些研究表明了魚類leptin可激活糖代謝系統(tǒng), 這與高血糖條件下觀察到的變化一致, 在魚類腦中增加或降低血糖水平[63,64]伴隨著GK的活性及其表達水平的變化、糖酵解能力以及葡萄糖和糖原水平的變化, 且這種變化與哺乳動物的糖代謝反應(yīng)在某種程度上相類似[65]。

哺乳動物中的研究認為機體的血糖水平與攝食調(diào)節(jié)及能量平衡密切相關(guān), 高血糖條件下食物的攝入被抑制[12]。而上述在絕大多數(shù)魚類研究中的結(jié)果顯示, 特異性的魚類leptin具有抑制魚類攝食的作用[16,17,25], 推測魚類leptin對攝食的調(diào)節(jié)也與對糖脂代謝的作用相偶聯(lián), 即魚類leptin通過調(diào)節(jié)糖(血糖)及脂類代謝進而調(diào)節(jié)魚類的攝食及能量代謝的平衡。眾所周知, 魚類, 特別是肉食性魚類, 對高糖具有不耐受性[66,67], 而魚類的食性與leptin以及糖脂代謝是否存在更密切的關(guān)系, 尚需深入研究。

3.3 Leptin的其他作用

已有研究證實 leptin與硬骨魚類的繁殖活動密切相關(guān)。leptin及其受體在大西洋鮭和斑馬魚的腦(腦垂體)及性腺中表達很豐富[15,19,42]。Peyon等[68]報道重組鼠leptin對舌齒鱸(Dicentrarchus labrax)腦垂體中促黃體生成素(luteinizing hormone, LH)的產(chǎn)生有直接作用。高濃度的重組人 leptin可刺激虹鱒離體腦垂體分泌促性腺激素(gonadotropin, GtH)[69];在北極紅點鮭性成熟季節(jié), leptin mRNA在肝臟中保持較高的表達水平[18]。另有研究報道[70], leptin可影響魚類的免疫系統(tǒng), 采用重組虹鱒 leptin和虹鱒白細胞共孵育后可激活STAT3(Signal transducer and activator of transcription 3, STAT3), NF-κB(nuclear factor kappa-light-chain-enhancer of activated B cells, NF-κB), 以及三個主要的 MAPK(mitogen-activated protein kinases, MAPK)級聯(lián)的信號通路(JNK, p38和 ERK); 并能減少虹鱒血液白細胞中超氧陰離子的量; 重組尼羅羅非魚(Tilapia nilotica)leptin-A 可增強羅非魚垂體催乳素的合成和釋放, 而垂體催乳素反過來也可抑制肝 leptin蛋白的合成和分泌, 推測這種相互調(diào)節(jié)作用在急性高滲適應(yīng)過程中對于動員能量儲備是必要的[71]; Baltzegar等[72]在尼羅羅非魚的研究也提示 leptin-A可能在其急性高滲應(yīng)激中和皮質(zhì)醇共同起重要的調(diào)節(jié)作用。魏 赟[73]對斜帶石斑魚(Epinephelus coioides)兩種同源的瘦素基因(leptin-A, leptin-B)進行了多態(tài)性研究, 并與斜帶石斑魚12個生長性狀進行關(guān)聯(lián)分析, 篩選出了4個與生長性狀緊密相關(guān)的分子標(biāo)記。

4 展望

綜上所述, leptin是一種具有多功能的激素, 在能量代謝、繁殖以及適應(yīng)環(huán)境等方面發(fā)揮關(guān)鍵作用。雖然在魚類中 leptin的研究已取得了一定的進展,但仍有很多重要的問題尚未解決, 如(1)魚類 leptin受體是否同時作為 leptin-A和 leptin-B的受體？或是受體下游的作用機制決定 leptin類型？在魚的全基因組中是否尚有未知的 leptin受體？(2)魚類leptin是否具有像哺乳動物leptin在骨骼生成、甲狀腺功能以及血管生成等方面的作用？進一步解析leptin在魚類中的多種生理作用, 可為最終闡明影響脊椎動物能量穩(wěn)態(tài)的 leptin系統(tǒng)的起源及進化奠定新的理論基礎(chǔ)。

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BIOLOGICAL CHARACTERISTICS AND FUNCTIONS OF LEPTIN IN FISH

LU Rong-Hua1, SUN Jun-Jun1, LIANG Xu-Fang2, NIE Guo-Xing1and YANG Feng1
(1. College of Fisheries, Henan Normal University, Xinxiang 453007, China; 2. College of Fisheries, Huazhong Agricultural University, Shizishan Street 1, Wuhan 430070, China)

Leptin is the product of ob gene and a kind of Type I cytokine. It is primarily synthesized and secreted by adipocytes and plays an important role in the regulation of ingestion, energy metabolism, skeletal development, thyroid function, and reproduction in mammals. To date leptin gene has been cloned in various teleostean groups, and there have been studies of the physiological functions of leptin. Previous reports have suggested that fish leptin is mainly synthesized in liver, and the amino acid sequence is different from that in mammals; however, the protein structure is highly conservative. Because of its crucial roles in ingestion, glucose and lipid metabolism, and reproduction, Leptin is potentially a new drug target for improving the glucose utilization efficiency in fish in the future. Therefore in this review we discussed about fish leptin in terms of its structure, expression, functions, tissue-specific distribution and receptors.

Leptin; Fish; Biological characteristics; Appetite regulation; Energy metabolism

Q344+.1

A

1000-3207(2015)03-0583-07

10.7541/2015.76

2014-04-23;

2014-07-15

國家自然科學(xué)基金項目(31172420, 31402311); 河南省基礎(chǔ)與前沿技術(shù)研究計劃項目(142300410158)

盧榮華(1977—), 女, 河南虞城人; 博士; 主要研究方向為魚類糖脂代謝調(diào)控機理研究。E-mail: laoaiyika@hotmail.com

梁旭方, 教授; E-mail: xfliang@mail.hzau.edu.cn