动物营养学报    2020, Vol. 32 Issue (12): 5614-5621    PDF    
吻素-1基因调控食欲的研究进展
徐少奇 , 唐妮 , 陈德芳 , 李志琼     
四川农业大学动物科技学院, 成都 611130
摘要: 吻素-1(KISS-1)基因于1996年在人类黑色素瘤细胞中被发现,其广泛分布于中枢神经系统和外周组织。KISS-1基因编码前体蛋白亲吻促动素(Kisspeptin)具有调控食欲、抑制肿瘤转移和促进繁殖等功能。KISS-1基因可能通过核连蛋白2(NUCB2)和催产素(OXT)途径、前阿片网膜皮质素(POMC)和神经肽Y(NPY)途径以及与瘦素、胰高血糖素样肽-1(GLP-1)和胃饥饿素等食欲调节因子互作来抑制绝大多数动物摄食。本文综述了KISS-1基因的结构、组织分布及食欲调控作用的研究进展,以期为动物的摄食和生长提供参考。
关键词: KISS-1    Kisspeptin    前阿片网膜皮质素    摄食    食欲调节因子    
Research Progress on KISS-1 Gene Regulate Appetite
XU Shaoqi , TANG Ni , CHEN Defang , LI Zhiqiong     
College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China
Abstract: KISS-1 gene was first discovered in human melanoma cells in 1996, and it is widely distributed in the central nervous system and peripheral tissues. Previous research shows that KISS-1 encodes the precursor protein Kisspeptin, which has various biological functions such as regulating appetite, inhibiting tumor metastasis and promoting reproduction. KISS-1 gene may inhibit feed intake in the majority of animals through the nesfatin-1 and oxytocin (OXT) pathway, pro-opiomelanocortin (POMC) and nueropeptide Y (NPY) pathway and interaction with leptin, glucagon like peptide-1 (GLP-1) and ghrelin. In this review, we focus on the main research progress of KISS-1 gene in structure, tissue distribution and the function of appetite to providing a reference for further research on animal feeding and growth.
Key words: KISS-1    Kisspeptin    POMC    feed intake    appetite regulation factor    

摄食为机体生存、生长、免疫和繁殖提供物质基础。外界条件和机体内部因素共同诱发摄食行为。当机体能量水平或营养素降低到某一阈值时,刺激下丘脑摄食中枢,通过摄食调控系统引发食欲进而产生摄食。动物的摄食由中枢摄食系统和外周摄食系统分泌食欲调节因子联合调控[1]。常见的食欲调节因子有增食欲素(orexin)、刺鼠相关蛋白(agouti-related protein,AgRP)、可卡因-安非他明调节转录肽(cocaine and amphetamine regulated transcript,CART)和吻素(KISS)-1等[2-5]。1996年,Lee等[6]发现了能抑制人黑色素瘤转移的新基因,将其命名为KISS-1。随后又在哺乳类[大鼠(Rattus norvegicus)、猴(Macaca mulatta)和羊(Ovis aries)等]、爬行类[(绿安乐蜥(Anolis carolinensis)]、两栖类[(非洲爪蟾(Xenopus tropicalis))]和鱼类[(斑马鱼(Danio rerio)、青鳉(Oryzias latipes)和欧洲海鲈(Dicentrarchus labrax)等]上发现了KISS-1基因[7-14]。然而,鸟类还未鉴定出KISS-1基因。绝大多数研究显示KISS-1基因可抑制动物摄食,但关于其调控摄食机制的研究较少。本文就KISS-1基因的结构、分布、摄食调控功能和机制作一综述。

1 KISS-1基因的结构

KISS-1基因是KISS基因的亚型之一。此外,KISS基因还存在KISS-2和KISS-3基因。进化分析表明,哺乳类中鉴定出KISS-1基因[仅鸭嘴兽(Ornithorhynchus anatinus)鉴定出KISS-2基因[11]];爬行类中鉴定出KISS-2基因;两栖类中鉴定出KISS-1a、KISS-1b和KISS-2基因;斑马鱼和青鳉等大多数鱼类中鉴定出KISS-1和KISS-2基因,星点东方鲀(Takifgu niphobles)和大西洋鲑(Salmo salar)等部分鱼类中只鉴定出KISS-2基因,而在腔棘鱼(Latimeria chalumnae)、象鲨(Cetorhinus maximus)和斑点雀鳝(Lepisosteus oculatus)中鉴定出KISS-1、KISS-2和KISS-3基因[12-13, 15-17]。由上可知,KISS-1基因存在于多种动物中,且鱼类中KISS-1基因的情况更为复杂和多样,这可能与鱼类的多重基因组复制事件有关。

KISS-1基因编码的前体蛋白亲吻促动素(Kisspeptin),最终裂解生成54、14、13和10个氨基酸的短肽,分别命名为Kisspeptin-54、Kisspeptin-14、Kisspeptin-13和Kisspeptin-10(图 1)。Kisspeptin-10为可激活受体的最小肽段,且在各物种间高度保守,仅在第3和10氨基酸位点出现变化。以斑马鱼Kisspeptin-10(YNLNSFGLRY)为例,与人Kisspeptin-10序列相似性为80%,与小鼠Kisspeptin-10序列相似性为90%,与青鳉Kisspeptin-10序列相似性为100%。提示研究KISS-1功能时,可将Kisspeptin-10作为研究对象。

KISS-1 gene:吻素-1基因;KISS-1 mRNA:吻素-1 mRNA;exon Ⅰ:外显子Ⅰ expressed region Ⅰ;exon Ⅱ:外显子Ⅱ expressed region Ⅱ;Kisspeptin亲吻促动素;Signal:信号肽signal peptide;KP-54:亲吻促动素-54 Kisspeptin-54;KP-14:亲吻促动素-14 Kisspeptin-14;KP-13:亲吻促动素-13 Kisspeptin-13;KP-10:亲吻促动素-10 Kisspeptin-10。 图 1 斑马鱼KISS-1基因及产物裂解示意图 Fig. 1 Sketch map of zebrafish KISS-1 gene and its product cracking
2 KISS-1基因的表达

目前关于KISS-1基因组织分布的研究主要集中于哺乳类和鱼类,KISS-1基因在中枢神经系统和外周组织中广泛分布。KISS-1基因主要分布于中枢神经系统的下丘脑、小脑和中脑等区域,而外周则主要分布于消化道和性腺中。Chen等[18]利用免疫组化等技术发现布氏田鼠(Lasiopodomys brandtii)KISS-1基因在下丘脑、小肠和性腺中高表达。在欧亚野猪(Sus scrofa)和羊等哺乳动物的试验中也出现类似结果[9, 19]。非洲爪蟾KISS-1a和KISS-1b基因在腹侧下丘脑、肠道和性腺中高表达[11]。Um等[20]利用原位杂交(ISH)和逆转录-聚合酶链反应(RT-PCR)技术发现,斑马鱼KISS-1基因在间脑和中脑中高表达,在下丘脑腹内侧核(ventromedial nucleus,VMN)和室周核(periventricular nucleus,PV)中表达量最高,而在脂肪组织中也少量分布。最近在卵形鲳鲹(Trachinotus ovatus)、抚仙金线鲃(Sinocyclocheilus tingi)和长江鲟(Acipenser dabryanus)等鱼类上发现KISS-1基因在下丘脑和垂体中高表达,在肠道、肌肉、肝脏和性腺中也有表达[21-23]。总之,KISS-1基因广泛分布于中枢和外周中,也提示该基因可能具有多种生物学功能。

3 KISS-1基因调控摄食

KISS-1基因自发现以来,已证明其具有抑制肿瘤转移、调控性激素分泌和调控摄食等功能[5, 24-25]。本文将重点介绍KISS-1基因在摄食调控中的作用。

3.1 禁食和限饲对KISS-1基因表达的影响

下丘脑作为摄食调控中枢,能感知机体的能量和代谢状态变化,进而调控食欲因子的表达和分泌。成年雄性恒河猴禁食处理后,下丘脑中KISS-1基因表达量显著下降[26]。大鼠和小鼠下丘脑中KISS-1基因表达量在禁食和限饲处理后也呈下降状态[27-28]。成年雄尼罗罗非鱼(Oreochromis niloticus)禁食后也得到类似结果[29]。然而,也有部分鱼类禁食或限饲处理后KISS-1基因表达量增加或不变。成年雄性欧洲海鲈和成年雄性和雌性塞内加尔鳎(Solea senegalensis)限饲后,下丘脑中KISS-1基因表达量增加[30-31]。然而,成年雌尼罗罗非鱼限饲后下丘脑KISS-1基因表达量不变,这与雄尼罗罗非鱼出现差异的原因可能是由性别不同所导致[32]。可见,当机体处于负能量状态时,哺乳动物下丘脑中KISS-1基因表达量均显著下降。而鱼类下丘脑中KISS-1基因表达量的变化情况不一致,可能与试验动物的种类、性别和生理状态相关[33]。此外,与哺乳动物相比,鱼类在禁食或限饲后下丘脑中KISS-1基因表达量的变化多样,提示KISS-1基因在鱼类中发挥摄食调控功能可能受更多因素的影响。

3.2 注射Kisspeptin-10对摄食量的影响

目前普遍认为Kisspeptin-10是KISS-1基因的主要功能片段。为验证KISS-1基因是否参与摄食调控,可采用注射外源性Kisspeptin-10,然后检测摄食量变化。

注射外源性Kisspeptin-10能显著抑制大鼠和小鼠摄食。成年雄性大鼠脑室注射6.0 μg Kisspeptin-10,摄食量显著降低,但注射3.8 μg Kisspeptin-10时摄食量则无显著变化[34]。与大鼠相比,小鼠中Kisspeptin-10的有效剂量较低。对禁食过夜的成年雄性小鼠脑室注射Kisspeptin-10(0.3、1.0和3.0 μg)后,摄食量呈剂量依赖型模式减少,而在自由进食条件下进行脑室注射时,Kisspeptin-10的抑食欲作用消失[35]。此外,小鼠腹腔注射Kisspeptin-10时也能减少摄食[36]。这提示KISS-1基因在中枢神经系统和外周组织中发挥抑食欲作用与动物种类、生理状态(是否禁食)、注射Kisspeptin-10剂量和注射方式等密切相关。

4 KISS-1基因的摄食调控机制

目前关于KISS-1基因摄食调控机制的文献报道较少,且研究结果存在差异。KISS-1基因抑制摄食的途径可能存在以下3种:1)通过核连蛋白2(nucleobindin-2,NUCB2)和催产素(oxytocin,OXT)抑制摄食;2)通过前阿片网膜皮质素(pro-opiomelanocortin,POMC)和神经肽Y(nueropeptide Y,NPY)抑制摄食;3)与其他食欲调节因子共同调控摄食。

4.1 KISS-1基因通过nesfatin-1和OXT抑制摄食

NUCB2在激素原转化酶作用下可剪切成nesfatin-1、nesfatin-2和nesfatin-3 3个片段。其中,nesfatin-1是一种抑食欲因子。大鼠脑室注射Kisspeptin-10后,可激活和增加视上核(supraoptic nucleus,SON)、室旁核(paraventricular nucleus,PVN)、孤束核(nucleus tractussolitarius,NTS)和弓状核(arcuate nucleus,ARC)等核区中NUCB2活化神经元数量,促进nesfatin-1分泌[34]。这提示KISS-1基因可以促进nesfatin-1的分泌来发挥抑制摄食的作用。

KISS-1基因还可以通过促进OXT的分泌来抑制摄食。OXT神经元主要分布于SON和PVN,分泌的OXT储存于垂体后叶。OXT在中枢神经系统能量代谢平衡的调控中具有重要作用,可抑制摄食。大鼠脑室注射Kisspeptin-10后可增加SON和PVN中的OXT活化神经元数量并促进OXT分泌,且摄食量显著下降。而用OXT受体拮抗剂(OXTR-A)预处理后,能减弱Kisspeptin-10的抑食欲作用[34]。在大鼠的静脉注射试验中也出现类似结果,Kisspeptin-10可增加血浆OXT含量及OXT神经元的放电频率[37-38]。这提示OXT在KISS-1的摄食调控通路中具有重要作用。

KISS-1基因在促进NUCB2分泌nesfatin-1和OXT分泌来发挥抑制摄食的同时,NUCB2神经元与OXT神经元之间的互作进一步抑制了摄食。OXT神经元和NUCB2神经元相重叠,通过正反馈调节互相激活,NUCB2神经元分泌的nesfatin-1,可激活NUCB2神经元本身及OXT神经元,而激活后的NUCB2神经元又可进一步激活OXT神经元,最终使PVN中的OXT分泌增多[39]。这暗示KISS-1神经元可能通过合成和分泌Kisspeptin-10来促进nesfatin-1和OXT的分泌,且NUCB2神经元与OXT神经元二者之间能够相互激活,最终使动物摄食减少。

4.2 KISS-1基因通过POMC和NPY抑制摄食

KISS-1神经元、POMC神经元和NPY神经元都在ARC中大量分布,彼此之间可能存在关联[40]。通过膜片钳技术发现Kisspeptin-10可激活小鼠ARC中的POMC神经元,且用Kisspeptin-10受体拮抗剂(肽234)能减弱这种效应[41]。NPY神经元通过开放钾离子通道抑制POMC神经元,并减弱Kisspeptin-10对POMC神经元的激活作用。此外,KISS-1神经元能分泌抑制性神经递质γ-氨基丁酸(γ-aminobutyric acid,GABA),抑制NPY神经元[42]。这提示KISS-1神经元能够通过激活POMC神经元及抑制NPY神经元发挥抑食欲作用。KISS-1神经元对NPY神经元的抑制作用可能是由POMC神经元所介导。NPY神经元与下丘脑ARC中的KISS-1神经元投射非常接近,且Kisspeptin-10的受体[G蛋白偶联受体54(GRP54)]在下丘脑的NPY神经元中也有表达[43]。当用Kisspeptin-10处理下丘脑NPY细胞系,NPY分泌增加[40]。下丘脑中POMC神经元和NPY神经元的活性相互抑制[44],而NPY细胞系中常常无法分泌POMC,所以导致Kisspeptin-10处理后NPY分泌增加的情况出现。总之,POMC和NPY作为重要的食欲调节因子,在KISS-1基因的摄食调控功能中发挥了极其重要的作用。

4.3 KISS-1基因与其他食欲调节因子共同调控摄食

中枢神经系统和外周组织中分布着大量食欲调控因子,彼此之间相互作用。已有报道显示,KISS-1基因可能与瘦素(Leptin)、胰高血糖素样肽-1(glucagon like peptide-1,GLP-1)、胃饥饿素(Ghrelin)和雷帕霉素靶蛋白(mallalian target of rapamycin,mTOR)等食欲因子共同调控摄食[36, 45-47]。ARC位于中央隆起附近,是下丘脑中参与摄食调控的核团之一。摄食相关信号可以自由通过ARC,将机体能量状态从外周传递到中枢。研究发现KISS-1基因在ARC中表达丰富,而该核团也是LeptinGLP-1和Ghrelin等基因高表达的部位。

4.3.1 Leptin促进KISS-1基因表达

KISS-1神经元能表达Leptin受体,可以作为Leptin作用的直接靶点[48]。绵羊脑室注射Leptin可增加ARC中KISS-1基因表达量,在小鼠下丘脑细胞系N6及促性腺激素释放激素(Gonadotropin-releasing hormone,GnRH)分泌神经母细胞中也得到了类似结果[27, 43]。此外,Leptin缺失型小鼠的ARC中KISS-1基因表达量显著低于正常小鼠,而腹腔注射Leptin后可恢复KISS-1基因表达量[49]。同时,也有研究显示小鼠腹腔注射Kisspeptin-10后可使血液中Leptin含量增多[36]。可见,KISS-1基因和Leptin之间存在相互调节的关系。

目前,关于Leptin调控KISS-1基因表达的途径可能有2种:1)Leptin通过环磷酸腺苷(cAMP)调节转录共激活因子1(cAMP-regulated transcriptional coactivator 1,CRTC1)调控KISS-1基因表达。通过小鼠GnRH神经元细胞系GT1-7的试验发现,Leptin能够使CRTC1去磷酸化并激活,而CRTC1可增强KISS-1启动子的活性,促进KISS-1基因表达[50]。2)Leptin通过mTOR调控KISS-1基因表达。mTOR是下丘脑中的一种能量感受器,同时具抑食欲作用[51]。大鼠脑室注射Leptin能增强mTOR的活性,而当下丘脑中mTOR失活后,会导致ARC和前腹侧脑室周围核团(anterior ventral periventricular nucleus,AVPV)中KISS-1基因表达量显著降低[47, 52]。这提示Leptin可能通过增强mTOR活性,以促进KISS-1基因的表达,但是否还有其他调控因子参与还需进一步探究。总之,Leptin可能通过CRTC1和mTOR调控KISS-1基因的表达,最终共同发挥摄食调控功能。

4.3.2 GLP-1促进KISS-1基因表达

GLP-1是由肠道L细胞分泌的肠促胰岛素,具抑食欲作用。小鼠ARC中的GLP-1神经元与KISS-1神经元紧密相连,且这些神经元中都能表达GLP-1受体[53]。进一步研究发现,GLP-1可促进KISS-1基因表达。对大鼠脑室注射GLP-1,可增加ARC中KISS-1基因表达[54]。此外,在胚鼠脑细胞中,用GLP-1处理后KISS-1基因表达量增加,而用GLP-1受体拮抗剂处理后增强作用完全消失。cAMP反应元件(cAMP response element,CRE)的启动子是cAMP/蛋白激酶A(PKA)信号通路的靶点,用GLP-1刺激胚鼠下丘脑细胞系rhypoe-8时,CRE启动子活性显著增加,且KISS-1基因表达量升高。用PKA抑制剂(H89)处理后,GLP-1对KISS-1基因表达的促进作用被完全抑制[45]。这提示GLP-1可能通过增强CRE启动子活性来促进KISS-1基因的表达,而具体机制仍需进一步探究。

4.3.3 Ghrelin抑制KISS-1基因表达

Ghrelin是由胃腺X/A样细胞释放的多肽,能促进动物摄食。在中枢神经系统中,Ghrelin主要分布于ARC、PVN和VMN等区域。Sarah等[46]对大鼠静脉注射Ghrelin,发现AVPV和ARC中KISS-1表达量降低。此外,在大鼠胰岛和CRI-D2细胞中也发现Ghrelin处理后KISS-1表达量降低[55]。这提示Ghrelin能够抑制KISS-1基因的表达,而其中所涉及的调控机制和作用方式还未见报导,未来应深入研究。

综上所述,目前KISS-1基因可能通过促进nesfatin-1和OXT分泌的途径、促进POMC和抑制NPY的途径来抑制摄食,此外,还可能通过与Leptin、GLP-1和Ghrelin等食欲因子的互作来抑制摄食(图 2)。鱼类上关于KISS-1摄食调控机制的研究极少,未来应加强相关研究,为鱼类养殖奠定理论基础。

Leptin:瘦素leptin;GLP-1:胰高血糖素样肽-1 glucagon-like peptide-1;Ghrelin:胃饥饿素ghrelin;KISS-1:吻素-1;Nesfatin-1:核连蛋白2 nucleobindin-2;OXT:催产素oxytocin;NPY:神经肽Y nueropeptide Y;POMC:前阿片网膜皮质素pro-opiomelanocortin;Stimulation:促进;Inhibition:抑制。
红色箭头表示促进,蓝色箭头表示抑制,黄色椭圆框表示抑食欲因子,绿色方框表示促食欲因子。
The red arrow represents stimulation, the blue arrow represents inhibition, the yellow oval box represents anorectic factor, and the green boxes represents orectic factor.
图 2 KISS-1基因调控摄食的可能机制 Fig. 2 Possible mechanisms of KISS-1 gene regulating feeding
5 小结

KISS-1基因从发现至今,探索了不同物种中KISS-1基因的结构、组织分布和功能,对该基因有了一定的认识,但仍然存在一些问题。在功能研究上,更多的研究者将其重点放在肿瘤和繁殖领域,而关于摄食调控的研究较少。机体的能量状态与繁殖密切相关,而KISS-1基因能够同时调控摄食和下丘脑-垂体-性腺轴,可见KISS-1基因可作为机体能量与繁殖的联系纽带。加强KISS-1基因在摄食调控中的功能研究,可进一步理解动物能量状态与繁殖之间的平衡关系。在研究的物种上,大多数集中在哺乳动物中,非哺乳动物上的研究还相对较少。水产养殖作为农业经济的支柱产业之一,应加强KISS-1基因在鱼类上的研究,以促进鱼类养殖,提高生长速度,提升经济效益。

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