动物营养学报    2021, Vol. 33 Issue (3): 1208-1215    PDF    
饲料单宁提高鱼类糖利用能力的作用机制研究进展
彭凯1,2,3 , 王国霞1,2,3 , 赵红霞1,2,3 , 黄燕华1,2,3     
1. 广东省农业科学院动物科学研究所, 广州 510640;
2. 广东省畜禽育种与营养研究重点实验室, 广州 510640;
3. 农业农村部华南动物营养与饲料重点实验室, 广州 510640
摘要: 鱼类先天对糖的利用能力差,摄食高糖饲料容易引发餐后高血糖症,危害鱼体健康,同时也限制了糖在饲料中的应用。采用营养调控手段增加鱼类对糖的耐受能力,有利于提高糖的利用效率,节约蛋白质资源。单宁是广泛分布于自然界的一类天然多酚化合物,具有显著的降血糖功效,其主要途径包括抑制糖代谢酶活性、刺激胰岛素分泌、抑制葡萄糖转运载体mRNA表达以及通过介导肠道特定菌群发挥降血糖生物活性。本文综述了鱼类糖不耐受的生理机制以及单宁降血糖作用机制的研究进展,旨为鱼类糖代谢研究及其健康养殖提供参考。
关键词: 鱼类    饲料    单宁    糖利用    
Advances in Studies on Mechanisms of Dietary Tannins Improving Sugar Utilization of Fish
PENG Kai1,2,3 , WANG Guoxia1,2,3 , ZHAO Hongxia1,2,3 , HUANG Yanhua1,2,3     
1. Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Guangzhou 510640, China;
2. Guangdong Key Laboratory of Animal Breeding and Nutrition, Guangzhou 510640, China;
3. Key Laboratory of Animal Nutrition and Feed Science in South China, Ministry of Agriculture and Rural Affairs, Guangzhou 510640, China
Abstract: Fish have poor innate ability to use sugar, and ingesting high-sugar feed will easily cause postprandial hyperglycemia, which will harm fish health and limit the application of sugar in feed. Increasing the tolerance of fish to sugar by means of nutrition regulation is beneficial to improve the efficiency of sugar utilization and save protein resources. Tannins are a kind of natural polyphenolic compounds widely distributed in nature, which possess significant hypoglycemic effect by inhibiting the activity of glucose metabolizing enzyme, stimulating insulin secretion and inhibiting the expression of glucose transporter mRNA, and exerting hypoglycemic biological activity by mediating specific intestinal flora. Research progress on the physiological mechanisms of sugar intolerance and the hypoglycemic mechanism of tannins were reviewed in this article, aiming to provide reference for the fish glucose metabolism research and its healthy breeding.
Key words: fish    feed    tannins    sugar utilization    

糖类物质是水产饲料的重要组分,也是鱼类廉价的能量来源。饲料中适量添加糖类物质可以降低蛋白质作为能量的消耗,节约蛋白质资源,减轻氮排泄对养殖水体的污染。然而,与陆生动物相比,鱼类先天对糖的利用能力差[1],尤其是肉食性鱼类在摄入高糖饲料后,容易出现持续高血糖症[2]。虽然鱼体存在利用糖的一系列酶和代谢途径,但鱼类对葡萄糖的耐受性和利用能力存在种类差异,持续的高血糖至少需要3 h才能恢复至正常水平[3],某些肉食性鱼类如大黄鱼,则需要24 h甚至更长时间恢复[3]。由于机体不能快速处理体内糖负荷,从而导致氧化应激、抗病力下降、生长缓慢甚至死亡等现象,危害鱼类生命健康。由此看来,鱼类对糖供能需求的增加与机体对糖利用能力的不足形成鲜明矛盾,使糖在水产饲料中的应用存在一定的局限性。

单宁是广泛分布于自然界的一类天然多酚化合物,是一种储量丰富的绿色可再生资源。长期以来,单宁被视为饲料“抗营养因子”,因此有关单宁的生物活性研究及其生产应用受到一定限制。实际上,低浓度单宁不仅不影响饲料的适口性,还能提高动物健康和生产性能[4-6]。据报道,单宁具有抗菌、抗氧化、抗炎、抗寄生虫、抗病毒、调节营养物质代谢等多种生物活性[7]。近来研究表明,单宁具有显著的降血糖效果,其作用机理可能与单宁调节糖代谢酶活性、调控胰岛β细胞功能、干预动物肠道菌群有关[6, 8-10]。本文综述了鱼类糖不耐受的生理机制以及单宁降血糖作用机制研究进展,以期为单宁生物活性的深入研究及指导生产实践提供理论依据。

1 鱼类糖不耐受的生理机制

鱼类与陆生动物在糖代谢方面存在显著差异,陆生动物主要利用糖为能源,而鱼类主要利用蛋白质为能源,因为鱼类对糖的利用率普遍较低[11-14]。鱼类在摄入高糖饲料之后,会出现长时间的“餐后高血糖症”,从而对鱼类组织器官、生长性能、营养利用效率、生理功能产生不利影响[15]。鱼类餐后高血糖症形成的主要原因包括葡萄糖感知和摄食调控体系不完善、糖代谢酶活性低、葡萄糖转运能力差、胰岛素分泌不足、胰岛素受体数量和亲和力不足。

动物通过反馈调节机制保持机体血糖稳态的关键在于体内广泛分布葡萄糖感应器和摄食调控神经元,它们能够监测血糖变化、触发激素分泌、激活神经系统,从而调控糖代谢。尽管在鱼类的脑中发现一些葡萄糖感应器的构成分子,如葡萄糖转运蛋白2(GLUT2)和葡萄糖激酶(GK),但尚未鉴定出葡萄糖感应器如葡萄糖兴奋性神经元(GE)和葡萄糖抑制性神经元(GI)的存在,鱼类血糖是否受其他神经元调控也不得而知[16]。鱼类下丘脑中存在调节摄食的神经肽类,但目前尚无证据表明鱼类也存在促进摄食和抑制摄食的神经元[16]。未来研究应当侧重于鱼类中枢神经系统整合营养与内分泌等信号机制,研究影响鱼类葡萄糖感知和摄食调控的关键神经元,这有利于调控鱼类对糖的摄食和代谢等生理活动,从根本上解决鱼类对糖不耐受的问题。

参与鱼体内糖酵解、糖异生、磷酸戊糖途径的限速酶在鱼类中已证实存在,但其活性较低且基因表达受饲料糖水平的影响[17]。鱼类没有唾液腺,因此口腔对淀粉和糖几乎没有消化,鱼类的α-淀粉酶由胰腺合成,然后分泌到小肠。胰腺α-淀粉酶活性是鱼类对淀粉和糖原消化的主要限制因子。肉食性鱼类(如大西洋鲑、虹鳟、海鲈)由于基因突变和缺失,使消化道内的α-淀粉酶活性很低[18]。摄入高糖可以促进草食性和杂食性鱼类胰腺分泌α-淀粉酶,但对肉食性鱼类α-淀粉酶的分泌没有影响[19]。当饲料中碳水化合物含量大于20%时,肉食性鱼类对淀粉的消化能力显著下降,表明鱼类对糖的利用能力存在局限性。此外,鱼类葡萄糖转运能力差,胰岛素依赖的葡萄糖转运载体葡萄糖转运蛋白(GLUT)数量少,阻碍了葡萄糖进入细胞进行代谢。鱼类是否存在GLUT还有争议,据报道,罗非鱼和虹鳟体内无GLUT[20],而棕鳟和银鲑体内存在GLUT4同源体,这可能是鱼类利用葡萄糖能力较差的原因之一[21]。对于鱼类葡萄糖转运载体的研究多集中在基因克隆和表达上,其转运机制、动力学研究和影响因素等尚处于起步阶段。

鱼类血浆胰岛素分泌量不足是导致鱼类高血糖症及影响鱼类糖代谢的主要原因之一。动物机体稳态下,鱼体胰岛素水平低于哺乳动物[22]。谭肖英等[23]报道,鱼类胰岛素分泌延迟于鱼类对糖的吸收速度,从而使吸收的葡萄糖不能被有效利用。目前,鱼类胰岛素基因表达机制尚不明确,但Hrytsenko等[24]发现,罗非鱼胰岛素基因转录是由胰岛β细胞特异性行为调节,且胰岛素基因转录对高糖刺激不敏感。这可能是鱼类胰岛素分泌不足的原因。鱼类胰岛素受体数量较陆生动物少,肉食性鱼比杂食性鱼的肌肉胰岛素受体数量和亲和力低,因此胰岛素受体数量不足也可能造成鱼类高血糖症,导致鱼类对糖的利用率较低。

2 单宁提高鱼类糖利用能力的作用机制

鱼类糖代谢的研究多以调配饲料为手段,但通过调配饲料或更换不同糖源,并不能从根本上解决鱼类不善于利用糖的问题。实际上,鱼类的糖代谢调节较为复杂,已知受神经中枢、内分泌因子和营养素等多重因子影响[16]。近年来发现,糖代谢与肠道内消化酶活性、葡萄糖转运载体基因表达量以及微生物菌群活动密切相关。单宁具有降血糖作用,但其降血糖机理较为复杂。概括起来,单宁可能通过抑制糖代谢相关酶活性[25]、刺激胰岛β细胞分泌胰岛素[26]、抑制葡萄糖转运载体mRNA表达[27]、刺激肠道L细胞分泌胰高血糖素样肽-1(GLP-1)[28]、调节肠道菌群[10]等途径降低血糖水平。

2.1 单宁促进糖酵解,抑制糖异生

单宁能够提高葡萄糖激酶、己糖激酶等糖原合成酶活性,抑制葡萄糖-6-磷酸酶、磷酸烯醇式丙酮酸酶等糖异生酶活性,从而加速糖原合成,减少葡萄糖生成[29-30]。研究表明,可可豆缩合单宁能够刺激骨骼肌细胞糖原合成,促进葡萄糖的吸收[31]。葡萄籽缩合单宁同样具有促进脂肪细胞糖原合成的能力[32]。在2型糖尿病小鼠模型中,苹果缩合单宁显著降低血糖水平,抑制糖异生[33]。在链脲佐菌素诱导小鼠糖尿病模型中,莲蓬缩合单宁能够提高小鼠肝脏丙酮酸激酶和磷酸果糖激酶的基因表达水平,加速糖酵解过程[34]。石榴花单宁能够竞争性抑制小肠α-葡萄糖苷酶活性,抑制餐后高血糖的快速上升[35]。细胞钙离子浓度升高是诱发糖尿病的一个重要原因,茶单宁可以增强细胞膜钙离子ATP酶活性,降低细胞内钙离子浓度并达到降血糖的功效[36]。单宁单体儿茶素还能通过清除自由基,保护细胞膜钙离子ATP酶活性,控制糖异生基因表达下降,以此延缓血糖上升[37]。概括起来,单宁通过下调胰腺组织中与糖酵解通路相关酶的活性或基因表达水平,促进糖酵解,抑制糖异生,从而降低血糖水平。

2.2 单宁诱导胰岛β细胞再生

单宁的降血糖作用可能与单宁刺激胰岛β细胞产生胰岛素以及增加胰岛素敏感性有关。Huang等[38]推测缩合单宁的降血糖作用可能归因于缩合单宁诱导了胰岛β细胞再生,从而增强了胰岛素受体的蛋白表达水平。Khan等[39]报道,肉桂单宁能够激活肝糖原合成酶和胰岛素受体激酶,增加葡萄糖摄取量,提高胰岛素敏感性。茶单宁可以刺激2型糖尿病模型小鼠肌肉组织中葡萄糖的吸收,促进胰岛β细胞产生胰岛素,改善体内葡萄糖平衡[40]。可可豆单宁单体表儿茶素通过增加HepG2细胞胰岛素受体(IR)、胰岛素受体底物1(IRS1)和胰岛素受体底物2(IRS2)磷酸化水平,激活糖原合成重要通路,如磷酸肌醇-3-激酶(PI3K)/蛋白激酶B(Akt)和AMP依赖蛋白激酶(AMPK)信号通路,增加葡萄糖转运载体GLUT2转运水平[9],提示单宁通过改善胰岛素信号通路,促进葡萄糖转运载体转移到细胞膜,调节葡萄糖吸收。González-Abuín等[41]发现,葡萄籽缩合单宁能够干预肥胖型大鼠二肽基肽酶4(DPP4)基因表达下调,促进胰岛β细胞分泌胰岛素,降低2型糖尿病小鼠血糖水平。

2.3 单宁介导肠道微生物调控血糖

肠道微生物与宿主生理代谢的相互关系是国际生物学研究的热点之一[42],然而肠道微生物在糖代谢中所扮演的角色尚处于探索阶段。作为鱼类营养物质代谢的主要场所,肠道及其微生态对糖代谢的影响至关重要。肠道栖息着数量庞大的微生物群落,肠道微生物是肠道发挥正常生理功能的基础,也是对动物发育不健全肠道酶系的有益补充。肠道中的拟杆菌可利用自身特有的结构域,协助肠道菌群降解糖类物质,提高宿主对糖的利用率[43]。积极探索鱼类肠道微生态并加以调整,对维持鱼类健康和提高生产性能具有积极的理论和实践意义。纵观国内外文献,肠道微生物对糖代谢的影响主要归纳为以下3个方面:1)鱼类肠道微生物可以直接分泌与糖代谢相关的胞外酶,从而促进多糖的分解[44];2)肠道特定菌属如劳特氏菌属(Blautia)、拟杆菌属(Bacteriodes)和Butyricoccus代谢产生的挥发性短链脂肪酸,如乙酸、丙酸和丁酸,能够直接被肠道吸收并提供给机体能量[45],同时作用于肠道L细胞表面受体,分泌胰高血糖素样肽[GLP-1、胰高血糖素样肽-2(GLP-2)]和内分泌调节肽[肽YY(PYY)],进而控制血糖和能量水平[46];3)肠道微生物通过调控葡萄糖转运载体mRNA表达量影响葡萄糖的利用[47-48]

单宁具有广谱抗菌性,其对大多数细菌、真菌和酵母菌具有一定的抑制作用[49]。Peng等[6]报道,紫色达利菊缩合单宁可以显著降低绵羊血糖水平,可能归因于单宁降低了瘤胃中布氏普雷沃氏菌(Prevotella bryantii)和嗜淀粉瘤胃杆菌(Ruminobacter amylophilus)数量。单宁还可能通过影响肠道微生态来调控血糖水平,即通过改变肠道微生物的种类和数量而影响细菌对肠道细胞的黏附[10, 50-51],从而影响糖类物质的消化和吸收,说明单宁可能通过干预动物肠道菌群调节糖代谢。刘钰锟[52]从罗非鱼肠道中筛选出了8株高效利用淀粉的细菌,发现Su1菌(与Bacillus toyonensis BCT-7112相似度99%)能够显著降低高淀粉饲料组罗非鱼的血糖水平,激活淀粉酶;额外添加Su1使罗非鱼肠道中疣微菌门(Verrucomicrobia)的比例上调,并推测Su1可能通过调控肠道菌群结构而发挥降血糖作用。Larsen等[53]研究表明,2型糖尿病模型动物肠道菌群失衡,表现为厚壁菌属丰度减少,变形菌属数量增加,且变形菌属数量与血糖水平呈正相关。王露[54]报道,糖尿病小鼠肠道细菌多样性和丰度明显改变,其中乳酸杆菌属和拟杆菌属数量下降,螺杆菌属和变形菌属等有害菌数量增加,治愈后小鼠肠道菌群多样性和丰度恢复正常,说明肠道菌群确实影响糖代谢。薛俊敏[55]通过小鼠肠道菌群失调模型的研究表明,茶单宁显著提高了厚壁菌门和拟杆菌门相对丰度,降低了变形菌门相对丰富,同时增加了小肠内乙酸、丁酸和异戊酸等短链脂肪酸含量。近期研究表明,肠道拟杆菌可通过介导胆汁酸甘氨熊脱氧胆酸(GUDCA)-肠道法尼醇X受体(FXR)代谢通路发挥降血糖作用[56]。FXR在胆汁酸合成与代谢、葡萄糖代谢中发挥重要角色[57]。金石[58]报道,饲喂大鼠缩合单宁可显著上调FXR基因表达水平。另有研究表明,葡萄籽缩合单宁对胆汁酸跨膜转运具有抑制作用[59]。由此可见,单宁有治疗糖尿病的功效,即通过介导肠道菌群特定菌属调控胆汁酸代谢通路,从而降低血糖水平,维持机体内糖稳态。

3 小结与展望

糖是鱼类廉价的能量来源,但其在饲料中的应用却受到限制,因为鱼类(尤其是肉食性鱼)摄食高糖饲料容易引发高血糖症,危害鱼类新陈代谢和生命健康。鱼类餐后出现的高血糖症主要归因于葡萄糖感知和摄食调控体系不完善、糖代谢酶活性低、葡萄糖转运能力差、胰岛素分泌不足以及胰岛素受体数量和亲和力不足。解决鱼类糖不耐受的问题有利于提高糖的利用率,减少蛋白质作为鱼类能源的消耗,缓解饲料蛋白质资源紧张。

单宁具有显著的降血糖作用,其作用机制包括抑制糖代谢相关酶活性、刺激胰岛β细胞分泌胰岛素、抑制葡萄糖转运载体mRNA表达、刺激肠道L细胞分泌GLP-1以及通过介导肠道特定菌群发挥降血糖功效,从而在解决鱼类高血糖症上展现出良好的应用前景。未来研究应侧重于鱼类中枢神经系统整合营养与内分泌调控糖代谢的信号机制,以及肠道菌群干预鱼类糖代谢的作用机理研究,为鱼类糖代谢研究及其健康养殖提供理论依据。

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