张婷艳综述 (彭咏梅审校复旦大学儿科医院,上海 200032) 摘要:围生期的营养因素可导致发育的适应,从而程序化地引起后期生命的病理性改变。妊娠期和哺乳期母亲摄入足够的必需脂肪酸EFA,对胎儿及其生后的发育非常重要。在动物和人的研究中发现,EFA和n6与n3多不饱和脂肪酸(PUFA)的不同比例,都将影响其后代的神经内分泌系统和免疫系统的生长发育,也可通过leptin相关机制影响其后代的后期生命。本文将着重论述EFA对脂肪组织生长、leptin浓度和免疫系统影响的研究进展。 关键词:必需脂肪酸;脂肪组织;leptin;免疫学
Abstract: Nutritional factors during a sensitive perinatal period may lead to developmental adaptations proposed to programme for pathological conditions later in life. An adequate supply of essential fatty acids EFA during pregnancy and lactation is crucial for optimal fetal and postnatal development. In animals and man variations in the levels of EFA and in the ratio of n6 to n3 polyunsaturated fatty acids PUFA affect growthdevelopent of the neuroendocrine and the immune systems of the offspring and might also have additional effects later in life via for instance leptinassociated mechanisms. The review will focus on the advancement of the study on EFA for adipose tissue growth leptin concentration and immune systems.
过去几十年,由于发达国家膳食中脂肪摄入的变化,导致多种疾病的发病急剧增加。必需脂肪酸(EFA)中n-6 与 n-3的比例变化与西方社会肥胖、糖尿病、过敏和心血管疾病(CVD)的增加有显著的关系。近年中国的疾病谱也有与西方相同的变化趋势,这与西方化膳食的引入不无关系。在全世界,寻找并确定对发育有害的因素是非常重要的。胎儿和围生期是生命的重要阶段,可能影响成年期的健康状况。这一关键时期受到特殊刺激或损害可能导致发育适应,而引起永久性结构改变,导致以后生命中生理或代谢的病理变化,也就是程序化改变。人类流行病学资料以及动物模型的研究表明,发生于胎儿和刚出生婴儿的损害与代谢相关性疾病的发病机制有关。代谢综合征是一类引起心血管系统疾病的高危因素,如肥胖、高脂血症、高胰岛素血症、胰岛素抵抗、葡萄糖不耐受、2型糖尿病以及高血压,这些疾病可影响1/4~5的个体。这些多因素疾病由基因和环境复杂的交互影响导致发病。母亲膳食中常量营养素的不足或不平衡以及对子代的长期影响,似乎与人类的上述疾病有密切关系。 已有报道指出,母乳喂养与人工喂养相比,前者与生命中低血压,2型糖尿病和肥胖的低发生率有关。母乳喂养潜在的保护作用机制是基于乳汁的成分,此外还有含多种生物活性物质的营养组分,包括EFA。EFA不能在活的有机体内合成,只能从食物中获得。EFA和它的衍生物,长链多不饱和脂肪酸(LCPUFA),对优化围生期胎儿和婴儿发育、作为膜的结构成分和功能调节器,起到关键性的作用。它们还能影响基因的表达和转录。多不饱和脂肪酸是指含有两个或两个以上不饱和双键的长链脂肪酸根据其结构中甲基端起第一个不饱和双键所联结的碳原子在碳链中的位置不同将此分为n-3、n-6、n-9等系列。 膳食中n-6/n-3 EFA的比例非常重要,因为n-6和n-3 EFA竞争代谢,它们具有不同的功能作用。在动物和人,母乳中不同的n-6/n-3 EFA比例可以引起神经系统和视网膜发育、免疫反应性和体格生长速率的不同变化。在人群中研究EFA对脂肪增长、leptin浓度和免疫系统的影响,有助于证明孕哺期母亲膳食中EFA含量及子代膳食中不同比例EFA可能调节乳汁和血的leptin水平;可能调节子代生长发育速率和认知发育的水平,可能调节免疫功能等结果。
必需脂肪酸对脂肪组织生长影响的早期研究
脂肪发育是激素、生长因子和营养因子综合调节的结果。在胎儿期和出生后的食物干预可改变这些因子的活性,从而改变脂肪组织的发育。食物中的脂肪能够改变机体脂质平衡和脂肪储存。与饱和脂肪相比,PUFA可以通过抑制肝脏脂肪合成、上调肝脏和骨骼肌脂肪酸氧化和增加机体总的糖原储存来限制脂肪细胞过度肥大。 LCPUFA通过调节与脂肪细胞发育有关的基因而对体重产生长期影响。目前认为,脂肪组织除作为能量储备组织外,也被看作是有重要内分泌作用的生物活性组织。它可分泌各种生物活性分子来调节神经内分泌和免疫系统,包括TNFa、IL6和leptin等。大鼠在胎儿期脂肪储存非常有限,这过程主要发生在生后。在人的胎儿期脂肪增加主要发生在宫内生长的最后 3个月。 膳食中脂肪的质量可影响成年鼠脂肪储存。如n-3 PUFA可限制脂肪储存所致的过度肥大。摄入富含n-3 PUFA的脂肪可降低脂肪组织甘油三酯的堆积,从而限制脂肪细胞的体积和脂肪组织生长,提高产热和抑制后期的脂肪分化。 对于n-3 PUFA和n-6 PUFA对脂肪组织生长特定的影响所知甚少。在成年鼠研究中,与n-6 PUFA食物相比,n-3 PUFA的食物可引起脂肪细胞减小及脂肪库减少。这个机制涉及到脂肪细胞分化的抑制和/或脂肪细胞分解的增加。 学术界早已提出生命早期EFA的供给和代谢与婴儿的生长有关。早产儿血浆脂质中LCPUFA和花生四烯酸(AA)的含量与身体体重有关 。 必需脂肪酸对脂肪组织生长的近期研究
早有van Niel等在猫的动物实验中发现食物中PUFA含量对其脂肪组织的影响,提出脂肪组织中PUFA含量可反映膳食中摄入的PUFA量。后在SpragueDawley大鼠实验中发现共轭亚麻酸(CLA)可降低WAT中甘油三酯和非酯化脂肪酸水平。Azain等在大鼠实验中发现CLA仅降低脂肪细胞体积的大小并没有降低脂肪细胞数量。Riserus等在中年人群的随机对照实验发现摄入CLA能减少腹部脂肪组织的堆积。Korotkova等在大鼠实验中也发现,n-3 PUFA食物组母鼠的子代鼠腹股沟WAT数量减少。后用SpragueDawley大鼠实验证实可通过CLA食物调节大鼠体脂水平和血浆中leptin水平。近来,在Crete和Cyprus对8岁儿童BMI及超重状态的研究中发现脂肪组织中AA与BMI及超重状态呈正相关。也有在小鼠实验中发现EFA缺乏食物组的脂肪组织中LA和AA含量下降,但不会影响机体总脂肪量,然而CLA缺乏食物组会影响机体总脂肪量。
必需脂肪酸对leptin影响的早期研究
普遍认为leptin浓度可影响人类和成年啮齿类动物脂肪体积。高脂肪膳食可引起机体总脂类含量增高,同时伴随着循环血中leptin浓度上升。过度饮食机体leptin浓度改变与机体脂肪改变密切相关。母鼠脂肪摄入的提高将引起母乳中脂类水平上升,从而引起小鼠血浆中leptin浓度的提高。近期研究表明膳食中脂肪的质量,特别是PUFA,通过调节脂肪细胞leptin的产生,进一步影响脂肪组织体积而影响leptin水平。 体内外实验均报道,n-3 PUFA在脂肪组织的基因表达和分泌中可上调leptin,也有下调的报道。体内实验中,在二十碳五烯酸(EPA)存在下,3T3L1脂肪细胞的leptin mRNA表达和leptin分泌升高。相反,另一体内实验表明EPA和二十二碳六烯酸(DHA)对3T3L1脂肪细胞的leptin mRNA表达和leptin分泌有剂量和时间依赖的抑制作用,还可降低3T3L1脂肪细胞和滋养层细胞受体活性。在啮齿类动物研究中发现摄入富含n-3 PUFA的食物可导致白色脂肪组织(WAT)leptin表达下降,然而摄入富含n-6 PUFA的食物则导致WAT leptin表达两倍的上升。Cha等研究发现给予大鼠富含n-3 PUFA食物尽管会显著减少脂肪储存和脂肪细胞重量,但也会引起高leptin血症。其它研究发现给予鱼油食物,动物的WTA重量和循环血中leptin浓度下降,或不变。以上研究都表明食物中的脂肪酸含量会影响循环血中leptin水平,但结果并不确定,这可能由于食物成分、喂养模式、实验动物种类的不同以及leptin表达的组织定位不同引起的。
必需脂肪酸对leptin影响的近期研究
近年关于EFA对leptin影响的研究,大多为动物实验研究,人群调查极少,且仅为描述性研究。Takahashi等在大鼠的动物实验中发现,给予动物高n-3 PUFA食物可引起动物WAT中leptin的浓度增高。Korotkova等通过大鼠实验证实母鼠食物中EFA含量对幼鼠血浆中leptin浓度的影响,发现EFA缺乏组大鼠母乳中leptin浓度比对照组低,其子代鼠血浆中leptin浓度也较对照组低。给母鼠膳食增加n-3 LCPUFA导致新生鼠生长速率、脂肪组织块及血清Leptin水平的降低。AA和前列腺素E2可以刺激脂肪组织中leptin释放。之后,Korotkova等又在大鼠的动物实验中发现,母鼠食物中n-3和n-6 PUFA的缺乏都会导致其子代鼠血浆中leptin浓度的下降,且伴随着幼鼠腹股沟脂肪组织数量以及腹股沟脂肪组织leptin mRNA表达的下降。同时,母鼠食物EFA的缺乏也会影响母乳leptin水平,但与对照组比较,母鼠食物中EFA缺乏导致的母乳leptin水平的下降仅发生在第2周和第3周。Korotkova等还用大鼠动物模型研究母鼠食物中n-6和n-3 PUFA比例变化对子代鼠血中leptin水平的影响,发现n-3 PUFA组与n-6/n-3 PUFA=10组比较,其子代鼠血浆中leptin浓度要小两倍。与n-6n-3组比较,进一步提高n-3组母鼠食物中n-6 PUFA的量,也不能提高其子代鼠血浆中leptin水平。在n-3组,脂肪组织体积和脂肪细胞体积的减小都可以用其血浆中leptin水平下降来解释。以上数据表明母亲膳食中总EFA量及n-6n-3 PUFA的比例变化都可影响其后代新生儿血浆中leptin水平。而且,给予母亲高比例的n-6/n-3 PUFA膳食会提高其后代体重,腹股沟WAT体积和脂肪细胞大小以及抑制WAT leptin mRNA表达。
必需脂肪酸对免疫系统影响的研究进展
此外,脂肪酸摄入失衡也可促进哮喘发生,富含LA的膳食能促进前列腺素E2和IL2,4生成。现已证实补充鱼油能降低白三烯(LT)等前炎性介质产生,虽然对哮喘的临床治疗作用有限,但妊娠期脂质摄入的变化对胎儿免疫发育能产生较大的影响。妊晚期,母亲的营养摄入和胎盘的营养分布并不均衡,此时的营养不良也会对快速分化的免疫系统和TH1TH2 的活性平衡产生微妙的影响。后对猪的动物实验发现AA的代谢产物可以诱导气道对乙酰胆碱的高反应性。膳食中高LA的摄入,导致组织产生前列腺素E2,反过来抑制TH1细胞增殖及其细胞因子的产生,从而调节细胞免疫。细胞免疫中TH1细胞减少会加重一些相关疾病,如肺结核、麻疹、肝细胞瘤、HIV的二重感染和恶性营养不良。这就是为什么非洲的亚撒哈拉地区好发以上疾病,可能在于他们膳食的主食为LA高含量的玉米,抑制TH1细胞相关的细胞免疫。在给予富含γLA(n-6 PUFA)和αLA(n-3 PUFA)的人群实验中,发现膳食组比对照组血浆中前列腺素E2明显下降,证明黑葡萄籽油可通过降低血浆中前列腺素E2产生来适度地提高免疫效应。近来,Korotkova等又通过大鼠实验证明了母鼠EFA的摄入调节其后代新生鼠对卵清蛋白的口服免疫耐受,发现母鼠摄入EFA其子代鼠通过摄入母乳发生口服耐受,表现为血清中抗体水平的下降以及对卵清蛋白的迟发型超敏反应。这个发现对于我们理解西方膳食结构与过敏发生率增加的关系有重要的意义。据报道,小鼠的小肠肠段和大肠对EFA缺乏具有不同的敏感性,众所周知在感染性肠道疾病(IBD)和乳糜泻病人,氨基酸代谢产物明显增加。肠道的脂肪酸成分能够随着膳食的改变而变化,并且影响营养素的吸收。已经发现肠道乳糜泻活动期病人有肠粘膜EFA的显著缺乏。虽可肯定EFA影响免疫功能,但这些改变究竟是继发于感染,还是肠粘膜对不同的FA成分具有基因易感性差异,而造成这些改变,仍缺乏研究。
未来工作展望
在回顾EFA对脂肪组织生长、leptin浓度和免疫系统影响的研究后,我们可以进一步开展EFA对发育的长期影响研究,现在已有这方面的动物实验。Korotkova等在大鼠实验发现母鼠摄取n-6/n-3膳食的子代鼠在生后28周体重明显高于母鼠摄取n-6 PUFA和n-3 PUFA膳食的子代鼠,其后代成年鼠血浆中胰岛素水平明显升高,且其后代成年雄鼠收缩压也明显升高。这可进一步使我们明确EFA与成人期疾病的关系。 在EFA对脂肪组织生长、leptin浓度和免疫系统影响的研究中,几乎均为动物实验研究,目前我们期待有人群中的前瞻性随机对照实验性研究,进一步明确EFA对人类脂肪增长、leptin浓度和免疫系统的影响,及对发育的长期前瞻性影响,以明确EFA与成人期疾病的关系,达到通过膳食的管理来阻抑这些疾病的迅速增加,而不是运用价格昂贵的药物干预这一目的。
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