引用本文
刘月帅, 刘彦, 曹忻, 冯涛. 哺乳动物胎盘营养感应研究进展[J]. 畜牧兽医学报, 2022, 53(5): 1321-1333.
LIU Yueshuai, LIU Yan, CAO Xin, FENG Tao. Research Progress on Mammalian Placental Nutrition Sensing[J]. Acta Veterinaria et Zootechnica Sinica, 2022, 53(5): 1321-1333.
哺乳动物胎盘营养感应研究进展
1. 北京市农林科学院畜牧兽医研究所，北京 100097;
2. 西北民族大学生命科学与工程学院，兰州 730030;
3. 北京市农林科学院-美国俄克拉荷马州立大学动物科学联合实验室，北京 100097
2. 西北民族大学生命科学与工程学院，兰州 730030;
3. 北京市农林科学院-美国俄克拉荷马州立大学动物科学联合实验室，北京 100097
摘要：妊娠期间母体营养的改变会影响胎儿的生长发育，而胎盘是母体-胎儿间进行气体、营养和代谢物交流的重要枢纽，哺乳动物胎盘营养感应系统响应母体和胎儿营养信号的变化，保证母体健康和胎儿生长发育。鉴于胎盘营养感应系统对哺乳动物繁育的重要性，本文从胎盘营养感应和胎盘养分分配方面综述了哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin，mTOR)、磷酸腺苷活化蛋白激酶(AMP-activated protein kinase，AMPK)、氨基己糖(Hexosamine)信号通路、糖原合成酶3(glycogen synthase kinase，GSK-3)、胰岛素/胰岛素样生长因子(insulin/insulin-like growth factor signaling pathway，IIS)等信号通路及其对妊娠期养分响应和对胎儿发育的影响，以期为哺乳动物的繁育提供参考依据。
关键词：哺乳动物 胎盘营养感应 胎盘养分分配 信号通路
Research Progress on Mammalian Placental Nutrition Sensing
1. Institute of Animal Husbandry and Veterinary Medicine (IAHVM), Beijing Academy of Agriculture and Forestry Sciences (BAAFS), Beijing 100097, China;
2. College of Life Science and Engineering, Northwest Minzu University, Lanzhou 730030, China;
3. Joint Laboratory of Animal Science between IAHVM of BAAFS and Division of Agricultural Science and Natural Resource of Oklahoma State University, Beijing 100097, China
2. College of Life Science and Engineering, Northwest Minzu University, Lanzhou 730030, China;
3. Joint Laboratory of Animal Science between IAHVM of BAAFS and Division of Agricultural Science and Natural Resource of Oklahoma State University, Beijing 100097, China
Abstract: Changes in maternal nutrition during gestation will affect the growth and development of the fetus. Placenta is an important interface for gas, nutrition and metabolite communication between maternal and fetus. The mammalian placental nutrition sensing system responds to the changes in maternal and fetal signals to ensure maternal health and promote the fetal growth and development. In view of its important role of the placental nutrition sensing system to mammalian reproduction, this article summarizes the effects of relevant signaling pathways including mammalian target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), hexosamine signaling pathway (Hexosamine), hlycogen synthase kinase 3 (GSK-3), insulin/insulin-like growth factor signaling pathway (IIS) and others on placental nutrition sensing and placental nutrient distribution to response nutrient changes in dam, subsequently to influence fetal development during pregnancy. All above are expected to provide theoretical basis for the breeding of mammals.
Key words:
mammalian placental nutrition sensing placental nutrient distribution signaling pathway
妊娠期间，母体营养作为胎儿营养的主要决定因素，会导致胎儿生长轨迹、基因表达和代谢途径的改变，并可能增加胎儿出生后的疾病风险[1]。胎盘是母体-胎儿间进行气体、营养和代谢物交流的界面，也是哺乳动物胚胎发生过程中形成的第一个器官[2]。胎儿的生长发育需要母体提供大量的能量，包括葡萄糖、氨基酸、蛋白质等，这与胎盘内在的营养感应信号通路有关[3-4]。胎儿对养分的需求随妊娠时间而改变，胎盘接收并响应来自母体和胎儿的营养代谢信号，以满足母体-胎儿间的养分平衡[5]。此过程中，胎盘通过其营养感应和养分分配系统响应母体和胎儿对营养需求的信号并做出反馈，包括改变激素(瘦素等)分泌、信号分子(胰岛素样生长因子等)等代谢信号的释放以调控胎儿发育[6]。此外，多胎哺乳动物胎儿数量较多，可能导致如胎盘养分分配不均、母体健康受损、胎儿生长发育受限、子宫拥挤等诸多问题，因此养分的分配方式除了母胎之间的合理分配外，还存在胎儿之间的养分分配[7]。目前，在哺乳动物(人、鼠和猪等)上的研究发现营养物质(葡萄糖、氨基酸、蛋白质、脂肪等)和氧气通过胎盘营养感应信号通路(mTOR、AMPK和IIS通路等)调控胎儿的发育[8-10]。但目前关于多胎哺乳动物尤其是猪的胎盘营养感应和养分分配的研究较少，其详细机制还需进一步研究。
1 胎盘营养感应和养分分配系统哺乳动物妊娠期间，胎盘营养感应和养分分配系统发挥了重要作用，主要涉及子宫内膜细胞、胎盘滋养层细胞、胎盘血管等[11]。母胎间营养物质的合理分配是保证妊娠正常进行和保护母体及胎儿健康的重要因素之一，这一过程中胎盘作为母胎间物质交换的桥梁，在感应胎儿营养需求、调控母体养分合理分配等方面发挥关键作用[12-13]。来自胎儿、母体和胎盘的营养信号共同调控胎盘营养转运能力来促进胎儿的生长发育，胎盘营养感应和养分分配功能受损及胎盘血管生成障碍会导致不良妊娠结局，包括胎儿宫内生长受限(intra-uterine growth restriction，IUGR)、子痫等妊娠疾病，甚至导致流产、早产、母胎死亡等[14-16]。
1.1 胎盘营养感应胎盘凭借其固有的营养感应信号通路积极地响应母体和胎儿的营养暗示，通过合体滋养层细胞整合母体和胎儿信号从而调控胎盘功能，在不损害母体健康前提下确保母体和胎儿之间资源的最优分配，该过程被称为胎盘养分感应(placental nutrition sensing)[5, 17]。母体供应和胎儿需求信号对胎盘功能的调节取决于母体营养紊乱的类型、持续时间和严重程度[17]。哺乳动物胚胎在母体子宫内由受精卵开始发育，各组织、器官从无到有，逐渐发育成熟，在这个变化过程中，母体营养、免疫状况也随胚胎发育状况的改变而变化，从而保护母体不受胚胎发育的影响同时保证胚胎的正常发育不受母体排斥的抑制，此过程细胞因子、激素等细胞间信号分子为母子间提供了交流的途径[18]。研究证明，人在妊娠期存在胎盘养分感应系统，其作用是向胎儿提供营养物质、排泄胎儿代谢产物和保护胎儿免受外来因素的影响[19]。目前在人类胎盘上已证明存在的养分感应器有AMPK、mTOR、IIS、氨基酸反应信号转导通路(amino acid response，AAR)、GSK-3、Hexosamine等[20-22]。孕期胎盘通过调控上述养分感应器及其它系统来改变胎儿养分供给或改变胎盘养分转运能力等来调节母体-胎盘-胎儿间的养分分配。研究表明，猪胎盘上也存在相应的营养感应系统，如刘炀[3]研究证实，猪胎盘上存在mTOR信号通路，并且受亮氨酸(leucine，Leu)浓度的影响，高浓度Leu抑制mTOR信号通路的表达，进而抑制猪胎盘滋养层细胞(placental trophectoderm cell，pTr)的增殖活力，降低了pTr氨基酸转运载体mRNA的表达。胰岛素生长因子IGF-Ⅰ、IGF-Ⅱ的mRNA在猪胎盘中也有表达，并且IGF-Ⅰ和IGF-Ⅱ能够上调葡萄糖转运载体，增强胎盘对葡萄糖的转运能力[4]。这些信号通路并不是独立存在，而是相互关联共同调控胎盘营养感应和养分分配系统的功能。
1.2 胎盘养分分配胎盘营养感应和养分分配系统是一个整体，彼此嵌合，很难割裂，其中胎盘养分分配主要有两方面内容。一是胎盘与母体间的养分合理分配。整个妊娠期间，母体和胎儿对营养的需求都在增加，所以胎盘与母体间养分合理的分配就显得尤为重要，对胎儿初生重和均匀度也有重要意义[20, 23]。胎儿发育与母体资源相互匹配，以应对母体营养不良等情况，同时保证胎儿正常发育[24]。胎儿在母体子宫内的生长发育依靠胎盘的营养供应，胎盘除了养分转运外，还是一个重要的调控器官，同时受到胎儿养分需求和母体养分供给的双重调控[25]。研究证实，胎盘养分供给的改变会对胎儿的初生重和生长轨迹造成影响[26]。同时，体重是新生儿健康的一个重要指标，是衡量胎儿生长发育、营养状况、健康程度的主要依据[27-28], 有证据表明胎盘营养感应与养分分配系统与胎儿的体重相关[29]。周坚等[30]研究发现，脐血与胎盘血中的胰岛素样生长因子水平与胎儿体重成正比; Lazo-de-la-Vega-Monroy等[28]发现，胎盘AMPK的蛋白表达与胎盘重和胎儿初生重为负相关，mTOR信号通路的蛋白表达与胎盘重和胎儿初生重存在正相关等; Town等[7]研究证实，猪胎盘重量与胎儿的初生重存在正相关。由此推测，哺乳动物胎盘养分分配可能通过影响胎盘发育或改变胎盘运输营养物质的能力来影响胎儿初生重。孕期充足的营养是保证母体健康和胎儿正常发育的关键，对胎盘养分分配系统的深入认识可作为改善妊娠结局的理论基础，为提高胎儿初生重和均匀度提供理论基础和技术支持[31-32]。二是不同胎盘间的养分分配。人是单胎动物，IUGR主要是因为胎盘功能不全、胎盘异常、滋养层细胞受损等导致营养和氧气转运的改变[33]。而猪和鼠是多胎动物，其胎儿发育不仅受胎盘功能和母体的调控，也可能与胎儿在子宫内的位置和子宫容量有关，并且猪不同胎盘之间养分的分配也可能存在差异[34-36]。人、鼠和猪等哺乳动物的胎盘结构存在差异[37]，胎盘结构对胎盘养分分配的影响还需进一步研究。目前，关于哺乳动物，尤其是多胎哺乳动物胎盘养分分配的相关研究和资料较少，未来这或将成为哺乳动物胎儿发育以及胎儿初生重或均匀度调控的研究热点内容之一。
1.3 胎儿初生重和均匀度的调控哺乳动物初生重和均匀度的调控涉及母体-胎儿间的营养分配[12]，多胎动物还应包括不同胎盘间的养分分配。猪上的研究发现，精氨酸(arginine，Arg)和Leu可通过mTOR通路影响pTr细胞的增殖和蛋白质合成，提高仔猪的初生重[38-39]。妊娠母猪日粮中添加L-肉碱可以通过IIS通路促进胎盘发育，提高胎儿初生重[40-42]。此外，妊娠母猪日粮中添加益生菌[43]、N-氨甲酰谷氨酸[44]等添加剂也有提高胎儿初生重和均匀度的作用。阻断怀孕小鼠胎盘mTOR信号的传导，导致胎盘重量和胎儿体重降低[12]，这也为mTOR通路调控胎儿初生重和均匀度提供了支持。在小鼠上的研究发现，缺氧降低胎儿体重，因为缺氧激活AMPK并通过调控mTORC1对营养物质的运输来抑制mTOR通路，导致胎儿发育受损[45-46]。妊娠期间，雌激素对人主动脉内皮细胞AMPK也有激活作用[47]。此外，胎儿初生重和均匀度与哺乳动物的品种、胎次、胎盘效率及胎盘血管数量有关; 胎盘效率高，胎盘血管生成多，胎儿的初生重和均匀度相对较好[48-49]。目前关于胎儿初生重和均匀度调控机制的相关研究较少，还需进一步研究。
2 胎盘营养感应相关的信号通路胎盘作为营养感受器，根据母体向胎盘和胎儿供给营养物质的能力，调节胎盘转运蛋白的表达和活性，从而调节胎儿的生长发育，对胎儿初生重和均匀度的调控有重要意义[50-51]。母体和胎儿间物质交换主要依靠胎盘滋养层细胞，通过胎盘上的营养感应器来调控养分的分配[37]。已知人胎盘营养感应器包括AMPK、IIS信号通路、mTOR信号通路、AAR、氨基己糖信号通路、GSK-3等[12, 20-22, 52-55]。
2.1 mTOR信号通路mTOR有两个蛋白复合物mTORC1(mTOR complexes 1)和mTORC2(mTOR complexes 2)，前者调控细胞生长、增殖和代谢，对于雷帕霉素的作用较为敏感，后者主要调节细胞骨架组织和细胞代谢，对雷帕霉素作用不敏感，但雷帕霉素长时间作用也会抑制mTORC2[56-57]。mTOR信号通路在胎盘营养感应系统发挥核心作用，研究表明mTOR信号作为营养感应分子参与胎盘功能和胎儿生长，响应母体的营养限制，该信号能调节细胞生长相关基因的转录和蛋白质的翻译，在胎儿肾的发育过程中mTOR信号通路也发挥重要作用[6, 51, 58-60]。mTOR通路通过支持胎盘的形成促进胎儿的发育[61]。有研究表明，缺氧会减少mTOR的磷酸化来抑制mTOR介导的蛋白质翻译，减少ATP消耗以保存细胞能量[62]，缺氧处理的人多核合体滋养层细胞中mTOR活性受到抑制，并诱导自噬发生[63]。而多胺可激活mTOR信号以刺激蛋白质合成[64]。
2.2 AMPK信号通路AMPK是调控代谢稳态的中枢调节因子，也是一种重要的营养感知分子[65]，在血管床和胎盘中普遍表达并且对胎盘的发育尤为重要[66-67]。在胚胎和胎盘发育过程中，为平衡氧环境与能量需求和维持新陈代谢的需要，AMPK在整合并响应众多且复杂的刺激时起到重要作用[9]。在低氧条件下，人类和小鼠胎盘迷路区域AMPK磷酸化增加进而促进母体子宫动脉血流[68-69]。Zhan等[70]研究发现，地塞米松通过抑制胎盘mTOR和AMPK通路、抑制葡萄糖转运体表达阻碍人胎盘的发育。张秀娟[71]和董书圣[72]的研究证明，猪胎盘上也存在AMPK信号通路，但多胎哺乳动物胎盘AMPK的相关研究较少，还需更多研究。
2.3 IIS信号通路IIS信号通路是由胰岛素(insulin，INS)、胰岛素样生长因子及其受体共同组成，动物生理的各个方面如新陈代谢、免疫和细胞生长、分化、增殖、迁移等生物学过程都受营养的调节，IIS信号通路则是这些过程的中心调节因子，哺乳动物很多器官中都存在IIS受体，不同的受体可能通过不同的信号通路行使不同的功能[73-74]。IIS的激活主要是通过胰岛素样肽(insulin-like peptide，ILP)配体进行的，这些配体仅依赖于营养物质和感觉信息的可获得性[75]。在哺乳动物中，INS、IGF-Ⅰ和IGF-Ⅱ是IIS酪氨酸激酶受体的配体，IGF-Ⅰ和IGF-Ⅱ的水平由GH和IGF结合蛋白决定，INS水平一方面根据机体的需求进行调节，另一方面受营养水平的影响，葡萄糖、氨基酸如谷氨酰胺和Leu的组合、游离脂肪酸等都会影响INS水平，INS水平提高能激活IIS途径促进营养的吸收和储存[76-77]。哺乳动物IIS网络的许多下游信号成分也具有多种形式和异构体，在组织分布和细胞定位等方面存在差异，使得IIS在不同组织中发挥的作用可能存在一定差异[78]。
2.4 氨基己糖途径氨基己糖途径以O-连接的N-乙酰氨基葡萄糖(O-GlcNAc)酰化为目标，该通路在妊娠早期的人类胎盘中较活跃，并能影响激素的产生和IGF信号的传递[5, 55, 79]。谷氨酰胺是氨基己糖信号途径的一种底物，葡萄糖和果糖通过尿苷二磷酸-N-乙酰氨基葡萄糖(UDP-GlcNAc)诱导滋养外胚层细胞增殖，反刍动物滋养外胚层细胞分泌的干扰素(interferon tau，IFNT)能与孕酮共同诱导子宫内膜上皮基因如孕激素受体(PR)基因的表达，促进胚胎的生长和发育[80-82]。猪的滋养外胚层细胞通过氨基己糖途径代谢葡萄糖和果糖，合成糖胺聚糖(如透明质酸，HA)和UDP-GlucNAc，HA是一种通过氨基己糖途径合成的糖胺多糖，是胎盘基质的主要成分，对血管生成和其他细胞功能至关重要，特别是对妊娠早期的胎盘[83-86]。HA有氨基葡萄糖和葡萄糖醛酸两种主要成分，氨基葡萄糖可能通过改变HA与葡萄糖间的关系，提高胎盘对葡萄糖的运输效率[87-88]。
2.5 糖原合成酶-3GSK-3作为葡萄糖传感器发挥作用，由两个基因编码产生两种蛋白GSK-3α和GSK-3β[89]。目前，学者们普遍认为GSK-3是调控细胞分化、细胞增殖和蛋白质合成的不同信号通路中的一个重要因子，可能在猪胎盘营养感应系统中也起到重要作用[90-91]。研究发现，GSK-3β与缺氧有关，其失活会导致胎盘缺陷和胎儿生长受限[92]。而去磷酸化的GSK-3β通过抑制糖原合成酶而阻断胎盘糖原生成，抑制GSK-3β活性导致葡萄糖向胎儿转移增加，胎盘不再以糖原的形式储存葡萄糖[93]。胎盘糖原储存改变与人类妊娠并发症如IUGR和糖尿病有关，糖尿病母亲胎盘糖原储存增加，以保护胎儿免受母体葡萄糖供应过多的影响[94-97]。GSK-3β也作用于INS、IGF-Ⅰ、Wnt信号通路的下游，这三个通路在胎盘细胞的增殖和分化过程发挥重要作用[98]。在猪上，GSK-3的研究主要集中在心肌组织[99]和母猪卵巢发育[100]等方面，关于胎盘GSK-3的相关研究较少。
3 胎盘营养感应对能量的响应母体营养不良会损害胎盘向胎儿运输营养物质，胎盘营养感应mTOR信号通路的活性随母体营养状态而改变[101-102]。AMPK是细胞的能量感受器，哺乳动物细胞内AMP/ATP或ADP/ATP的比值增加会激活AMPK，对mTORC1途径产生抑制作用[65, 103]。细胞内AMP/ATP的比例是AMPK活性的主要调节因子，提高细胞内AMP浓度会导致AMPK磷酸化和激活，而高浓度的ATP可能拮抗AMP对AMPK的刺激作用[104-106]。AMPK信号通路与体内葡萄糖代谢稳态有关，AMPK活化能提高组织的INS敏感性，促进肌肉葡萄糖的摄取，减少肝葡萄糖的产生[107-108]。能量状态降低激活AMPK，AMPK通过提高参与分解代谢的蛋白质的活性或表达来促进ATP产生，同时关闭几乎所有生物合成途径如脂质、碳水化合物、蛋白质和核糖体RNA的生物合成来保存ATP[103]。因葡萄糖供应减少或线粒体呼吸被抑制降低细胞能量供给会导致INS激活mTOR的能力下降，阻断细胞能量代谢途径会影响细胞周期活动，从而抑制细胞增殖，并促进其凋亡[109-110]。Hu等[111]研究发现，妊娠期高能量饮食诱导的肥胖增加了猪胎盘氧化应激，且胎盘血管生成减少，而胎盘血管生成异常可导致IUGR，进而导致胎儿初生重较低[112]。Vallet等[87]研究发现，母猪妊娠后期补充氨基葡萄糖可增加胎盘重量，改变胎儿血糖和果糖动态。低能量供应对胎儿的发育没有影响[113-114]，可能是母体储存的能量被调动以满足胎儿的生长需要。Campos等[115]研究发现，当母猪饲料摄入量减少时，母体的营养储备被调动以支持胎盘和胎儿的发育。
3.1 胎盘营养感应对脂肪的响应AMPK是脂肪代谢的关键调节因子，胎盘脂肪酸的积累受脂质运输和细胞代谢的影响，AMPK活化能促进脂解，减少脂肪沉积和氧化应激的发生[107, 116-117]。AMPK的表达水平可能与胎盘脂肪沉积有关[72]。母体肥胖时胎盘AMPK活性降低，胎盘脂肪转运受到影响，脂肪堆积导致胎盘受到脂肪毒性、氧化应激及炎症的影响，致使胎盘功能下降和胎儿初生重下降[108, 118]。Tian等[108]研究发现，肥胖母猪胎盘AMPK蛋白表达较低，抑制AMPK信号转导。而AMPK的激活可以阻止炎症信号通路[118-119]，防止棕榈酸诱导的视网膜周细胞的脂质毒性[119]，这为胎盘AMPK通路响应脂肪变化提供了支持。对肥胖孕妇的研究表明，胎盘脂质增加，脂质毒性增强与AMPK活性降低相关，AMPK蛋白水平受脂滴相关蛋白基因Cidea表达的调控，而Cidea基因表达与能量稳态调控有关[118, 120]。肥胖孕妇胎盘中AMPK磷酸化水平与胎儿初生重呈负相关，胎盘AMPK活性降低激活了mTORC1和IIS信号通路，导致母体体重指数增加并促进胎儿发育[26]。
3.2 胎盘营养感应对氨基酸的响应mTOR通路是胎盘必需氨基酸运输的重要调节因子，也是胎盘对氨基酸响应的主要通路，其中氨基酸转运蛋白是营养感应系统的关键组成部分，直接影响胎儿的发育[121-122]。氨基酸可以刺激mTORC1，增强氨基酸转运蛋白的表达，将母体营养供应和胎儿发育关联起来[123]。细胞内Leu浓度改变会激活mTOR信号通路，mTOR下调会减少胎盘Leu的运输，导致胎儿生长的改变; mTOR信号还能调节L-氨基酸转运体的活性，该转运体是Leu通过合体滋养层细胞微绒毛转运的主要途径[124]。Wang等[101]发现，Leu浓度升高引起真核细胞起始因子4E结合蛋白(4E-BP1)和核糖体蛋白S6激酶1(S6K1)的磷酸化水平升高，激活mTOR通路促进胎盘氨基酸转运蛋白(LAT1、SNAT1、SNAT2、4F2 hc和rBAT)的表达，以促进胎猪发育，提高仔猪的初生重。其中SNAT2是氨基酸转运体的经典例子，其活性的缺乏会降低mTORC1的活性，导致蛋白质合成障碍[125]。NO和多胺是Arg分解代谢的产物，对胎盘生长至关重要，饲料中添加Arg促进胎盘和胎儿的生长[126]。一些研究也发现补充Arg可以防止IUGR发生，促进IUGR胎儿发育，并增加初生重[127-129]。Kong等[130]研究发现，随着Arg浓度增加，pTr细胞中蛋白质合成、NO浓度和总mTOR增加，蛋白质降解减弱，其原因主要是Arg通过激活mTOR信号，刺激GH和INS分泌，促进胎盘中蛋白质的合成[131]。在绵羊上的研究表明，Arg与Leu协同激活mTOR信号，进而刺激pTr细胞的肥大、增殖和迁移[132]。妊娠早期猪胎盘中多胺浓度与胎盘重量呈正相关，其中腐胺通过激活mTOR信号通路来刺激猪滋养外胚层细胞蛋白质的合成[133-134]。Jansson等[26]发现，产超重婴儿的肥胖女性胎盘INS/IGF-Ⅰ和mTOR活性、氨基酸转运体活性和SNAT2蛋白表达增加，推测这种作用可能是通过激活INS和mTOR信号通路来实现的。这也为胎盘mTOR信号通路响应氨基酸变化而促进胎儿生长发育提供了支持。
3.3 胎盘营养感应对蛋白质的响应孕期母体蛋白质摄入是胎盘和胎儿生长发育的关键决定因素[135]。蛋白质和氨基酸缺乏在妊娠不同阶段造成的危害程度不同，一般妊娠早期较为严重[136]。不同妊娠阶段，胎儿和母体对蛋白质和氨基酸的需求也不同[137]。母猪饲喂不同蛋白水平的日粮会影响胎儿代谢相关基因的表达，包括糖皮质激素受体(NR3C1)、过氧化物酶体增殖物激活受体α(PPARα)、胰岛素受体(INSR)等[138]，这些代谢基因与胎盘营养感应信号通路的关系还需进一步研究。因此怀孕期间蛋白质补充需保持平衡，以免造成氨基酸过量或失衡[131, 139]。在小鼠上的研究也表明妊娠期适宜的蛋白质补充会促进胎儿的生长发育[140]。
综上，胎盘营养感应系统对营养素包括能量、氨基酸、脂肪和蛋白质等的响应对胎儿的发育至关重要。此外，胎盘营养感应系统还可能响应其他营养物质的变化从而影响胎儿的发育，包括多不饱和脂肪酸、葡萄糖、维生素和微量元素(硒等)等[141-142]。
3.4 其他胎盘在子宫中的位置不同，胎盘效率也不同，对胎儿重量也会产生影响[143]。研究发现子宫-输卵管交界处的胎盘效率更高，与能量代谢相关的蛋白质丰度较高，营养供应更充足，大白猪从子宫颈到子宫颈-输卵管交界处的胎儿重量呈线性增加，这是因为不同位置胎盘的蛋白质表达存在差异，如葡萄糖转运蛋白，但梅山猪上却未观察到此现象[144]，这可能与猪的品种有关，具体原因需进一步研究。还有学者提出，胎儿体重不同，与该胎儿周围胎儿的性别有关[145]。因此推测，不同胎儿胎盘营养感应系统对营养转运的调控存在一定差异，且相互影响，具体机制需深入研究。
研究表明，细胞营养变化影响mTOR对胎盘细胞自噬的抑制作用，目前尚不清楚是否是因脂肪供应改变造成这种影响[65, 146]。在母猪日粮中添加酵母核苷酸(yeast nucleotide，YN)能够通过mTORC1-PPAR途径调控胎儿养分转运，进而降低IUGR和死胎的发生率[147]。
4 小结综上所述，哺乳动物胎盘营养感应和养分分配系统中存在多种信号通路，并且这些信号通路与能量、脂肪、氨基酸等营养物质的转运调节关系密切，mTOR、AMPK、IIS信号通路等在母体-胎盘-胎儿间建立复杂联系，以响应母体和胎儿能量及其他营养如蛋白质、脂肪、氨基酸等的变化，对胎盘发育、母体健康以及胎儿生长发育起到至关重要的作用。胎盘mTOR信号通路主要是调节胎盘营养物质的转运和分配并对AMPK、IIS信号通路等的调节做出反应，这些通路相互作用，共同调节胎盘营养的转运和代谢。目前关于哺乳动物胎盘营养感应信号通路的研究主要集中在人、鼠上，在猪等其他哺乳动物胎盘上的相关研究较少，深入研究猪胎盘营养感应和养分分配系统，在此基础上提高多胎哺乳动物初生重和均匀度可能是今后繁殖学重要的研究方向之一。
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