生命早期母源性过量果糖摄入对子代大鼠糖脂代谢的影响及机制研究

Nowadays, WHO and many countries have paid more attention to added sugars. As the main constituent of added sugars, fructose was widely used in many kinds of processed foods. Fructose has been recognized as a carbohydrate with the health-care function, which can instead of sucrose. However, in recent studies, it is found that excessive fructose intake for a long time could cause the liver infiltrated by triglyceride, induce insulin resistance, and increase the risk of many chronic diseases. There is still a controversy about the association between excessive fructose intake in early life and glycometabolism and lipid metabolism in the offspring, the mechanism is also unclear. Moreover, some limitations can be found in some studies, including the dose of fructose is too high, lacking of sucrose or glucose groups as contrast, and single time point observation in the offspring. These limitations lead to the lack of credibility and extrapolation. Therefore, this project will give 10% fructose to the female rats in their pregnancy and lactation, and take distilled water group and 10% glucose group as contrast. Observe the glycometabolism and lipid metabolism levels on the day of in utero, birth, weaning, and growing up in the offspring. Through the changes of the placenta, DNA methylation levels in key genes, gut microbiota characteristics, and the relationship between DNA methylation and gut microbiota, ascertain the effect of maternal excessive fructose intake in early life on glycometabolism and lipid metabolism in offspring rats and its mechanism.

添加糖现已受到WHO和各国的高度关注，果糖作为添加糖的主要成分之一，被广泛应用于各类加工食品中。果糖曾被认为是一种可取代蔗糖的具有保健功能的糖类，但近些年的研究发现长期过量果糖摄入可使肝脏中大量甘油三酯的堆积，引发胰岛素抵抗，增加多种慢性疾病的发生风险。生命早期母源性过量果糖摄入对子代糖脂代谢的影响尚存在争议，机制也仍不明确，且在实验设计中多存在果糖干预剂量过高、缺少蔗糖或葡萄糖对照、对子代单一时间点的观察等局限性，使研究结果缺乏可信性和外推性。因此，本项目拟在孕期和哺乳期对母鼠进行10%果糖饮水干预，并设立蒸馏水组和10%葡萄糖组作为对照，在子代大鼠出生前、出生当天、断乳、成年四个时间点进行动态观察，通过孕鼠胎盘结构变化、各时间点子代大鼠糖脂代谢关键基因DNA甲基化和肠道菌群的检测，以及DNA甲基化水平与肠道菌群的相关性分析，探讨生命早期母源性过量果糖摄入对子代大鼠糖脂代谢的影响及机制。

生命早期母源性过量果糖摄入对子代糖脂代谢的影响尚存在争议，机制仍不明确。本项目在孕期和哺乳期对母鼠进行果糖饮水干预，并设立蒸馏水组和葡萄糖组作为对照，在子代大鼠出生前、出生当天、断乳、成年四个时间点进行动态观察，通过孕鼠胎盘结构和功能状态、各时间点子代大鼠糖脂代谢关键基因的表达、DNA甲基化、肠道菌群的检测，探讨生命早期母源性过量果糖摄入对子代大鼠糖脂代谢的影响及机制。本项目研究发现，孕鼠在妊娠期间摄入过量果糖能够导致胎盘组织中尿酸的过度累积，并引起胎盘氧化还原状态的失衡，在氧化损伤作用下，胎盘功能受损，最终导致胎儿生长受限。胎盘是连接母体和胎儿的关键“桥梁”，孕期高果糖暴露引发的胎盘功能受损不仅能够直接影响胎儿宫内的生长发育，还可能间接的与胎儿出生后未来长期的糖脂代谢紊乱有关。妊娠期过量果糖暴露能够导致孕鼠口服糖耐量受损，妊娠期和哺乳期过量果糖暴露能够引起子代出生、断乳、成年三个时间点不同程度的糖脂代谢紊乱，尤其对雌性子代的脂代谢影响更为显著和持久，这与子代出生后各时间点脂质合成相关基因持续性高表达有关。DNA甲基化修饰是营养程序化作用的潜在机制之一，然而本项目研究显示妊娠期过量果糖暴露不会引起子代出生、断乳、成年三个时间点肝脏全基因组甲基化水平和甲基转移酶表达水平的显著性改变，因此尚没有充足的证据证实生命早期高果糖暴露能够引起DNA甲基化修饰异常。肠道菌群最初来源于母体，最早定植于子代肠道的菌群对后期肠道菌群的演变有着直接的影响。孕期高果糖暴露可导致孕鼠自身及新生子代大鼠肠道内容物中菌群多样性及丰富度的显著改变，部分菌门、菌属也呈现出不同程度的不良变化趋势，是引起子代糖脂代谢紊乱的可能原因之一。本项目的实验设计更加严谨，使研究结果更具可信性和外推性，可为孕期和哺乳期这一特殊群体添加糖摄入量限量的制定提供一定的理论基础。