大鼠不同时期高脂饮食对子代糖脂代谢的影响及机制研究

目的 探讨Sprague-Dawley母鼠不同时期高脂饮食对子代糖脂代谢的影响及相关机制。 方法 根据孕前及孕期哺乳期饮食的不同，将母鼠随机分为4组（n=9）：CC组（孕前、孕期哺乳期均正常饮食）、HC组（孕前高脂饮食、孕期哺乳期正常饮食）、CH组（孕前正常饮食、孕期哺乳期高脂饮食）、HH组（孕前、孕期哺乳期均高脂饮食）；子代生后3周断奶后，全部给予正常饮食。记录母鼠孕前、孕期体重及仔鼠体重。取各组幼年期（3周）、成年期（12周）雄性仔鼠，检测空腹血糖（glucose，GLU）、胰岛素（insulin，INS）及肝脏三酰甘油（triglyceride，TG）、总胆固醇（total cholesterol，TC）水平，计算胰岛素抵抗指数（homeostasis model assessment of insulin resistance，HOMA-IR）、糖耐量试验（glucose tolerance test，GTT）及胰岛素耐量试验（insulin tolerance test，ITT）的曲线下面积（area under the curve，AUC）；取肝脏组织行苏木精-伊红染色和油红O染色，观察肝脏脂质沉积；检测肝脏糖脂代谢关键基因IR、IRS、AKT和FASN、SREBP1c、PPARα的mRNA及其蛋白表达水平。 结果 孕前高脂饮食组（HC组、HH组）母鼠体重较正常饮食组（CC组、CH组）显著增加（P<0.001）；HC组、CH组、HH组母鼠孕期增重较CC组显著增加（P<0.001）。生后3周时，HC组、CH组、HH组的仔鼠体重、肝脏TG及TC含量，以及FASN、SREBP1c、PPARα的mRNA及其蛋白表达水平均较CC组显著增加（P<0.05），肝脏脂质沉积增加，其中HH组增加最显著；HH组的空腹GLU及INS水平、HOMA-IR、GTT-AUC、ITT-AUC及肝脏p-IRS蛋白表达水平均较CC组显著增加，肝脏IR、IRS的mRNA及其蛋白表达水平均较CC组显著降低（P<0.05）。生后12周时，HC组、CH组、HH组的仔鼠体重、空腹GLU及INS水平、HOMA-IR、GTT-AUC、ITT-AUC、肝脏TG及TC含量、p-IRS蛋白表达水平，以及FASN、SREBP1c、PPARα的mRNA及其蛋白表达水平均较CC组显著增加（P<0.05），肝脏脂质沉积增加，其中HH组增加最显著；HC组、CH组、HH组IR、IRS、AKT的mRNA水平均较CC组显著降低，IR、IRS、p-AKT蛋白表达水平均较CC组显著降低（P<0.05）。HC组与CH组在不同时期的糖脂代谢水平未见显著性差异（P>0.05）。 结论 大鼠怀孕前后不同时期的高脂饮食对子代的糖脂代谢具有不同的影响，孕前、孕期、哺乳期全程高脂饮食对子代糖脂代谢影响最大；大鼠高脂饮食对其子代糖脂代谢的影响考虑与糖脂代谢基因的表达改变有关。 引用格式:

Effect of high-fat diet for rats at different stages on glucose and lipid metabolism in offspring and related mechanisms

Objective To study the effect of high-fat diet for maternal Sprague-Dawley rats at different stages on glucose and lipid metabolism in offspring and related mechanisms. Methods According to the diet before pregnancy and during pregnancy and lactation, maternal rats were randomly divided into four groups (n=9 each): CC (control diet before pregnancy and during pregnancy and lactation), HC (high-fat diet before pregnancy and control diet during pregnancy and lactation), CH (control diet before pregnancy and high-fat diet during pregnancy and lactation), and HH (high-fat diet before pregnancy and during pregnancy and lactation), and all offspring rats were given control diet after weaning. The body weight of maternal rats was recorded before and during pregnancy. Male offspring rats were selected from each group at the juvenile stage (3-week old) and the adult stage (12-week old) to measure the levels of fasting blood glucose (FBG) and fasting insulin (FINS) and the levels of triglyceride (TG) and total cholesterol (TC) in the liver. Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) index was calculated, and the area under the curve (AUC) was calculated for glucose tolerance test (GTT) and insulin tolerance test (ITT). Lipid deposition in the liver was observed, and the mRNA and protein expression levels of the key genes in glucose and lipid metabolism (IR, IRS, and AKT), FASN, SREBP1c, and PPARα in the liver were also measured. Results Compared with the control diet groups (CC and CH groups), the groups with high-fat diet before pregnancy (HC and HH groups) had a significant increase in body weight (P<0.001). Compared with the CC group, the HC, CH, and HH groups had a significantly greater increase in body weight (P<0.001). Compared with the CC group, the HC, CH, and HH groups had significant increases in body weight, the levels of TG and TC in the liver, and the mRNA and protein expression levels of FASN, SREBP1c, and PPARα in the offspring rats at week 3 after birth (P<0.05), as well as a significant increase in lipid deposition in the liver, with the most significant increase of the parameters in the HH group. Compared with the CC group, the HH group had significant increases in the levels of FBG and FINS, HOMA-IR index, GTT-AUC, ITT-AUC, and the protein expression level of p-IRS in the liver and significant reductions in the mRNA and protein expression levels of IR and IRS in the liver in the offspring rats at week 3 after birth (P<0.05). Compared with the CC group, the HC, CH, and HH groups had significant increases in body weight, the levels of FBG and FINS, HOMA-IR index, GTT-AUC, ITT-AUC, the levels of TG and TC in the liver, protein expression level of p-IRS in the liver, and the mRNA and protein expression levels of FASN, SREBP1c, and PPARα in the offspring rats at week 12 after birth (P<0.05), as well as a significant increase in lipid deposition in the liver, with the most increase of the parameters in the HH group. Compared with the CC group, the HC, CH, and HH groups had significant reductions in the mRNA expression levels of IR, IRS, and AKT and the protein expression levels of IR, IRS, and p-AKT in the offspring rats at week 12 after birth (P<0.05). There were no significant differences in the levels of glucose and lipid metabolism between the HC and CH groups at various stages (P>0.05). Conclusions High-fat diet for rats at different stages before and after pregnancy has different effects on glucose and lipid metabolism of offspring rats, and high-fat diet before pregnancy and during pregnancy and lactation has the greatest effect. The effect of high-fat diet on glucose and lipid metabolism of offspring rats is considered associated with the changes in the expression of genes involved in glucose and lipid metabolism.