| Fetal Origins adult disease(FOAD) and Developmental Origins of Health and Disease Hypothesis(DOHa D) all emphasized that maternal nutrition plays an important role on the growth and development of offspring. Previous research have found that maternal poor nutrition during pregnancy could increase the susceptbility of metabolic diseases in offspring. Due to the morbidity of obesity, especially childhood obesity, was rising rapidly, people gradually pay more attention to the effect of maternal high fat and overnutrition during pregnance on the susceptbility of offspring metabolic diseases. So we aim to build the rat model of maternal high fat diet which may induce steatohepatitis and change of lipid metabolism in the early life of offspring, and explore their possible mechannisms.Part 1: Maternal high-fat diet alters liver lipid metabolism in early life of rat offspringObjectives To observe the impact of maternal high-fat diet during pregnancy and lactation on body metabolism in the early life of rats offspring and explore the relationship between maternal high fat diet and change of physiological characteristics in the early life of offspring, as well as liver pathological changes. Methods Female Sprague-Dawley rats were fed either an high fat diet(HF-F0) or control(CON-F0)diet before mating and throughout gestation and to lactation of 3 weeks, liver tissue were sampled for pathological observation, meanwhile, hemospasia from heart for metabolism-related parameter test. Results The body weight of the offspring was significantly lower at postnatal day 1(P=0.027), while was significantly heavier at postnatal day 7 and 21 in the HF-F1 group compared with the CON-F1group(P=1.00E-04). The levels of area under the curve of glucose tolerance, serum triglycerides and total cholesterol and the triglycerides content in liver were significantly higher(P vale were 3.00E-04, 0.025, 0.031 and 0.01 respectively)in the HF-F1 group at PND 21, while it also revealed an exaggerated form of diet-induced fatty liver by histopathological analysis: at PND1 and PND7, diffused lipid droplets were observed in livers from the HF-F1 group, in addition, the liver from the HF-F1 group at PND21 day exhibited a distinct microanatomy with both vacuolar and macro-vesicular steatosis. Conclusions Maternal high fat diet until lactaion period could reduce glucose tolerance, and had a great effect on hyperlipemia and hepatic steatosis on 3-week-old offspring.Part 2: Maternal high-fat diet alters liver lipid metabolism-related genes in early life of rat offspringObjectives To investigate the influence of maternal high fat diet on the expression of hepatic metabolic genes in the early life of offspring. Methods By establishing the animal model of maternal high fat diet induced hepatic steatosis, when their offspring delactation an PND21, we detect the expression of their liver genes by Affymetrix Gene Chip Rat 230 2.0 Array, and the genes differentially expressed between the offspring at weaning were identified, at the same time, Real-Time PCR was used to validate the gene expression profile generated by the microarray analysis which related to lipid metabolism.Results Compared with CON-F1, there were 120 differentially expressed genes identified in the liver between the two groups, among them 76 genes(63.3%) were increased-regulated, whereas 44 genes(36.7%) were expressed at down levels in the HF-F1 offspring. Hierarchical clustering was received through Pearson correlation analysis. The heat maps display the gene sets related to lipid metabolism either in up-regulated or down-regulated category. Microarray analysis and Real-Time PCR all revealed that the expression of key genes related to lipid synthesis were changed, such as the trend of Srebf1 and its target genes Fas,Acaca were up-regulated in HF-F1 group(P values were 0.084, 0.465 and 0.156),while the trend of PPARγ gene was downward(P=0.444), but Me1 and Scd1 gene,which were also related to lipid synthesis were markedly increased-regulated(P value were 0.002 and 0.027 respectively). We also observed the remarkable difference in expression of genes involved in lipid oxidation, Real-Time PCR showed that the expression of key transcription factor PPARα and its target genes Cpt1α, which is the speed limit enzyme of fatty acid β oxidation, were increased(P value were 0.015 and0.017 respectively) in HF-F1 group. as well as dehydrogenase Ehhadh(P=0.001), We also detected that Acsl3 involved in fatty acids activation was down-regulated at a transcriptional level(P=0.021). Conclusions Maternal high fat diet during pregnance and lactation could inhibit offspring rat expression of genes involved in de novo lipogenesis, at the same time induce its β-oxidation vicariously. The change might protect as compensatory stress response against poor nutrition in their early developmental environment. but the protective roles could not be improved to reverse the development of hepatic steatosis.Part 3: Maternal high-fat diet alters the expression of genes involved in P53 signaling pathway in early life of rat offspringObjectives To investigate the different expression of key genes in P53 signaling pathway in HF-F1 offspring induced by maternal high fat diet. Methods By establishing the animal model of maternal high fat diet induced hepatic steatosis, we detected the liver differently expressed genes in P53 signaling pathway generated by the Affymetrix microarray analysis in HF-F1 offspring, and Real-Time PCR was used to validate the results. Results Real-Time PCR revealed that the trend of expression of main gene P53 and its target gene P21 was upward compared to CON-F1(P value was 0.063 and 0.076 respectively). The downstream gene NOXA of P53 and downstream gene Ccnd1(cyclin D1) were markedly up-regulated in HF-F1 compared to CON-F1(P value was 0.045 and 0.023), and the downstream gene PUMA of P53 and downstream gene Ccne2(cyclin E2) were also up-regulated in HF-F1, which have no statistical significance(P value was 0.194 and 0.095) although. Conclusions Maternal high fat diet may induced the activity of P53 signaling pathway in the early life of offspring, which may involved in the development of steatosis. |
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