Effect And Mechanism Of High Birth-Weight On Long-Term Lipid Metabolism

Objective:The present study was designed to investigate the effect of high birth-weight（Large-for-gestational-age,LGA）on cardiometabolic disease risks in childhood and adulthood and its epigenetic mechanism;to investigate the maternal risk factors of high birth-weight and the effect of maternal high TG level(≥90^th)during early pregnancy on maternal and neonatal outcomes;to determine the effect of intrauterine over-nutritional exposure on lipid metabolism in male offspring and its mechanism.Materials and Methods:Following the prospective case-control study design,we recruited subjects and compared their cardiometabolic risk factors:1)Fifty-eight children aged 3-6 years born LGA,matched with 123 subjects born Appropriate-for-gestational-age（AGA）.2)128 adults aged 20-40 born LGA,matched with 270 born AGA.Meanwhile,genome-wide DNA methylation in umbilical blood was assayed in AGA and macrosomia（≥4000g,LGA）;According to our cohort design,information of 51996 deliverys in our hospital between 2013 and 2016 was collected and logistic regression was used to analyse the risk factors of LGA,and the effects of high TG level;to examined the lipid profiles of male offspring from mother feeding with HFD during gestation and given HFD again when 8 weeks old after born.Results:Children born LGA had significantly higher serum level of total cholesterol（TC）,low-density lipoprotein-cholesterol（LDL-c）,and insulin,ratio of TC/high-density lipoprotein-cholesterol（HDL-c）compared to children born AGA.Adults born LGA also showed higher serum TG,TC,and blood pressure;A total of 327 methylation variable positions（MVPs）were filtered（differences of≥7%,located within islands）,which mapped to 213 genes.Function analysis showed 16 genes enriched in“cardiovascular disease”,and four genes of them contributed to hyperlipidemia;The mainly risk factors of LGA were height 165-174cm,height≥175cm,BMI during early pregnancy≥25.0,glucose 5.1-6.9m M,and TG>2.05m M（P<0.01,AOR>1.3）.Univariate analysis showed that per unit increase in TG was associated with an increased risk of PIH,preeclampsia,GDM,early preterm,and LGA.High TG significantly increased the risks of preterm in women with high GWG,while this adverse effect of high TG disappeared in women with low GWG.Male offspring from HFD mother had higher body weight from birth until 3 weeks after born than that of Controls,and higher serum TG,TC levels in 3 weeks old,but comparable in 8 weeks old.After fed with 3 weeks of HFD,higher levels of lipids were detected in the HFD group,and more lipids deposit in the liver tissue.m RNA expressions of Cpt1a and Cpt2in liver of HFD male offspring were significantly down-regulated in 3weeks old.Lower expression of Cpt2 persisted in 8 weeks and 12 weeks old.Conclusions:High birth-weight increased the cardiometabolic risks in children and adults,and it might be associated with the reprogrammed methylation in the group of genes correlated to cardiovascular disease.As one of the mainly risk factors,high TG also increased maternal complications of pregnancy and preterm risks.Limiting GWG might be a valid mean to cover its unfavorable effect on preterm risk.Intrauterine over-nutritional exposure increased lipids profile of male offspring,which might be associated with the impaired fatty acid oxidation via consistently down-regulated Cpt2expression.