Effects of choline on fetal growth and lipid accretion in gestational diabetes

 描述（由申请人提供）：妊娠糖尿病（GDM），定义为母体高血糖症，影响7%的妊娠。GDM导致胎儿过度生长或巨大儿，这对后代的健康产生不利影响，包括更大的肥胖风险。目前，医学营养治疗是GDM护理过程的一个组成部分，其调节大量营养素摄入和体重增加以使母体血糖正常化。然而，减轻母体高血糖不能充分解决增加的胎盘脂质转移和胎儿脂质积聚，这是巨大儿的主要原因。胆碱是一种必需的微量营养素，在怀孕期间，其需求量大幅增加。PI先前已经表明，人类产前胆碱补充剂可降低胎儿应激和改善胎盘血管发育。我们的试验数据表明，怀孕小鼠补充胆碱激活过氧化物酶体增殖物激活受体α途径，这可能会增加脂肪酸分解。补充胆碱还可以预防人类和动物的脂肪肝。我们假设母体补充胆碱可以预防GDM诱导的巨大儿和后代的过度肥胖。在目的1中，我们将在妊娠期糖尿病小鼠模型中确定母体胆碱摄入对胎儿生长和脂质稳态的影响。将在妊娠期间给6周龄C57 BL/6 J小鼠（n=6/组/时间点）喂食高脂肪饮食以诱导GDM或喂食对照饮食。将向饲料中添加三种水平的酒石酸氢胆碱（0.25、0.5或1 mg/kcal饲料），以产生胆碱缺乏、对照或补充亚组。我们将评估母体胆碱摄入量是否会降低胎盘和胎儿重量，并减少妊娠中期和早产2.5天的脂肪积累。在目标2中，我们将确定母体胆碱摄入量对受GDM影响的后代的长期体重调节和肥胖的影响。在断奶后6周，对妊娠期间胆碱摄入量不同（与目标1相同）的GDM或对照母鼠（n=6母鼠）的C57 BL/6 J幼仔（n= 2只幼仔/母鼠/处理组）饲喂低脂饲料或高脂饲料（致肥胖），以评估产前胆碱补充是否降低对照或致肥胖产后环境中后代的体重增加和肥胖。在这些研究的结论中，我们将描述胆碱在预防GDM巨大儿和后代过度肥胖方面的功效。这项研究的结果将为人类研究奠定基础，使用胆碱作为GDM的无害和成本有效的干预措施。

 DESCRIPTION (provided by applicant): Gestational diabetes mellitus (GDM), defined by maternal hyperglycemia, affects 7% of pregnancies. GDM results in fetal overgrowth, or macrosomia, which adversely influences offspring health including greater risk of obesity. Currently, medical nutrition therapy is an integral part of the GDM care process which regulates macronutrient intake and weight gain to normalize maternal blood glucose. However, attenuating maternal hyperglycemia cannot sufficiently address the increased placental lipid transfer and fetal lipid accretion, which are the major causes of macrosomia. Choline is an essential micronutrient, whose requirement increases substantially during pregnancy. The PI has previously shown that prenatal choline supplementation in humans leads to lower fetal stress and better vascular development of the placenta. Our pilot data suggests that choline supplementation in pregnant mice activates the peroxisome proliferator-activated receptor alpha pathway, which may increase fatty acid breakdown. Choline supplementation also prevents fatty liver disease in humans and animals. We hypothesize that maternal choline supplementation will prevent GDM-induced macrosomia and excessive adiposity across the lifespan of the offspring. In Aim 1, we will determine the effects of maternal choline intake on fetal growth and lipid homeostasis during gestation in a mouse model of GDM. Six-week-old C57BL/6J mice (n=6/group/time point) will be fed either a high fat diet to induce GDM during pregnancy or a control diet. Three levels of choline bitartrate (0.25, 0.5 or 1 mg/kcal of diet) will be added to he diets to generate choline deficient, control or supplemented subgroups. We will assess whether maternal choline intake decreases placental and fetal weight and reduces fat accumulation at mid-gestation and 2.5 days preterm. In Aim 2, we will determine the effects of maternal choline intake on long-term body weight regulation and adiposity in offspring affected by GDM. C57BL/6J pups (n= 2 pups/ dam/ treatment) from GDM or control dams (n=6 dams) with varied choline intake during gestation (same as Aim 1) will be fed either a low fat diet or a high fat die (obesogenic) for 6 weeks after weaning, in order to assess whether prenatal choline supplementation reduces weight gain and adiposity of the offspring in a control or obesogenic postnatal environment. At the conclusion of these studies, we will have delineated the efficacy of choline in preventing GDM macrosomia and excessive adiposity of offspring. Results of the study will lay the ground work for human studies that use choline as an innocuous and cost effective intervention for GDM.