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

 描述(申请人提供)：妊娠期糖尿病(GDM)，由母亲高血糖定义，影响7%的怀孕。妊娠期糖尿病会导致胎儿过度生长，或巨大儿，这会对后代的健康产生不利影响，包括更大的肥胖风险。目前，医学营养疗法是妊娠期糖尿病护理过程中不可或缺的一部分，它调节大量营养素的摄入量和体重增加，以使母亲血糖正常化。然而，降低母亲的高血糖并不能充分解决胎盘脂肪转移和胎儿脂肪堆积的增加，这是巨大儿的主要原因。胆碱是一种基本的微量营养素，在怀孕期间其需求量会大幅增加。PI先前已经表明，人类产前补充胆碱可以降低胎儿压力，改善胎盘的血管发育。我们的初步数据表明，在怀孕小鼠中补充胆碱激活了过氧化物酶体增殖物激活的受体α途径，这可能会增加脂肪酸的分解。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妊娠期糖尿病引起的巨大儿和子代一生中的过度肥胖。在目标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血脂稳态的影响。6周龄C57BL/6J小鼠(n=6只/组/时间点)在孕期饲喂高脂饲料诱发妊娠期糖尿病或对照组。在日粮中添加三种水平的重酒石酸胆碱(0.25、0.5或1毫克/千卡)，以产生胆碱缺乏、对照或补充亚组。我们将评估孕妇摄入胆碱是否会减少胎盘和胎儿的体重，并减少怀孕中期和早产2.5天时的脂肪堆积。在目标2中，我们将确定母亲胆碱摄入对受妊娠期糖尿病影响的子代的长期体重调节和肥胖的影响。GDM或对照母鼠(n=6只)孕期胆碱摄入量不同的C57BL/6J仔鼠(n=2只/治疗组)在断奶后6周内分别饲喂低脂饲料或高脂饲料(肥胖)，以评估在对照或肥胖的产后环境中，产前补充胆碱是否能减少子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效果。这项研究的结果将为使用胆碱作为一种无害且具有成本效益的妊娠期糖尿病干预措施的人体研究奠定基础。

 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.