The GROWTH Study, Glycemia Range and Offspring Weight and adiposity in response To Human milk

摘要 孕期母体新陈代谢是代谢性疾病发生的关键因素。 暴露在母亲高血糖和肥胖环境中的后代会增加肥胖和紊乱的几率 葡萄糖代谢。哺乳期也是编程的关键窗口。乳汁发生始于 因此，在妊娠的后半期，人乳(HM)的生物合成是母体代谢的敏感因素。 HM营养成分的个体间差异揭示了母体代谢对乳汁生物合成的影响。一个 关于HM的组成是否改变了程序化后代的发育途径，存在知识差距 在子宫里。孕妇的代谢状态包括妊娠期糖尿病(GDM)和肥胖会改变HM的营养状况， 包括牛奶脂肪酸(FA)。我们的研究确定了变异的HM亚油酸和双高-伽马-亚麻酸 (DGLA)在母亲糖尿病、高血糖和肥胖的情况下，以及HM棕榈酸和DGLA 与婴儿生长发育的关系。然而，母体新陈代谢对整个范围的任何影响 关于HM成分和后代计划的血糖水平尚未在详细的 子宫内暴露情况的分析。我们的目标是了解HM对母体代谢的易感性 影响后代新陈代谢，确定减轻不利发展规划的干预措施。这 该提案的目标是确定怀孕期间母亲血糖对HM成分和HM的影响 HM营养素对子代肥胖的影响。翻译科学的方法将决定母性 血糖改变乳腺上皮细胞基因表达，以及HM脂类如何在 母体血糖调节婴儿脂肪。我们最重要的假设是母体血糖正常 病理范围影响HM的组成，进而影响后代的代谢编程 反映在儿童早期的肥胖上。利用围棋妈妈的详细代谢表型 队列，我们将在产后1个月、2个月和6个月对450名妇女进行前瞻性的HM概况分析 妊娠期间和怀孕后的相关母亲血糖，重点关注已知的调节后代的HM血脂 肥胖(目标1)。在表达的HM中脱落的乳腺上皮细胞将使用转录组学进行评估 (子目标1)。为了重复性，HM血脂将与招募女性的单独验证队列进行比较 与GDM一起。我们将在1个月、2个月、6个月和2岁时测量后代的身体成分，以识别肥胖， 考虑到儿童饮食(目标2)。人类婴儿前体脂肪细胞株将暴露于收集的HM脂类 并按母亲血糖的四分位数分组，以确定改变婴儿脂肪细胞发育的机制 (目标3)。完成目标将定义具有全面代谢的妊娠队列中的HM组成 在整个孕期和哺乳期血糖和BMI的范围内进行分析。后代的生长和发育 翻译研究将促进对哺乳期暴露如何改变子宫编程的理解。这 将通过揭示降低不利后代代谢健康风险的干预措施来进一步推动这一领域。

ABSTRACT Maternal metabolism during pregnancy is a key contributor to developmental origins of metabolic disease. Offspring exposed to maternal hyperglycemia and obesity have increased rates of obesity and disordered glucose metabolism. The lactation period is also a critical window for programming. Lactogenesis initiates in the second half of gestation, thus human milk (HM) biosynthesis is susceptible maternal metabolism. Interindividual variation in HM nutrients reveals the influence of maternal metabolism on milk biosynthesis. A knowledge gap exists as to whether HM composition alters developmental pathways of offspring programmed in utero. Maternal metabolic states including gestational diabietes (GDM) and obesity alter HM nutrient profiles, including milk fatty acids (FA). Our studies identified altered HM linoleic acid and dihomo-gamma-linolenic acid (DGLA) in conditions of maternal diabetes, hyperglycemia, and obesity, as well as HM palmitic acid and DGLA associations with infant growth. However, any impact of maternal metabolism across the entire range of glycemia on both HM composition and offspring programming has not been evaluated in context of detailed profiling of in utero exposures. Our goal is to understand how HM susceptibility to maternal metabolism impacts offspring metabolism, identifying interventions to mitigate adverse developmental programming. This proposal’s objective is to determine the impact of maternal glycemia in pregnancy on HM composition and effects of HM nutrients on offspring adiposity. Translational science approaches will determine how maternal glycemia alters mammary gland epithelial cell gene expression and how HM lipids across the range of maternal glycemia regulate infant adipoctyes. Our overarching hypothesis is that maternal glycemia in normal and pathologic ranges impacts HM composition, which in turn influences offspring metabolic programming as reflected by early childhood adiposity. Capitalizing on the detailed metabolic phenotyping of the GO MOMs cohort, we will conduct prospective HM profiling at 1, 2 and 6 months post-partum in a cohort of 450 women to associate maternal glycemia during and after pregnancy, focusing on HM lipids known to regulate offspring adiposity (Aim 1). Mammary epithelial cells shed in expressed HM will be evaluated using transcriptomics (SubAim 1). For reproducibility, HM lipids will be compared to a separate validation cohort enrolling women with GDM. We will measure offspring body composition to discern adiposity at months 1, 2, and 6 and 2 years, accounting for childhood diet (Aim 2). A human infant preadipocyte strain will be exposed to HM lipids collected and grouped by quartiles of maternal glycemia to determine mechanisms altering infant adipocyte development (Aim 3). Completing the aims will define HM composition in a pregnancy cohort with comprehensive metabolic profiling throughout pregnancy and lactation across the range of glycemia and BMI. Offspring growth and translational studies will advance understanding of how lactation exposures modify in utero programming. This will further the field by revealing interventions to reduce risk of adverse offspring metabolic health.