OMEGA-3 SUPPLMENTATION DECREASES INFLAMMATION AND FETAL OBESITY IN PREGNANCY

除了成年人和儿童肥胖的增加，在过去的20年里，出生体重也显著增加。根据我们的初步数据，孕妇孕前肥胖是新生儿和青少年肥胖的最大危险因素。我们研究的长期目标是研究减少胎儿肥胖的治疗策略。肥胖和怀孕都是与慢性低度炎症相关的胰岛素抵抗状况。因此，我们假设怀孕期间n-3 PUFA膳食补充剂可以作为胰岛素增敏剂，降低周围胰岛素抵抗和炎症。如果正确的话，这种机制应该会降低母体营养物质对胎儿的可利用性，从而减少出生时的肥胖。我们计划在有剖宫产史的超重/肥胖妇女中进行n-3 PUFA补充和安慰剂的前瞻性随机双盲对照试验，从妊娠早期开始并在整个妊娠期间维持。这项建议有两个具体目的。具体目的1是评价补充n-3多聚脂肪酸对孕妇胰岛素敏感性的影响。在基线和饮食干预后，使用lsott、间接碳量法体成分（BODPOD）和血浆血脂来测量孕妇的胰岛素敏感性和胰岛素代谢。目的2：评价n-3多聚脂肪酸对超重/肥胖孕妇炎症状态的影响。我们假设补充n-3 PUFA通过防止单核细胞激活和巨噬细胞在WAT的积累，从而降低全身促炎细胞因子的浓度，从而减少妊娠期间的慢性炎症。我们计划描述循环单核细胞和血浆脂肪因子的纵向变化，以确定两组随时间的炎症模式。我们还利用流式细胞术、免疫组织化学和基因表达分析来确定浸润WAT的巨噬细胞的丰度和表型。此外，pparty作为n-3 PUFA调节胰岛素敏感性作用的中心靶点的作用可以通过表征pparty在WAT中的表达来检验。此外，我们将研究n-3 pÙf4对原代培养脂肪细胞中脂联素和pparty调控基因表达的直接影响。总之，本研究在超重/肥胖人群中结合了临床和实验方法，以评估n-3 PUFA对炎症和胰岛素抵抗的影响。还需要获得胎儿身体成分的初步数据，以便以后解决预防母体肥胖对发育中的胎儿的长期不利影响（发育规划）。

ln addition to the increase in obesity in adutt and chitdren, there has been a significant increase in birth weights over the tast 2 decades. Based on our pretiminary data, maternal pregravid obesity is the strongest risk factor for neonatal as we[[ as adotescent obesity. The [ong' ierm goats of our research are to examine therapeutic strategies to decrease fetal adiposity. Obesity and pregnancy are both insutin resistant conditions associated with chronic low-grade inftammation. Therefore, we hypothesize that n-3 PUFA dietary supplements during pregnancy witl act as insulin sensitizers decreasing peripheral insulin resistance and inflammation. lf correct this mechanism should decrease avaitabitity of maternal nutrients to the fetus and subsequently reduce adiposity at birth. We ptan a prospective randomized double btind control triat of n-3 PUFA supplementation and ptacebo in overweight/obese women, with a previous cesarean delivery, initiated in earty pregnancy and maintained throughout pregnancy. This proposal has two specific aims. Specific aim 1 is to evatuate the effect of n-3 PUFA supplementation on maternat insulin sensitivitv. Measures of maternat insutin sensitivity and tipi{ metabolism witl be made using the lsogtt, indirect catorimetry body composition (BODPOD) and plasma tipid profite at basetine and after dietary intervention. jpecific aim 2 witt assess the effect of n-3 PUFA on the inftammatorv status in overweieht/obese preqnant women. We hypothesize that n-3 PUFA supptementation decreases cl'rronic inftammation during pregnancy by preventing monocyte activation and accumulation of macrophages in WAT thus lowering systemic concentration of proinflammatory cytokines. We ptan to characterize the longitudinal changes in circutating monocytes and plasma adipokines in order to define the inflammatory patterns in both groups over time. We witt also determine the abundance and phenotype of macrophages infittrating WAT using flow cytometry, immunohistochemistry and gene expression profiting. Furthermore, the rote of PPARy as a central target of n-3 PUFA action to regutate insutin sensitivity witt be examined by characterizing the expression of PPARy in WAT of both supptemented and control groups. Additionatty, w€ witl investigate the direct affect of n-3 pÙf4 on the expression of adiponectin and PPARy regulated genes in primary cuttured adipocytes. ln'summary, this proposal combines both ctinical and motecutar methodotogies in an overweight/obese subject population in order to assess the effect of n-3 PUFA on inftammãtion and insuiin resistance. Pretiminary data witt also be obtained on fetat body composition in order to later address the prevention of the long term adverse effects (devetopmental programming) of maternal obesity in the developing fetus.