Poor nutrition and fetal development: preadipocyte adaptation in a primate model

描述（由申请方提供）：流行病学研究表明，低出生体重与成人内脏肥胖相关，这是代谢综合征的一个标志，表明在胎儿营养不良的情况下存在前脂肪细胞（PA）的区域编程。没有研究表明潜在的机制。原理：胎儿脂肪组织（AT）主要沉积在妊娠晚期，并涉及PA分化。了解不同储库间胎儿PA分化的差异很重要，因为它们可能会编程脂肪分布模式。我们将使用与人类相似的灵长类动物模型，并分析人类无法获得的组织细胞。我们提供的初步数据网膜（OM）和皮下（SQ）仓库来自近足月狒狒胎儿的对照母亲喂养自由采食（CTR）或母亲营养限制（MNR）喂养70%的食物喂养CTR整个怀孕。假设：我们假设30%的总体MNR 1）在SQ中比OM脂肪更多地抑制PA分化，并且增加对脂肪生成刺激因子的敏感性更少; 2）通过相对于其蛋白酶妊娠相关血浆蛋白A（PAPP-A）增加IGF结合蛋白-2、-4和-5来降低SQ中而不是OM脂肪中局部IGF-I的生物利用度;和3）导致作为MNR的特异性靶点的脂肪生成的其它旁分泌调节剂的储库-独特表达谱。具体目标：我们将使用我们的狒狒MNR模型来1）评估MNR对局部体外PA分化的影响和2）确定局部IGFBPs/PAPP-A系统和其他机制的作用。方法：我们将使用来自P01的CTR和MNR胎仔的AT样本，该P01目前资助胎盘、脑和肾脏研究，但不包含PA研究。将妊娠狒狒随机分配至CTR或MNR组。在妊娠0.9周的剖腹产时，解剖并培养胎儿OM、SQ腹部和股骨AT，以通过对脂质积累、分泌蛋白（通过ELISA）和表达谱（通过基因阵列）进行染色来确定PA分化。结论：研究母体饮食对局部脂肪形成的影响对于了解脂肪分布模式的机制至关重要。创新：这项研究的新奇在于完全缺乏关于胎儿脂肪形成的数据，模型及其机械方法。环境：环境需要资源。纸巾免费提供。影响和铺设总结：产前营养不良的环境会改变不同部位脂肪细胞前体的反应性，导致脂肪优先储存在腹部，增加成人慢性疾病的风险。重要的是要确定所涉及的发展机制，因为他们出现制定诊断，预防和治疗策略。公共卫生相关性：影响和铺设总结：产前营养不良的环境会改变不同部位脂肪细胞前体的反应性，导致脂肪优先储存在腹部，增加成人慢性疾病的风险。重要的是要确定所涉及的发展机制，因为他们出现制定诊断，预防和治疗策略。

DESCRIPTION (provided by applicant): Epidemiological studies indicate that low birth weight is associated with adult visceral obesity, a hallmark of metabolic syndrome suggesting regional programming of preadipocytes (PA) in the presence of poor fetal nutrition. No studies exist to indicate underlying mechanisms. RATIONALE: Fetal adipose tissue (AT) is primarily deposited in the final trimester and involves PA differentiation. Understanding the differences in fetal PA differentiation among depots is important since they may program fat distribution patterns. We will use a primate model with recognized similarities to humans and analyze cells from tissues impossible to acquire in humans. We provide preliminary data from omental (OM) and subcutaneous (SQ) depots derived from near term baboon fetuses of control mothers fed ad libitum (CTR) or maternal nutrient restriction (MNR) fed 70% of food fed CTR throughout pregnancy. HYPOTHESES: We hypothesize that 30% global MNR 1) inhibits PA differentiation more and increases sensitivity to adipogenesis-stimulating factors less in SQ than OM fat; 2) decreases local IGF-I bioavailability in SQ but not OM fat via an increase of IGF binding proteins-2, - 4, and -5 relative to their protease pregnancy associated plasma protein-A (PAPP-A); and 3) leads to depot- distinctive expression profiles of other paracrine modulators of adipogenesis that are specific targets of MNR. SPECIFIC AIMS: We will use our baboon MNR model to 1) assess effects of MNR on regional in vitro PA differentiation and 2) determine the role of the local IGFBPs/PAPP-A system and other mechanisms. APPROACH: We will use AT samples from CTR and MNR fetuses from a P01 currently funded for studies on placenta, brain, and kidney but containing no studies on PA. Pregnant baboons are randomly assigned to CTR or MNR. At C-Section at 0.9 gestation, fetal OM, SQ abdominal and femoral AT are dissected and cultured to determine PA differentiation by staining for lipid accumulation, secreted proteins (by ELISA), and expression profiles (by gene arrays). OBJECTIVES: Studies on effects of maternal diet on regional adipogenesis are vital to understand mechanisms of fat distribution patterns. INNOVATION: The study's novelty is lies in the combination of complete lack of data on fetal adipogenesis in developing depots, the model, and its mechanistic approaches. ENVIRONMENT: The environment has the resources needed. Tissues are available at no cost. IMPACT AND LAY SUMMARY: A poor prenatal nutritional environment alters reactivity of fat cell precursors in different sites differently and leads to a tendency to store fat preferentially inside the abdomen increasing risk for adult chronic diseases. It is important to identify developmental mechanisms involved as they emerge to develop diagnostic, preventative and therapeutic strategies. PUBLIC HEALTH RELEVANCE: IMPACT AND LAY SUMMARY: A poor prenatal nutritional environment alters reactivity of fat cell precursors in different sites differently and leads to a tendency to store fat preferentially inside the abdomen increasing risk for adult chronic diseases. It is important to identify developmental mechanisms involved as they emerge to develop diagnostic, preventative and therapeutic strategies.