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

营养不良和胎儿发育：灵长类动物模型中的前脂肪细胞适应

基本信息

批准号：
7572467
负责人：
YOURKA Dimova TCHOUKALOVA
金额：
$ 7.4万
依托单位：
LSU PENNINGTON BIOMEDICAL RESEARCH CTR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-08 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7572467
关键词：
Abbreviations Abdomen Adipocytes Adipose tissue Adult Affect Atherosclerosis Binding Binding Proteins Biological Availability Body Patterning Body fat Brain Cells Central obesity Chronic Disease Cleaved cell Data Deposition Development Dexamethasone Diabetes Mellitus Diagnostic Diet Endocrine Environment Enzyme-Linked Immunosorbent Assay Epidemiologic Studies Equilibrium Exhibits Fatty acid glycerol esters Fetal Development Fetus Figs - dietary Food Funding Gene Expression Genes Glucocorticoids Growth Growth Factor Receptors Health Sciences Hormonal Human Hyperplasia Hypertrophy In Vitro Insulin-Like Growth Factor Binding Protein 4 Insulin-Like Growth Factor I Insulin-Like Growth-Factor-Binding Proteins Kidney Lead Lipids Low Birth Weight Infant Metabolic Metabolic syndrome Metalloproteases Modeling Molecular Profiling Mothers Newborn Infant Nutritional Obesity Omentum PAPP Papio Pattern Peptide Hydrolases Persons Phenotype Placenta Play Pregnancy Pregnancy-Associated Plasma Protein-A Preventive Primates Production Protein Secretion Proteins Randomized Regulation Relative (related person)Research Resources Risk Risk Factors Role Site Staining method Stains Stimulus System Technology Texas Therapeutic Tissue Sample Tissues Tumor Necrosis Factor-alpha Tumor Necrosis Factors Universities Variant Visceral Woman abdominal fat cost deprivation feeding fetal fetal reactivity fetus nutrition human IGFBP2 protein inhibitor/antagonist innovation lipid biosynthesis maternal nutrient restriction men mother nutrition neutralizing antibody nutrition offspring paracrine pregnant prenatal programs public health relevance regional difference response subcutaneous

项目摘要

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.

描述（由申请人提供）：流行病学研究表明，低出生体重与成人内脏肥胖有关，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前脂肪细胞（PA）的区域编程。没有研究表明潜在的机制。基本原理：胎儿脂肪组织 (AT) 主要在妊娠末期沉积并涉及 PA 分化。了解不同储库之间胎儿 PA 分化的差异很重要，因为它们可能会编程脂肪分布模式。我们将使用与人类具有公认相似性的灵长类动物模型，并分析来自人类不可能获得的组织的细胞。我们提供了来自网膜 (OM) 和皮下 (SQ) 仓库的初步数据，这些仓库来自于在整个怀孕期间随意喂养 (CTR) 或母体营养限制 (MNR) 喂养的食物喂养 CTR 的 70% 的对照母亲的近期狒狒胎儿。假设：我们假设 30% 的总体 MNR 1) 与 OM 脂肪相比，在 SQ 中更多地抑制 PA 分化，并更少地增加对脂肪生成刺激因子的敏感性； 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，降低SQ中的局部IGF-I生物利用度，但不降低OM脂肪； 3) 导致作为 MNR 特定靶点的其他脂肪生成旁分泌调节剂的储存库独特表达谱。具体目标：我们将使用狒狒 MNR 模型 1）评估 MNR 对局部体外 PA 分化的影响，2）确定局部 IGFBP/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 胎儿的 AT 样本，该样本目前资助用于胎盘、大脑和肾脏研究，但不包含 PA 研究。怀孕的狒狒被随机分配到 CTR 或 MNR。在妊娠 0.9 岁时的剖腹产中，解剖并培养胎儿 OM、SQ 腹部和股骨 AT，通过脂质积累、分泌蛋白（通过 ELISA）和表达谱（通过基因阵列）染色来确定 PA 分化。目的：研究母亲饮食对局部脂肪生成的影响对于了解脂肪分布模式的机制至关重要。创新：该研究的新颖性在于完全缺乏发育库中胎儿脂肪生成的数据、模型及其机制方法。环境：环境拥有所需的资源。纸巾免费提供。影响和简单总结：不良的产前营养环境会不同程度地改变不同部位脂肪细胞前体的反应性，并导致脂肪倾向于优先储存在腹部内，从而增加成人慢性疾病的风险。重要的是要确定所涉及的发育机制，以制定诊断、预防和治疗策略。公共卫生相关性：影响和外行摘要：不良的产前营养环境会不同程度地改变不同部位脂肪细胞前体的反应性，并导致脂肪倾向于优先储存在腹部内，从而增加成人慢性病的风险。重要的是要确定所涉及的发育机制，以制定诊断、预防和治疗策略。