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

• 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
• 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

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。理由：胎儿脂肪组织（AT）主要在妊娠晚期沉积，并与PA分化有关。了解不同储存库之间胎儿PA分化的差异是重要的，因为它们可以编程脂肪分布模式。我们将使用与人类相似的灵长类动物模型，分析不可能在人类中获得的组织细胞。我们提供的初步数据来自于近期狒狒胎儿的网膜（OM）和皮下（SQ）储存库，这些胎儿来自于在整个妊娠期间自由喂养（CTR）或营养限制喂养（MNR） 70% CTR的对照母亲。假设：我们假设30%的全球MNR 1)在SQ中比OM脂肪更能抑制PA分化并增加对脂肪生成刺激因子的敏感性；2)通过IGF结合蛋白-2、- 4和-5相对于蛋白酶妊娠相关血浆蛋白- a （pap - a）的增加，降低SQ而不是OM脂肪的局部IGF- i生物利用度；3)导致作为MNR特异性靶点的脂肪形成的其他旁分泌调节因子的表达谱不同。具体目的：我们将利用我们的狒狒MNR模型，1)评估MNR对体外区域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：我们将使用来自一个P01的CTR和MNR胎儿的AT样本，该样本目前已被资助用于胎盘、大脑和肾脏的研究，但未包含PA的研究。怀孕的狒狒被随机分配到CTR或MNR。在妊娠0.9剖宫产时，解剖和培养胎儿OM、SQ腹部和股骨At，通过对脂质积累、分泌蛋白（ELISA）和表达谱（基因阵列）的染色来确定PA分化。目的：研究母体饮食对区域脂肪形成的影响对了解脂肪分布模式的机制至关重要。创新：该研究的新颖之处在于完全缺乏胎儿脂肪形成的数据，该模型及其机制方法。环境：环境拥有所需的资源。纸巾是免费的。影响和意义：不良的产前营养环境会改变不同部位脂肪细胞前体的反应性，导致脂肪倾向于在腹部优先储存，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。摘要：不良的产前营养环境会以不同的方式改变不同部位脂肪细胞前体的反应性，导致脂肪倾向于在腹部优先储存，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。