Programmed Adipogenesis and Lipid Dysregulation

程序性脂肪生成和脂质失调

• 批准号: 7847292
• 负责人: Mina Desai
• 金额: $ 14.48万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-17 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7847292
• 关键词: Abbreviations; Address; Adipocytes; Adipose tissue; Adult; Age; Agonist; Binding; Biological Assay; Birth Weight; Body fat; CCAAT-Enhancer-Binding Protein-alpha; CCAAT-Enhancer-Binding Protein-beta; CCAAT-Enhancer-Binding Proteins; CCAAT-enhancer-binding protein-delta; Cell Culture Techniques; Cell physiology; Chromatin; Data; Development; Diet; Discipline of Nursing; Down-Regulation; Elements; Embryo; Epigenetic Process; Fatty acid glycerol esters; Fatty-acid synthase; Fetal Growth; Fetal Growth Retardation; Food; Gene Expression; Growth; Heritability; Lactation; Lead; Lipids; Low Birth Weight Infant; Luciferases; MAPK1 gene; MAPK8 gene; Mediating; Mediator of activation protein; Metabolic syndrome; Modeling; Modification; Molecular Biology; NCOA2 gene; Newborn Infant; Nuclear Receptors; Obesity; PPAR gamma; Phosphorylation; Physiology; Pregnancy; Protein Kinase; Public Health; Rattus; Regulation; Regulatory Element; Reporter; Resveratrol; Retinoids; Risk; Role; Series; Signal Transduction; Simulate; Small Interfering RNA; Steroid Receptors; Sterols; Subfamily lentivirinae; Techniques; Technology; Testing; Therapeutic Intervention; Thyroid Hormone Receptor; Time; Up-Regulation; Weight Gain; abstracting; base; biological adaptation to stress; extracellular; food restriction; high risk; in vivo; insight; intraperitoneal; lipid biosynthesis; lipoprotein lipase; nursing standards; offspring; postnatal; programs; promoter; research study; rosiglitazone; subcutaneous; transcription factor; transcriptional intermediary factor 1

Abstract Intrauterine growth restricted (IUGR) newborns have an increased risk of adult obesity and metabolic syndrome. Importantly, newborns with the lowest birth weight have 18 times more risk of metabolic syndrome than newborns with heaviest birth weight. We have established a rat model that recapitulates this paradox. Specifically, maternal food restriction (MFR) during the second-half of rat pregnancy results in IUGR newborns. When provided normal nursing and postweaning diet (FR/AdLib), these offspring demonstrate rapid catch-up growth and adult obesity with lipid abnormalities. Mechanistically, our studies indicate that increased adiposity in FR/AdLib offspring is a result of programmed upregulation (prior to the development of obesity) of the adipogenesis signaling cascade, in particular, the adipogenic transcription factor, PPAR¿2. Thus, the proposed project will determine the underlying mechanism for this paradoxical upregulation of PPAR¿ in programmed obesity. Notably, our preliminary data implicate the role of PPAR¿ co-regulators. Specifically, (i) decreased co- repressor, NCoR, (ii) increased co-activator, SRC1, and (iii) reduced inhibition of PPAR¿2 via ERK1/2-mediated phosphorylation. These may all contribute to PPAR¿-mediated programmed adipogenesis. We thus hypothesize that (1) down regulation of PPAR¿2 co-repressors is the mechanism for PPAR¿-mediated adipogenesis in FR/AdLib offspring, and (2) epigenetic modification of these factors explains the altered gene expression, as well as offers the opportunity for preventative or therapeutic interventions. To confirm the putative role of PPAR¿, in vivo studies will stimulate PPAR¿ (rosiglitazone) and inhibit (BADGE) PPAR¿ directly and via increased co-repressor levels (resveratrol), and determine the impact of these modifications on downstream lipid targets. We will confirm the role of co-repressors (SIRT1, SMRT and NCoR) and/or co- activators (SRC1 and TIF2) using lentivirus and siRNA technology in primary adipocyte cell cultures. We will further investigate the effects of PPAR¿2 on its downstream lipid targets. To determine the mechanism of altered gene expression, we will examine the epigenetic modification of co-repressor/co-activator and PPAR¿, while exploring the heritability of epigenetic modifications. In all studies, we will contrast the mechanisms of enhanced adipogenesis due to programmed versus diet-induced metabolic syndrome (DIMS). This series of experiments utilizes integrative techniques that involve molecular biology, cellular physiology, and whole body physiology. These studies will provide major new insights and potential therapeutic interventions for gestationally programmed adipogenic mechanisms.

抽象的 内在限制（IUGR）新生儿的成人肥胖和代谢风险增加 综合征。重要的是，出生体重最低的新生儿的代谢风险增加了18倍 比最大的出生体重的新生儿。我们已经建立了一个概括此悖论的大鼠模型。 具体而言，在大鼠妊娠的第二半期间，孕产妇粮食限制（MFR）导致IUGR新生儿。 当提供正常护士和断奶后饮食（FR/ADLIB）时，这些后代表现出快速追赶 生长和成人肥胖，脂质异常。从机械上讲，我们的研究表明肥胖增加 在fr/adlib中，后代是对编程的上调（在开发肥胖之前）的结果 脂肪形成信号传导级联反应，掺杂转录因子，ppAr¿2。 项目将确定PPAR的这种矛盾上调的基本机制 肥胖。值得注意的是，我们的初步数据暗示了PPAR共共同调节器的作用。特别是（i）改进的共同 阻遏物，ncor，（ii）增加共活化剂，src1和（iii）通过ERK1/2介导的PPAR抑制降低 磷酸化。这些都可能有助于PPAR介导的编程脂肪形成。因此，我们 假设（1）降低PPAR的调节2共抑制器是PPAR®介导的机制 fr/adlib后代的脂肪形成，（2）这些因素的表观遗传修饰解释了基因的改变 表达，并为预防或治疗干预提供了机会。确认 PPAR的假定作用，体内研究将刺激PPAR（Rosiglitazone）并直接抑制（徽章）PPAPER 并通过增加的共抑制水平（白藜芦醇），并确定这些修饰对 下游脂质靶标。我们将确认共抑制器（SIRT1，SMRT和NCOR）和/或共同的作用 在原发性脂肪细胞培养物中使用慢病毒和siRNA技术的激活剂（SRC1和TIF2）。我们将 进一步研究PPAR¿2对其下游脂质靶标的影响。确定机制 基因表达改变，我们将检查共抑制剂/共激活因子和pPAR®的表观遗传修饰， 同时探索表观遗传修饰的遗传力。在所有研究中，我们将对比 由于编程与饮食诱导的代谢综合征（DIMS）而引起的脂肪生成增强。这个系列 实验利用涉及分子生物学，细胞生理和全身的集成技术 生理。这些研究将为您提供主要的新见解和潜在的治疗干预措施 妊娠编程的掺杂机制。