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 宫内生长受限 (IUGR) 新生儿成人肥胖和代谢的风险增加 综合症。重要的是，出生体重最低的新生儿患代谢综合征的风险是正常人的 18 倍 高于出生体重最重的新生儿。我们建立了一个老鼠模型来概括这一悖论。 具体而言，大鼠妊娠后半期的母亲食物限制（MFR）会导致新生儿IUGR。 当提供正常哺乳和断奶后饮食 (FR/AdLib) 时，这些后代表现出快速追赶 生长和成人肥胖伴有脂质异常。从机制上讲，我们的研究表明肥胖增加 在 FR/AdLib 后代中，这是细胞程序性上调（在肥胖发生之前）的结果。 脂肪生成信号级联，特别是脂肪生成转录因子 PPAR¿2。因此，建议的 项目将确定程序化 PPAR 的这种矛盾上调的根本机制 肥胖。值得注意的是，我们的初步数据暗示了 PPAR 共同监管者的作用。具体来说，（i）减少了共同 阻遏蛋白 NCoR，(ii) 增加共激活蛋白 SRC1，以及 (iii) 通过 ERK1/2 介导减少对 PPAR¿2 的抑制 磷酸化。这些可能都有助于 PPAR¿ 介导的程序性脂肪生成。我们因此 假设 (1) PPAR¿2 共阻遏物的下调是 PPAR¿ 介导的机制 FR/AdLib 后代的脂肪形成，以及 (2) 这些因素的表观遗传修饰解释了改变的基因 表达，并提供预防或治疗干预的机会。为了确认 PPAR¿ 的假定作用，体内研究将直接刺激 PPAR¿（罗格列酮）并抑制 (BADGE) PPAR¿ 并通过增加辅阻遏物水平（白藜芦醇），并确定这些修饰对 下游脂质目标。我们将确认共抑制因子（SIRT1、SMRT 和 NCoR）和/或共抑制因子的作用 在原代脂肪细胞培养物中使用慢病毒和 siRNA 技术激活剂（SRC1 和 TIF2）。我们将 进一步研究 PPAR¿2 对其下游脂质靶点的影响。确定机制 改变基因表达，我们将检查共阻遏物/共激活物和 PPAR¿的表观遗传修饰， 同时探索表观遗传修饰的遗传性。在所有研究中，我们将对比以下机制： 程序性代谢综合征（DIMS）与饮食诱发代谢综合征（DIMS）相比，脂肪生成增强。这个系列的 实验利用涉及分子生物学、细胞生理学和全身的综合技术 生理。这些研究将为以下疾病提供重要的新见解和潜在的治疗干预措施： 妊娠程序性脂肪生成机制。