Programmed Adipogenesis and Lipid Dysregulation

程序性脂肪生成和脂质失调

• 批准号: 7988477
• 负责人: Mina Desai
• 金额: $ 32.11万
• 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: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7988477
• 关键词: Address; Adipocytes; Adipose tissue; Adult; Age; Agonist; Binding; Biological Assay; Birth; Birth Weight; Body fat; Cell Culture Techniques; Cell physiology; Childhood; Data; Development; Diabetes Mellitus; Diet; Discipline of Nursing; Down-Regulation; Elements; Epigenetic Process; Exhibits; Exposure to; Fatty acid glycerol esters; Gene Expression; Growth; Lead; Life; Link; Lipids; Low Birth Weight Infant; Luciferases; Mediating; Metabolic syndrome; Modeling; Modification; Molecular Biology; NCOA2 gene; Newborn Infant; Nicotine; Nutrient; Obesity; Overnutrition; Physiology; Pre-Eclampsia; Pregnancy; Public Health; Rattus; Regulation; Relative Risks; Reporter; Resveratrol; Risk; Risk Factors; Role; Series; Shapes; Signal Transduction; Simulate; Techniques; Testing; Therapeutic Intervention; Up-Regulation; Weight Gain; base; early onset; feeding; food restriction; high risk; in utero; insight; lipid biosynthesis; nursing standards; nutrition; offspring; postnatal; programs; promoter; public health relevance; research study; rosiglitazone

DESCRIPTION (provided by applicant): The relationship between birth weight and adult metabolic syndrome is a "U-shaped" curve. Both, low and high birth weights have been linked to adult obesity, suggesting increased risk at both ends of the spectrum. Thus, reductions from "optimal" growth in utero, be it from constrained growth (e.g., maternal preeclampsia, nicotine) or excessive growth (e.g., maternal obesity, diabetes) increases the relative risk of adult metabolic syndrome. Further, postnatal excess nutrition or rapid catch-up growth is an additive risk factor. To simulate this scenario, we have developed two rat models, one of maternal under-nutrition and one of overnutrition. Our previous model of maternal food restriction (FR) during pregnancy results in low birth weight newborns. When provided normal nursing and postweaning diet, these offspring exhibit rapid catch-up growth and adult obesity with lipid abnormalities. In contrast, our recent model of maternal obesity and high fat diet during pregnancy (HF) results in normal birth weight newborns. However, with continued nursing by HF dams, these offspring demonstrate accelerated growth and early onset of obesity with lipid abnormalities, evident by 3 weeks of age. Despite the putative nutrition differences, our studies indicate that the mechanism(s) of increased adiposity in FR and HF offspring is a result of programmed upregulation (at birth, prior to the development of obesity) of the adipogenesis signaling cascade. Specifically, at one day of life, both FR and HF offspring exhibit increased adipose tissue PPAR?2 gene expression with downregulation of co-repressor NCoR, and upregulation of co-activator SRC1. Thus, the changes in co-regulators may well be the fundamental underlying factor(s) contributing to programmed adiposity, though we postulate that this occurs via different mechanisms under nutrient limitation or nutrient excess. We hypothesize that (1) downregulation of NCoR and/or upregulation of SRC1 is the mechanism for PPAR?2 mediated adipogenesis in HF and FR offspring, and (2) epigenetic modification of these factors explains the altered gene expression, as well as offering the opportunity for preventative or therapeutic interventions. We will determine the underlying mechanism(s) for this paradoxical upregulation of PPAR?2 in programmed obesity. We will elucidate the role of PPAR?2 corepressors (NCoR, SIRT1, SMRT) and co-activators (SRC1, TIF2), and determine whether epigenetic modification of these factors and/or PPAR?2 is the mechanism for programmed adiposity. We will systematically address this by identifying the specific role of PPAR?2 co-repressors, co-activators and epigenetic modulation, and study the effects on its downstream lipid target. We will suppress PPAR?2 directly or via its co-repressor and determine the adipogenic and lipogenic effects. Lastly, we will test the inheritance of epigenetic modification in F2 progeny. We will contrast the mechanisms of programmed adipogenesis versus diet-induced metabolic syndrome (DIMS). These studies will provide new insights, and potential therapeutic interventions for gestationally programmed adipogenic mechanisms that lead to childhood and adult obesity. PUBLIC HEALTH RELEVANCE: Obesity has emerged as a preeminent public health problem. Low or normal birth weight newborns with rapid postnatal weight gain have high risk of obesity. As increased body fat is one of the key features of obesity, the proposed studies will investigate the mechanism in which fat signaling factors are altered.

描述（由申请人提供）：出生体重与成人代谢综合征之间的关系是“ U形”曲线。低出生体重和高出生体重都与成年肥胖有关，表明两端的风险增加。因此，从子宫中“最佳”增长的减少，无论是从约束的生长（例如母体先兆子痫，尼古丁）还是过度生长（例如母体肥胖，糖尿病）会增加成人代谢综合征的相对风险。此外，产后多余的营养或快速追赶增长是添加剂危险因素。 为了模拟这种情况，我们开发了两种大鼠模型，其中一种是孕产妇不足的模型，也是营养不良之一。 我们以前的孕产妇限制模型（F​​R）在怀孕期间导致新生儿出生的低出生体重。当提供正常的护理和断奶后饮食时，这些后代会出现快速的追赶生长和成人肥胖，并具有脂质异常。相比之下，我们最近的孕妇肥胖症和怀孕期间高脂饮食模型导致新生儿出生体重正常。但是，随着HF大坝的持续护理，这些后代表现出加速的生长和肥胖症早期发作，并以脂质异常发作，到3周大。尽管有假定的营养差异，但我们的研究表明，FR和HF后代的肥胖性增加的机制是掺杂信号级联的编程上调（出生时，出生时，出生时）的结果。具体而言，在生命的一天中，FR和HF后代都表现出增加的脂肪组织PPAR？2基因表达，并下调共抑制剂NCOR和共激活剂SRC1的上调。因此，共同调节因子的变化很可能是导致编程肥胖的基本基本因素，尽管我们假设这是在营养限制或养分过剩的情况下通过不同的机制发生的。我们假设（1）NCOR的下调和/或SRC1上调是PPAR的机制？我们将确定在程序性肥胖症中PPAR的这种矛盾上调的基本机制。我们将阐明PPAR？2核心器（NCOR，SIRT1，SMRT）和共激活因子（SRC1，TIF2）的作用，并确定这些因素和/或PPAR的表观遗传修饰是否是编程脂肪的机制。我们将通过确定PPAR？2共抑制剂，共激活因子和表观遗传调制的特定作用来系统地解决此问题，并研究对其下游脂质靶标的影响。我们将直接或通过其共抑制剂抑制PPAR？2，并确定脂肪和脂肪生成效应。最后，我们将测试F2后代表观遗传修饰的遗传。我们将对比编程的脂肪形成与饮食诱导的代谢综合征（DIMS）的机制。这些研究将提供新的见解，并为导致儿童肥胖的妊娠成脂肪生成机制提供潜在的治疗干预措施。 公共卫生相关性：肥胖症已成为杰出的公共卫生问题。低出生体重或正常出生后体重增加的新生儿具有肥胖的高风险。由于增加的体内脂肪是肥胖的关键特征之一，因此拟议的研究将研究改变脂肪信号因子的机制。