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(申请人提供)：出生体重和成人代谢综合征之间的关系是一个“U”型曲线。出生体重过低和过高都与成人肥胖有关，这表明这两种疾病的风险都有所增加。因此，子宫内“最佳”生长的减少，无论是生长受限(例如，母体先兆子痫、尼古丁)或过度生长(例如，母体肥胖、糖尿病)，都会增加成人代谢综合征的相对风险。此外，出生后营养过剩或快速追赶生长是一个额外的风险因素。为了模拟这种情况，我们开发了两种大鼠模型，一种是母亲营养不良，另一种是营养过剩。我们以前的孕妇在怀孕期间限制食物(FR)的模型会导致低出生体重的新生儿。当提供正常的护理和断奶后的饮食时，这些后代表现出快速的追赶生长和成年肥胖并伴有血脂异常。相比之下，我们最近的母体肥胖和孕期高脂饮食(HF)模型会导致正常出生体重的新生儿。然而，在HF DAMs的持续哺育下，这些后代表现出生长加速和早期肥胖并伴有血脂异常，在3周大的时候就很明显。尽管可能存在营养差异，但我们的研究表明，FR和HF后代肥胖增加的机制(S)是脂肪生成信号级联的程序性上调(出生时，肥胖发生之前)的结果。具体地说，在生命的一天，FR和HF后代都表现出脂肪组织PPAR？2基因表达的增加，同时下调了辅助抑制因子NCoR，上调了辅助激活因子SRC1。因此，辅调节因子的变化很可能是导致程序性肥胖的根本潜在因素(S)，尽管我们假设这是在营养限制或营养过剩下通过不同的机制发生的。我们假设(1)NCoR下调和/或SRC1上调是PPAR？2介导的HF和FR子代脂肪形成的机制，(2)这些因子的表观遗传修饰解释了基因表达的变化，并为预防或治疗干预提供了机会。我们将确定程序性肥胖中PPAR？2矛盾上调的潜在机制(S)。我们将阐明PPAR？2共抑制因子(NCoR、SIRT1、SMRT)和共激活因子(SRC1、TIF2)的作用，并确定这些因子和/或PPAR？2的表观遗传修饰是否是程序性肥胖的机制。我们将通过确定PPAR？2共抑制子、共激活子和表观遗传调节的特定作用来系统地解决这一问题，并研究对其下游脂质靶标的影响。我们将直接或通过其辅助抑制物抑制PPAR？2，并确定其成脂和成脂作用。最后，我们将测试表观遗传修饰在F2后代中的遗传。我们将对比程序性脂肪生成和饮食诱导代谢综合征(DIMS)的机制。这些研究将为导致儿童和成人肥胖的妊娠程序性成脂机制提供新的见解和潜在的治疗干预措施。 与公共健康相关：肥胖已成为一个突出的公共健康问题。出生后体重迅速增加的低出生体重或正常出生体重的新生儿患肥胖症的风险很高。由于体脂增加是肥胖的关键特征之一，拟议中的研究将探讨脂肪信号因子改变的机制。