Programmed Adipogenesis and Lipid Dysregulation

程序性脂肪生成和脂质失调

• 批准号: 8460565
• 负责人: Mina Desai
• 金额: $ 25.46万
• 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/8460565
• 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; Peroxisome Proliferator-Activated Receptors; 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.

描述（申请人提供）：出生体重与成人代谢综合征之间的关系呈“U”形曲线。低出生体重和高出生体重都与成人肥胖有关，这表明两端的风险都会增加。因此，子宫内“最佳”生长的减少，无论是生长受限（例如，产妇先兆子痫、尼古丁）还是过度生长（例如，产妇肥胖、糖尿病），都会增加成人代谢综合征的相对风险。此外，产后营养过剩或快速追赶性生长是附加风险因素。 为了模拟这种情况，我们开发了两种大鼠模型，一种是母亲营养不足的大鼠模型，另一种是营养过剩的大鼠模型。 我们之前的母亲怀孕期间食物限制（FR）模型会导致新生儿出生体重过低。当提供正常的哺乳和断奶后饮食时，这些后代表现出快速的追赶性生长和成年肥胖并伴有脂质异常。相比之下，我们最近的孕期肥胖和高脂肪饮食模型（HF）导致新生儿出生体重正常。然而，随着 HF 母鼠的持续哺乳，这些后代表现出加速生长和早期肥胖伴脂质异常，到 3 周龄时就很明显。尽管存在假定的营养差异，但我们的研究表明，FR 和 HF 后代肥胖增加的机制是脂肪生成信号级联程序性上调（出生时，肥胖发生之前）的结果。具体而言，在出生后的某一天，FR 和 HF 后代均表现出脂肪组织 PPAR?2 基因表达增加，同时辅阻遏物 NCoR 下调，辅激活剂 SRC1 上调。因此，共同调节因子的变化很可能是导致程序性肥胖的根本因素，尽管我们假设这种情况是在营养限制或营养过剩的情况下通过不同机制发生的。我们假设 (1) NCoR 的下调和/或 SRC1 的上调是 HF 和 FR 后代中 PPAR?2 介导的脂肪生成的机制，(2) 这些因素的表观遗传修饰解释了基因表达的改变，并提供了预防或治疗干预的机会。我们将确定程序性肥胖中 PPAR?2 这种矛盾上调的潜在机制。我们将阐明 PPAR?2 辅抑制因子（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 共阻遏物、共激活物和表观遗传调节的具体作用来系统地解决这个问题，并研究对其下游脂质靶点的影响。我们将直接或通过其共阻遏物抑制 PPAR?2，并确定脂肪生成和脂肪生成作用。最后，我们将测试 F2 后代中表观遗传修饰的遗传。我们将对比程序性脂肪生成机制与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编程脂肪形成机制提供新的见解和潜在的治疗干预措施。