Programmed Adipogenesis and Lipid Dysregulation

程序性脂肪生成和脂质失调

• 批准号: 8271394
• 负责人: Mina Desai
• 金额: $ 26.39万
• 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/8271394
• 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. 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）：出生体重与成人代谢综合征之间的关系呈"U形"曲线。出生体重低和出生体重高都与成年肥胖有关，这表明这两种情况的风险都增加了。因此，从子宫内"最佳"生长的减少，无论是从受约束的生长（例如，母体先兆子痫，尼古丁）或过度生长（例如，母亲肥胖、糖尿病）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，一种是母亲营养不良，另一种是营养过剩。 我们以前的母亲在怀孕期间的食物限制（FR）的结果在低出生体重新生儿模型。当提供正常的护理和断奶后的饮食，这些后代表现出快速追赶增长和成年肥胖与脂质异常。相比之下，我们最近的模型，母亲肥胖和高脂肪饮食在怀孕期间（HF）的结果在正常出生体重的新生儿。然而，随着HF母鼠的持续喂养，这些后代表现出加速生长和早发肥胖伴脂质异常，在3周龄时明显。尽管存在假定的营养差异，但我们的研究表明，FR和HF后代中肥胖增加的机制是脂肪形成信号级联的程序性上调（出生时，肥胖发生前）的结果。具体来说，在一天的生活，FR和HF后代表现出增加脂肪组织过氧化物酶体增殖物激活受体？2基因表达下调的辅阻遏NCoR，和上调的辅激活SRC1。因此，共调节因子的变化很可能是导致程序性肥胖的根本因素，尽管我们假设这在营养限制或营养过剩下通过不同的机制发生。我们推测（1）NCoR的下调和/或SRC 1的上调是PPAR？2介导的HF和FR后代的脂肪形成，和（2）这些因子的表观遗传修饰解释了改变的基因表达，以及提供预防或治疗干预的机会。我们将确定潜在的机制（S），这种矛盾的上调过氧化物酶体增殖物激活受体？程序性肥胖2例。我们将阐明的作用，过氧化物酶体增殖物激活受体？2辅阻遏物（NCoR，SIRT 1，SMRT）和辅激活物（SRC 1，TIF 2），并确定是否表观遗传修饰这些因素和/或过氧化物酶体增殖物激活受体？2是程序性肥胖的机制。我们将系统地解决这一问题，通过确定具体的作用，过氧化物酶体增殖物激活受体？2共抑制子、共激活子及其表观遗传调控，并研究其对下游脂质靶点的影响。我们会抑制过氧化物酶体增殖反应？2直接或通过其辅阻遏物，并确定脂肪形成和脂肪形成的效果。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形成与饮食诱导的代谢综合征（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脂肪形成机制提供新的见解和潜在的治疗干预措施。 公共卫生相关性：肥胖已成为一个突出的公共卫生问题。低出生体重或正常出生体重的新生儿出生后体重迅速增加，肥胖的风险很高。由于体内脂肪增加是肥胖的主要特征之一，因此拟议的研究将调查脂肪信号因子改变的机制。