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呈“u”型关系。低和高出生体重都与成人肥胖有关，这表明两者的风险都增加了。因此，从子宫内的“最佳”生长减少，无论是由于受限生长（例如，母体子痫前期、尼古丁）还是过度生长（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，产后营养过剩或快速追赶生长是一个附加的风险因素。为了模拟这种情况，我们开发了两种大鼠模型，一种是母亲营养不足，另一种是营养过剩。我们之前的怀孕期间母亲食物限制（FR）模型导致低出生体重新生儿。当提供正常的护理和断奶后饮食时，这些后代表现出快速的追赶生长和成人肥胖伴脂质异常。相比之下，我们最近的孕妇肥胖和孕期高脂肪饮食模型（HF）导致新生儿出生体重正常。然而，随着HF母鼠的持续护理，这些后代表现出生长加速和早发性肥胖，并伴有脂质异常，在3周龄时表现明显。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是程序性上调（在出生时，在肥胖发展之前）脂肪生成信号级联的结果。具体来说，在一天的生命中，FR和HF后代都表现出脂肪组织PPAR？2基因表达下调共抑制因子NCoR，上调共激活因子SRC1。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潜在因素，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的下调和/或SRC1的上调是PPAR的机制？2介导的HF和FR后代的脂肪生成，以及(2)这些因素的表观遗传修饰解释了基因表达的改变，并为预防或治疗干预提供了机会。我们将确定PPAR这种矛盾上调的潜在机制。2个是程序性肥胖。我们将阐明PPAR的作用。2个共抑制因子（NCoR, SIRT1， SMRT）和共激活因子（SRC1, TIF2），并确定这些因子的表观遗传修饰和/或PPAR？2是程序性肥胖的机制。我们将通过确定PPAR的具体作用来系统地解决这个问题。2共抑制因子、共激活因子和表观遗传调控，并研究其对下游脂质靶标的影响。我们会抑制PPAR？2直接或通过其协同抑制因子，并确定脂肪的生成和增脂作用。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程序性脂肪生成机制提供新的见解和潜在的治疗干预措施。