Programmed Adipogenesis and Lipid Dysregulation

摘要 胎儿宫内生长受限（IUGR）新生儿成年后肥胖和代谢紊乱的风险增加。 综合征重要的是，出生体重最低的新生儿患代谢综合征的风险高出18倍 比出生体重最重的新生儿要多。我们已经建立了一个大鼠模型，概括了这个悖论。 具体而言，母体食物限制（MFR）在下半年的大鼠妊娠结果在IUGR新生儿。 当提供正常喂养和断奶后饮食（FR/AdLib）时，这些后代表现出快速追赶 生长和成人肥胖伴脂质异常。从机制上说，我们的研究表明， 在FR/AdLib后代中，肥胖是由于（在肥胖发展之前） 脂肪形成信号级联，特别是脂肪形成转录因子，过氧化物酶体增殖物激活受体2。因此，拟议的 该项目将确定这种自相矛盾的PPAR上调的潜在机制， 肥胖值得注意的是，我们的初步数据暗示了PPAR协同调节因子的作用。具体而言，（i）减少了共- 阻遏物，NCoR，（ii）增加共激活物，SRC 1，和（iii）减少通过ERK 1/2介导的抑制PPAR <$2 磷酸化这些都可能有助于PPARm介导的程序性脂肪形成。我们因此 假设（1）PPAR <$2辅阻遏物的下调是PPAR <$介导的 FR/AdLib后代的脂肪形成，以及（2）这些因素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。确认 体内研究将直接刺激（罗格列酮）和抑制（BADGE）PPAR <$<$， 并通过增加辅阻遏物水平（白藜芦醇），并确定这些修饰对 下游脂质靶点。我们将确认辅抑制因子（SIRT 1、SMRT和NCoR）和/或辅抑制因子的作用 在原代脂肪细胞培养物中使用慢病毒和siRNA技术检测活化剂（SRC 1和TIF 2）。我们将 进一步研究PPAR 2对其下游脂质靶点的影响。为了确定 改变基因表达，我们将研究表观遗传修饰的共阻遏/共激活和过氧化物酶体增殖物激活受体， 同时探索表观遗传修饰的遗传性。在所有的研究中，我们将对比 程序性代谢综合征与饮食诱导的代谢综合征（DIMS）导致的脂肪生成增强。这一系列 实验利用分子生物学、细胞生理学和全身的综合技术， physiology.这些研究将提供重要的新见解和潜在的治疗干预措施， 妊娠程序性脂肪形成机制。

Abstract Intrauterine growth restricted (IUGR) newborns have an increased risk of adult obesity and metabolic syndrome. Importantly, newborns with the lowest birth weight have 18 times more risk of metabolic syndrome than newborns with heaviest birth weight. We have established a rat model that recapitulates this paradox. Specifically, maternal food restriction (MFR) during the second-half of rat pregnancy results in IUGR newborns. When provided normal nursing and postweaning diet (FR/AdLib), these offspring demonstrate rapid catch-up growth and adult obesity with lipid abnormalities. Mechanistically, our studies indicate that increased adiposity in FR/AdLib offspring is a result of programmed upregulation (prior to the development of obesity) of the adipogenesis signaling cascade, in particular, the adipogenic transcription factor, PPAR¿2. Thus, the proposed project will determine the underlying mechanism for this paradoxical upregulation of PPAR¿ in programmed obesity. Notably, our preliminary data implicate the role of PPAR¿ co-regulators. Specifically, (i) decreased co- repressor, NCoR, (ii) increased co-activator, SRC1, and (iii) reduced inhibition of PPAR¿2 via ERK1/2-mediated phosphorylation. These may all contribute to PPAR¿-mediated programmed adipogenesis. We thus hypothesize that (1) down regulation of PPAR¿2 co-repressors is the mechanism for PPAR¿-mediated adipogenesis in FR/AdLib offspring, and (2) epigenetic modification of these factors explains the altered gene expression, as well as offers the opportunity for preventative or therapeutic interventions. To confirm the putative role of PPAR¿, in vivo studies will stimulate PPAR¿ (rosiglitazone) and inhibit (BADGE) PPAR¿ directly and via increased co-repressor levels (resveratrol), and determine the impact of these modifications on downstream lipid targets. We will confirm the role of co-repressors (SIRT1, SMRT and NCoR) and/or co- activators (SRC1 and TIF2) using lentivirus and siRNA technology in primary adipocyte cell cultures. We will further investigate the effects of PPAR¿2 on its downstream lipid targets. To determine the mechanism of altered gene expression, we will examine the epigenetic modification of co-repressor/co-activator and PPAR¿, while exploring the heritability of epigenetic modifications. In all studies, we will contrast the mechanisms of enhanced adipogenesis due to programmed versus diet-induced metabolic syndrome (DIMS). This series of experiments utilizes integrative techniques that involve molecular biology, cellular physiology, and whole body physiology. These studies will provide major new insights and potential therapeutic interventions for gestationally programmed adipogenic mechanisms.