Epigenetics of Weight Loss and Glycemic Improvement

 描述(申请人提供)：这项随机对照临床试验的目标是调查通过减肥干预减少肥胖是否会导致单核细胞和脂肪细胞中的胆固醇基因网络发生有益的变化，这与全身血糖变化有关。最近的研究表明，脂肪组织中单核细胞来源的巨噬细胞和脂肪细胞的相互作用在脂肪组织炎症中起着关键作用，这可能将肥胖与胰岛素抵抗联系在一起。破坏细胞内胆固醇 在动物实验研究中，细胞内的动态平衡，如单核/巨噬细胞和脂肪细胞，是导致胰岛素抵抗的细胞内在因素之一。我们最近对纯化的人类单核细胞的转录转录研究将这些发现扩展到人类，并特别确定了一个共表达的胆固醇代谢基因网络，其表达变化与2型糖尿病(T2 DM)相关(p趋势：5.07x10-10)，以及导致T2 DM的两个重要风险因素-肥胖(p：1.6x10-18)和炎症(p：2.0x10-7)。此外，在我们对16名没有对照组的肥胖者进行的初步研究中，减肥似乎逆转了单核细胞中胆固醇代谢基因的这些变化。我们假设肥胖和炎症改变了单核细胞的胆固醇代谢基因网络，增加了细胞内胆固醇的积聚，这些变化与脂肪细胞的相关变化一起增加了胰岛素抵抗，扰乱了血糖调节，从而导致T2 DM。为了说明这个胆固醇基因网络在减肥诱导的血糖改善中的作用，我们将200名年龄在40-60岁的肥胖和糖尿病前期成年人随机分配到饮食诱导减肥干预(Diet，N=100)或健康生活方式教育干预(Control，N=100)。我们将通过以下具体目标来实现我们的目标：1)测试减肥干预是否重新平衡肥胖者单核细胞和脂肪细胞中的甲基化/转录水平；以及2)确定减肥诱导的单核细胞和脂肪细胞中的甲基化和转录变化是否与全身血糖改善相关。我们还将利用体外模型探索观察到的人类单核细胞的分子变化是否会改变人类脂肪细胞、骨骼肌细胞和肝细胞的葡萄糖代谢。由一组具有遗传流行病学、分子生物学和生物信息学专业知识的科学家团队进行的临床试验和病毒实验研究的表观遗传学、转录和临床数据的整合，将提供关于细胞胆固醇代谢调节和T2 DM易感性的新见解，可能导致新的治疗和预防目标。

 DESCRIPTION (provided by applicant): The goal of this randomized, controlled clinical trial is to investigate whether decreasing obesity through a weight loss intervention induces beneficial changes in the cholesterol gene network in monocytes and adipocytes that are associated with whole body glycemic changes. Recent studies suggest that interaction of monocyte-derived macrophages and adipocytes in adipose tissue plays a crucial role in adipose tissue inflammation, which may link obesity to insulin resistance. Disruption of intracellular cholesterol homeostasis in cells, such as monocytes/macrophages and adipocytes, is one of the cell-intrinsic factors shown to be responsible for insulin resistance in animal experimental studies. Our recent transcriptomic study of purified human monocytes extends these findings to humans, and specifically identifies a network of co-expressed cholesterol metabolism genes whose altered expression is associated with type 2 diabetes mellitus (T2DM) (p- trend: 5.07x10-10), as well as two important risk factors for T2DM - obesity (p: 1.6 x10-18) and inflammation (p: 2.0x10-7 for interleukin-6). Furthermore, weight loss appeared to reverse these alterations of the cholesterol metabolism genes in monocytes in our pilot study of 16 obese persons without a control group. We hypothesize that obesity and inflammation alters the cholesterol metabolism gene network in monocytes to increase intracellular cholesterol accumulation, and these changes along with related changes in adipocytes increase insulin resistance and disrupt glucose regulation, which subsequently lead to T2DM. To illustrate the role of this cholesterol gene network in weight loss-induced glycemic improvements, we will randomly assign 200 obese and prediabetic adults aged 40-60 years to diet-induced weight loss intervention (Diet, N=100) or healthy lifestyle education intervention (Control, N=100). We will achieve our goal through the following specific aims: 1) To test whether weight loss intervention rebalances methylomic/transcriptomic profiles in monocytes and adipocytes from obese persons; and 2) To determine whether weight loss-induced methylation and transcriptional changes in human monocytes and adipocytes correlate with whole body glycemic improvements. We will also explore whether the observed molecular changes in human monocytes alter glucose metabolism in human adipocytes, skeletal myocytes, and hepatocytes using in vitro models. The integration of epigenetic, transcriptional, and clinical data from the clinical trial and in viro experimental studies, carried out by a team of scientists with expertise in genetic epidemiology, molecular biology, and bioinformatics, will provide novel insights concerning the regulation of cellular cholesterol metabolism, and susceptibility to T2DM, potentially leading to new treatment and prevention targets.