Epigenetics of Weight Loss and Glycemic Improvement

减肥和血糖改善的表观遗传学

基本信息

批准号：
9258428
负责人：
JINGZHONG DING
金额：
$ 66.36万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-09 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9258428
关键词：
Abdomen Adipocytes Adipose tissue Adult Affect Animals Bioinformatics Biological Models Body Weight decreased Caloric Restriction Cell Communication Cell physiology Cells Cholesterol Cholesterol Homeostasis Clinical Data Clinical Trials Control Groups DNA Methylation Data Diet Educational Intervention Epidemic Epigenetic Process Equation Experimental Designs Fatty Acids Genes Genetic Transcription Gluconeogenesis Goals Health education Hepatocyte Human Immune In Vitro Incubated Individual Infiltration Inflammation Inflammatory Insulin Insulin Resistance Interleukin-6 Interleukin-7 Intervention Intrinsic factor Lead Linear Regressions Link Mediating Metabolic Methylation Modeling Molecular Molecular Biology Muscle Fibers Non-Insulin-Dependent Diabetes Mellitus Obesity Observational Study Participant Pathologic Processes Pilot Projects Play Predisposition Prevention Randomized Randomized Controlled Clinical Trials Risk Factors Role Scientist Signal Transduction Societies Stress Testing Tissues aged blood glucose regulation cell growth regulation experimental study genetic epidemiology genome-wide glucose metabolism glucose tolerance glucose uptake healthy lifestyle in vitro Model in vivo insight macrophage monocyte novel public health relevance subcutaneous therapy design transcriptomics trend weight loss intervention

项目摘要

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.

描述（由适用提供）：这项随机对照临床试验的目的是研究通过减肥干预措施减少肥胖症是否会引起与全身血糖变化相关的单核细胞和脂肪细胞中胆固醇基因网络的有益变化。最近的研究表明，脂肪组织中单核细胞衍生的巨噬细胞和脂肪细胞的相互作用在脂肪组织注射中起着至关重要的作用，这可能将肥胖与胰岛素抵抗联系起来。细胞内胆固醇的破坏细胞中的体内稳态，例如单核细胞/巨噬细胞和脂肪细胞，是在动物实验研究中证明是胰岛素抵抗的细胞中性因素之一。 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 infection (p:白介素-6的2.0x10-7。此外，在我们对没有对照组的16名肥胖者的试点研究中，单核细胞中胆固醇代谢基因的这些改变似乎逆转了这些改变。我们假设肥胖和感染会改变单核细胞中胆固醇代谢基因网络，以增加细胞内胆固醇的积累，并且这些变化以及脂肪细胞的相关变化增加了胰岛素抵抗和破坏葡萄糖的调节，随后导致T2DM。为了说明该胆固醇基因网络在减肥引起的血糖改善中的作用，我们将随机分配200名40-60岁的肥胖和糖尿病前成年人，以饮食引起的减肥干预（饮食，n = 100）或健康的生活方式教育干预措施（对照，n = 100）。我们将通过以下特定目标来实现我们的目标：1）测试单核细胞和脂肪细胞中甲基含量/转录组概况的重量甲基甲基甲基甲基属/转录组是否来自肥胖者； 2）确定人单核细胞和脂肪细胞的甲基化和转录变化是否与全身血糖改善相关。我们还将探索人类单核细胞中观察到的分子变化是否改变了使用体外模型的人脂肪细胞，骨骼肌细胞和肝细胞的谷胱甘肽代谢。来自临床试验和Viro实验研究的表观遗传，转录和临床数据的整合，由一组具有遗传学流行学，分子生物学和生物信息学专家的科学家团队进行，将提供有关细胞胆固醇代谢性的细胞代谢性和敏感性的新颖见解，并具有针对T2DDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDD的洞察力。