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：
9906896
负责人：
JINGZHONG DING
金额：
$ 45.74万
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 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9906896
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 Epigenetic Process Equation Experimental Designs Fatty Acids Genes Genetic Transcription Gluconeogenesis Goals Health education Hepatocyte Human In Vitro Incubated Individual 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 Obesity Epidemic Observational Study Participant Pathologic Processes Pilot Projects Play Prediabetes syndrome Predisposition Prevention Randomized Randomized Controlled Clinical Trials Risk Factors Role Scientist Signal Transduction Societies Stress Structure Testing Tissues Tumor-infiltrating immune cells 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 methylomics 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（由申请人提供）：这项随机对照临床试验的目的是调查通过减肥干预减少肥胖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。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炎症中起着至关重要的作用，这可能将组织肥胖与细胞内胆固醇破坏联系起来。在动物实验研究中，细胞（例如单核细胞/巨噬细胞和脂肪细胞）的稳态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组研究将这些发现扩展到人类，并特别确定了一个。共表达胆固醇代谢基因网络，其表达改变与 2 型糖尿病 (T2DM) 相关（p-趋势：5.07x10-10），以及两个重要的T2DM 的危险因素包括肥胖（p：1.6 x10-18）和炎症（白细胞介素 6 的 p：2.0x10-7）。此外，在我们的初步研究中，减肥似乎可以逆转单核细胞中胆固醇代谢基因的这些改变。我们研究了 16 名肥胖者（没有对照组），肥胖和炎症会改变单核细胞中的胆固醇代谢基因网络，从而增加细胞内胆固醇的积累，而这些变化以及脂肪细胞的相关变化会增加胰岛素抵抗和胰岛素抵抗。扰乱血糖调节，从而导致 T2DM。为了说明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期成年人接受饮食诱导的减肥干预（饮食）。，N=100）或健康生活方式教育干预（对照，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甲基组/转录组谱。肥胖者的单核细胞和脂肪细胞；2) 确定体重减轻引起的人类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。一组科学家使用体外模型整合了来自临床试验和体外实验研究的表观遗传、转录和临床数据。遗传流行病学、分子生物学和生物信息学方面的专业知识将提供有关细胞胆固醇代谢调节和 T2DM 易感性的新见解，有可能带来新的治疗和预防目标。