Interactions between prenatal obesogen exposure and Total Western diet lead to a transgenerational thrifty phenotype: functional and epigenomic analysis of effects in fat and liver

产前肥胖素暴露与全西方饮食之间的相互作用导致跨代节俭表型：对脂肪和肝脏影响的功能和表观基因组分析

• 批准号: 10264776
• 负责人: BRUCE BLUMBERG
• 金额: $ 46.9万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-16 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10264776
• 关键词: ATAC-seq; Address; Adipocytes; Adipose tissue; Adult; Affect; Age; Animals; Award; Basal metabolic rate; Blood; Blood Glucose; Body mass index; Cardiovascular Diseases; Cell Compartmentation; Cell Count; ChIP-seq; Chemicals; Chromatin; Chromatin Structure; Clinical; Clinical Management; DNA; DNA Methylation; Desire for food; Development; Diabetes Mellitus; Diet; Dietary Fats; Dietary Practices; Disease; Endocrine Disruptors; Endocrine system; Energy Intake; Energy Metabolism; Environmental Risk Factor; Exhibits; Exposure to; Fasting; Fatty acid glycerol esters; Female; Generations; Genes; Health; Health Care Costs; Hi-C; High Fat Diet; Hispanics; Human; Hypertension; Individual; Knowledge; Lead; Leisures; Leptin; Link; Lipids; Liver; Malignant Neoplasms; Mediating; Mesenchymal Stem Cells; Metabolic; Metabolism; Modeling; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Obesity Epidemic; Patients; Phenotype; Physical activity; Plasma; Predisposition; Preventive; Process; Public Health; Research; Resistance; Rodent; Role; Satiation; Signal Transduction; Testing; Testis; Therapeutic; Thinking; Time; Tissues; Weight; Weight Gain; Woman; Xenobiotics; Youth; cell type; combat; diet and exercise; dieting; early life exposure; energy balance; epigenome; epigenomics; experimental study; exposed human population; falls; fetal loss; hormone regulation; in vivo; insight; mRNA Expression; male; multiple omics; non-alcoholic fatty liver disease; obesity management; obesogen; obesogenic; offspring; pregnant; prenatal; prenatal exposure; prevent; sperm cell; transcriptome; transcriptome sequencing; tributyltin; western diet

PROJECT SUMMARY Obesity is a serious public health concern, largely because obesity and related disorders (e.g., cardiovascular disease, type II diabetes, hypertension, cancers, etc.) add more than $200 billion annually to US health care costs. The current clinical paradigm for obesity is one of energy intake versus energy expenditure, with clinical management focused on diet and exercise. Diet and exercise are important factors in obesity, particularly the energy dense Western dietary pattern, but they do not fully account for the obesity epidemic. US adults were 2.3 kg/m2 higher in BMI in 2006 than in 1988, even at comparable caloric intake and energy expenditure. Emerging evidence supports an important role for exposure to endocrine disrupting chemicals (EDCs)in obesity. We identified tributyltin (TBT) as an environmental “obesogen” - a chemical that leads to weight gain, in vivo. In utero exposure to environmentally-relevant levels of TBT increased fat depot weight, reprogrammed mesenchymal stem cells to favor the adipogenic fate and caused non alcoholic fatty liver disease in F1-F4 male offspring. We reproduced these transgenerational phenotypes in two independent experiments and found that male F4 descendents of F0 TBT-treated animals became obese when dietary fat was increased. This fat persisted after the animals were returned to normal low fat chow. TBT-treated animals and their descendents were resistant to fasting-induced fat loss, indicating that these animals do not mobilize fat to the same extent as controls during fasting. We found that fat in F4 male descendants of TBT treated dams showed persistent DNA hypomethylation in regions encompassing important metabolic genes such as the Lep gene, increased leptin mRNA expression, elevated plasma leptin levels, and that these hypomethylated regions in fat were less accessible in sperm chromatin of F3/F4 males. We proposed that these animals exhibited a transgenerational "thrifty phenotype" caused by altered chromatin structure and accessibility. We hypothesize that TBT exposure modifies the epigenome across multiple generations, sensitizing animals to weight gain and that this “thrifty phenotype” is revealed or exacerbated by increased dietary fat. Two specific aims are proposed: 1) How does TBT exposure exacerbate the effects of “Total Western Diet” leading to weight gain?, and 2) How does TBT exposure make animals resistant to fat loss? Answering these key questions will address knowledge gaps in the field that are relevant to human health. The proposed research will reveal which molecular mechanisms may underlie the effects of obesogens and how a Western dietary pattern interacts with obesogen exposure to predispose toward fat gain and promote the transgenerational programming of obesity. This will greatly inform the thinking of clinicians and the public in understanding individual susceptibility to obesity and how best it may be treated and prevented in individuals. The successful completion of this research will illuminate the molecular mechanisms underlying the role of xenobiotic chemicals on obesity, and may provide insights into how the obesity epidemic can be curtailed.

项目概要 肥胖是一个严重的公共卫生问题，主要是因为肥胖和相关疾病（例如心血管疾病） 疾病、II 型糖尿病、高血压、癌症等）每年为美国医疗保健增加超过 2000 亿美元 目前肥胖症的临床范例是能量摄入与能量消耗的比较，临床上。 饮食和运动的管理重点 饮食和运动是肥胖的重要因素，尤其是肥胖。 西方人的能量密集型饮食模式，但并不能完全解释美国成年人的肥胖流行情况。 即使热量摄入和能量消耗相当，2006 年 BMI 仍比 1988 年高出 2.3 kg/m2。 新出现的证据支持暴露于内分泌干扰化学物质 (EDC) 中的重要作用 我们将三丁基锡 (TBT) 确定为一种环境“致肥胖物质”——一种导致体重增加的化学物质， 在子宫内暴露于环境相关水平的 TBT 会增加脂肪库的重量，重新编程。 间充质干细胞有利于脂肪形成的命运并导致 F1-F4 中的非酒精性脂肪肝 我们在两个独立的实验中复制了这些跨代表型，并发现 当膳食脂肪增加时，接受 TBT 处理的 F0 动物的雄性 F4 后代会变得肥胖。 在将动物恢复到正常的低脂饮食后，TBT 治疗的动物及其后代仍然存在。 对禁食引起的脂肪减少有抵抗力，表明这些动物不能以相同程度动员脂肪 作为禁食期间的对照，我们发现经 TBT 处理的母鼠的 F4 雄性后代的脂肪表现出持续性。 包含重要代谢基因（例如 Lep 基因）的区域 DNA 低甲基化增加 瘦素 mRNA 表达，血浆瘦素水平升高，并且脂肪中这些低甲基化区域较少 我们认为这些动物表现出跨代性。 我们发现 TBT 暴露导致染色质结构和可及性改变。 改变多代的表观基因组，使动物对体重增加敏感，并且这种“节俭” 提出了两个具体目标：1）如何 TBT 暴露加剧了“全西方饮食”导致体重增加的影响？以及 2) TBT 如何影响体重？ 暴露会使动物抵抗脂肪减少吗？回答这些关键问题将解决以下方面的知识差距： 与人类健康相关的领域。拟议的研究将揭示哪些分子机制。 可能是致肥胖因素的影响的基础，以及西方饮食模式如何与致肥胖因素的接触相互作用 容易增加脂肪并促进肥胖的跨代编程，这将提供很大的信息。 参议员和公众在了解个人对肥胖的易感性以及如何最好地了解这一问题上的想法 这项研究的成功完成将阐明分子机制。 外源化学物质对肥胖作用的潜在机制，并可能提供有关外源化学物质如何影响肥胖的见解。 肥胖流行可以得到遏制。