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: 10659049
• 负责人: BRUCE BLUMBERG
• 金额: $ 46.36万
• 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/10659049
• 关键词: ATAC-seq; Address; Adipocytes; Adipose tissue; Adult; Affect; Age; Animals; Award; Basal metabolic rate; Black Populations; 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; Environment; Environmental Risk Factor; Exhibits; Exposure to; Fasting; Fatty acid glycerol esters; Female; Generations; Genes; Health; Health Care Costs; Hi-C; High Fat Diet; Hispanic; Hispanic Populations; 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; Persons; 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; 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.

项目摘要 肥胖是一个严重的公共健康问题，主要是因为肥胖和相关疾病（例如心血管 疾病，II型糖尿病，高血压，癌症等）每年向美国医疗保健增加超过2000亿美元 费用。肥胖的当前临床范式是能量摄入量与能量消耗的一种，临床 管理专注于饮食和运动。饮食和运动是肥胖的重要因素，尤其是 能量密集的西方饮食模式，但并不能完全解释肥胖症的流行。美国成年人是 2006年，BMI的2.3 kg/m2甚至比1988年高，即使在可比的热量摄入量和能量消耗也是如此。 新兴证据支持暴露于内分泌破坏化学物质（EDC）的重要作用 肥胖。我们将tributyltin（TBT）确定为一种环境“肥胖原”，一种导致体重增加的化学物质 体内。在子宫内暴露于与环境相关的TBT水平增加的脂肪仓库重量增加，重新编程 间充质干细胞有利于脂肪脂肪，并在F1-F4中引起非酒精脂肪肝病 男性后代。我们在两个独立的实验中重现了这些转化的表型，发现 当饮食脂肪增加时，经F0 TBT处理的动物的雄性F4后代变得肥胖。这个脂肪 将动物归还正常的低脂脂肪后，持续了。 TBT处理的动物及其后代 对禁食引起的脂肪损失有抵抗力，表明这些动物不会在同一程度上动员脂肪 作为禁食期间的控件。我们发现，在TBT处理的大坝的F4男性后代中，脂肪持续 涵盖重要代谢基因（例如LEP基因）的区域中DNA低甲基化，增加 瘦素mRNA表达，血浆瘦素水平升高，脂肪中的这些甲基化区域较少 可在F3/F4雄性的精子中访问。我们提出这些动物暴露了一种变革 由染色质结构和可及性改变引起的“节俭表型”。我们假设TBT暴露 修改多代的表观基因组，使动物对体重增加敏感，并且这种“节俭 饮食脂肪增加表明或加剧了表型。提出了两个具体目的：1）如何如何 TBT暴露加剧了“总西方饮食”导致体重增加的影响？和2）TBT如何 暴露会使动物抗脂肪流失？回答这些关键问题将解决知识差距 与人类健康相关的领域。拟议的研究将揭示哪些分子机制 可能是肥胖症的影响以及西方饮食模式如何与肥胖的暴露相互作用 倾向于脂肪增加并促进肥胖的变革性编程。这将非常了解 临床医生和公众在理解个人对肥胖症的敏感性以及如何最好的想法 在个人中受到治疗和预防。这项研究的成功完成将阐明分子 异种生物化学物质对肥胖的作用的基础机制，并可能提供有关如何如何的见解 肥胖流行可以减少。