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.

项目总结