Effects of DDE exposure on adipose tissue function, weight loss and metabolic improvement after bariatric surgery: A new paradigm for study of lipophilic chemicals

DDE 暴露对减肥手术后脂肪组织功能、体重减轻和代谢改善的影响：亲脂性化学物质研究的新范式

• 批准号: 9884568
• 负责人: VAIA LIDA CHATZI
• 金额: $ 67.89万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9884568
• 关键词: Address; Adipocytes; Adipose tissue; Adolescent; Adolescent obesity; Adult; Age; Animal Model; Animals; Archives; Attenuated; Behavioral; Biometry; Blood; Body Weight decreased; Body mass index; Cell Line; Cells; Chemicals; Child; Chlorinated Hydrocarbons; Clinical; Clinical Data; Cohort Effect; Complement; Data; Diabetes prevention; Dichlorodiphenyl Dichloroethylene; Dose; Dyslipidemias; Energy Metabolism; Environmental Epidemiology; Experimental Models; Exposure to; Fatty acid glycerol esters; Functional disorder; Future; Gene Expression; Glucose; Goals; Health; Homeostasis; Human; Hyperglycemia; Impairment; In Vitro; Insecticides; Insulin; Insulin Resistance; Intervention; Lead; Lipolysis; Measures; Metabolic; Metabolic Diseases; Modeling; Molecular; Morbid Obesity; Natural experiment; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Observational Study; Outcome; Participant; Pathway interactions; Predisposition; Prevalence; Prevention; Prospective Studies; Regulation; Research; Research Design; Research Personnel; Rodent; Subgroup; System; Teenagers; Testing; Thermogenesis; Tissue Sample; Tissue-Specific Gene Expression; Tissues; Toxic effect; Toxicology; Visceral; Youth; adult obesity; bariatric surgery; base; clinically relevant; cohort; dichlorodiphenyltrichloroethane; epidemiology study; experimental study; human study; innovation; insulin regulation; insulin signaling; interest; lipid biosynthesis; lipophilicity; metabolome; metabolomics; multiple omics; novel; novel strategies; obesity in children; obesogen; obesogenic; persistent organic pollutants; polybrominated diphenyl ether; primary outcome; sociodemographics; tool; toxicant; transcriptome; translational study; treatment strategy; Address; Adipocytes; Adipose tissue; Adolescent; Adolescent obesity; Adult; Age; Animal Model; Animals; Archives; Attenuated; Behavioral; Biometry; Blood; Body Weight decreased; Body mass index; Cell Line; Cells; Chemicals; Child; Chlorinated Hydrocarbons; Clinical; Clinical Data; Cohort Effect; Complement; Data; Diabetes prevention; Dichlorodiphenyl Dichloroethylene; Dose; Dyslipidemias; Energy Metabolism; Environmental Epidemiology; Experimental Models; Exposure to; Fatty acid glycerol esters; Functional disorder; Future; Gene Expression; Glucose; Goals; Health; Homeostasis; Human; Hyperglycemia; Impairment; In Vitro; Insecticides; Insulin; Insulin Resistance; Intervention; Lead; Lipolysis; Measures; Metabolic; Metabolic Diseases; Modeling; Molecular; Morbid Obesity; Natural experiment; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Observational Study; Outcome; Participant; Pathway interactions; Predisposition; Prevalence; Prevention; Prospective Studies; Regulation; Research; Research Design; Research Personnel; Rodent; Subgroup; System; Teenagers; Testing; Thermogenesis; Tissue Sample; Tissue-Specific Gene Expression; Tissues; Toxic effect; Toxicology; Visceral; Youth; adult obesity; bariatric surgery; base; clinically relevant; cohort; dichlorodiphenyltrichloroethane; epidemiology study; experimental study; human study; innovation; insulin regulation; insulin signaling; interest; lipid biosynthesis; lipophilicity; metabolome; metabolomics; multiple omics; novel; novel strategies; obesity in children; obesogen; obesogenic; persistent organic pollutants; polybrominated diphenyl ether; primary outcome; sociodemographics; tool; toxicant; transcriptome; translational study; treatment strategy

Abstract The environmental obesogen hypothesis posits that lipophilic persistent organic pollutants (POPs) accumulate in adipose tissue (AT) and can disrupt metabolic systems. However, the underlying molecular mechanisms of these toxicants on AT function remain poorly understood. As the most studied POP, dichlorodiphenyl- dichloroethylene (DDE), a persistent metabolite of the insecticide dichlorodiphenyl-trichloroethane (DDT), provides a model for assessing the metabolic health impact of lipophilic POPs. Almost all U.S. children and adolescents have detectable DDE blood levels. Despite abundant evidence from experimental studies showing that DDE disrupts metabolic homeostasis, mechanisms underlying metabolic disruption by DDE in humans are unclear. We therefore propose a novel study design for investigating mechanisms of DDE metabolic effects in humans, based on a remarkable archive of clinical data and visceral AT samples from the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) study and an in vitro human adipocyte experimental model. We hypothesize that the large metabolic changes after bariatric surgery provide a “natural experiment” that will magnify effects of the prototypical obesogen DDE, and that DDE in visceral AT will attenuate the reduction in body mass index and insulin resistance after bariatric surgery in a concentration-dependent manner (Aim 1). Although we know that high doses of DDE impair thermogenesis and insulin signaling in animal models, we still do not know whether these mechanisms underlie metabolic disruption by DDE in humans. We will assess effects of DDE on these pathways in a human primary adipocyte cell line, an experimental model that will be free from the potential for uncontrolled confounding in human observational studies and that may also identify new pathways (Aim 2). We will then test these pathways in metabolome and transcriptome profiles of human AT from Teen-LABS study participants, using a hierarchical modeling approach (Aim 3). Finally, we will integrate results from the DDE omics analyses in human AT and in the adipocyte cell line, using a novel latent variable modeling framework, to identify subgroups of adolescents who have less weight loss and less improvement in insulin resistance after bariatric surgery, based on their DDE exposure and multi-omics profile in AT (Aim 4). The proposed research will be the first human study to examine mechanisms of DDE toxicity to AT in humans, using adipose tissue-specific exposure and omic measures, and clinically relevant metabolic outcomes such as BMI and insulin resistance. A strong interdisciplinary team of investigators brings expertise in environmental epidemiology, bariatric surgery, toxicology, omics, and biostatistics. Our study, integrating in vitro and human observational approaches, has the potential to establish a new paradigm for the study of lipophilic obesogenic chemicals and to advance our understanding of environmental contributions to obesity and type 2 diabetes.

抽象的 环境性肥胖原假设认为亲脂性持久性有机污染物（POP）积累 在脂肪组织（AT）中，可以破坏代谢系统。但是，基本的分子机制 这些有毒物质对AT功能的理解仍然很少。作为二十二苯基的最多的流行音乐 二氯乙烯（DDE），杀虫剂二氯苯基 - 三氯乙烷（DDT）的持续代谢产物， 提供了一种评估亲脂性POP的代谢健康影响的模型。几乎所有美国儿童 青少年具有可检测到的DDE血液水平。尽管来自实验研究的大量证据表明 DDE破坏了代谢稳态，DDE在人类中的代谢中断的机制是 不清楚。因此，我们提出了一种新的研究设计，用于研究DDE代谢作用机制 人类，基于临床数据的显着档案和在青少年londudinal的样本上的内脏档案 评估减肥手术（青少年）研究和体外人脂肪细胞实验模型。我们 假设减肥手术后的大型代谢变化提供了一个“自然实验” 放大原型肥胖原dde的影响，并且在内脏中DDE会减少降低 减肥手术后的体重指数和胰岛素抵抗以浓度依赖性方式（AIM 1）。 尽管我们知道，高剂量的DDE损害了动物模型中的热生成和胰岛素信号，但我们仍然 不知道这些机制是否是DDE在人类中的代谢破坏的基础。我们将评估效果 在人类主要脂肪细胞细胞系中这些途径上的DDE，这是一种实验模型 人类观察研究中不受控制的混淆的潜力，这也可能确定了新的 途径（目标2）。然后，我们将在人类的代谢组和转录组曲线中测试这些途径 使用层次建模方法（AIM 3），来自青少年研究参与者。最后，我们将整合 使用新型的潜在变量，来自人类和脂肪细胞细胞系中人类和脂肪细胞系中的DDE OMICS的结果 建模框架，以识别体重减轻较小且改善较少的青少年子组 减肥手术后的胰岛素抵抗，基于其DDE暴露和AT（AIM 4）中的多摩变概况。 拟议的研究将是第一个研究DDE毒性机制的人类研究， 使用脂肪组织特异性暴露和OMIC测量以及临床相关的代谢结果（例如 BMI和胰岛素抵抗。一个强大的跨学科研究团队为环境带来了专业知识 流行病学，减肥手术，毒理学，法律和生物统计学。我们的研究，整合体外和人类 观察方法有可能建立一个新的范式来研究亲脂性肥胖症 化学物质并促进我们对肥胖和2型糖尿病的环境贡献的理解。