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

摘要 环境致肥者假说假定亲脂性持久性有机污染物(POPs)会累积 在脂肪组织(AT)中，并可扰乱代谢系统。然而，其潜在的分子机制 这些毒物对AT功能的影响仍然知之甚少。作为研究最多的持久性有机污染物，二氯二苯基- 二氯乙烯(DDE)，杀虫剂二氯二苯基三氯乙烷(DDT)的持久代谢物， 为评估亲脂性持久性有机污染物对代谢健康的影响提供了一个模型。几乎所有的美国儿童和 青少年有可检测到的DDE血液水平。尽管来自实验研究的大量证据表明 DDE扰乱代谢动态平衡，其潜在的人体代谢紊乱机制是 不清楚。因此，我们提出了一种新的研究设计，用于研究DDE代谢影响的机制。 人类，基于出色的临床数据档案和青少年时期的内脏AT样本 减肥外科(Teen-Labs)研究和体外人类脂肪细胞实验模型的评估。我们 假设减肥手术后的巨大新陈代谢变化提供了一个“自然实验”，它将 放大典型肥胖原DDE的作用，内脏AT中的DDE将减弱 体重指数和减肥手术后胰岛素抵抗的浓度依赖关系(目标1)。 尽管我们知道高剂量的DDE会损害动物模型中的产热和胰岛素信号，但我们仍然 不知道这些机制是否导致DDE对人类代谢的干扰。我们将评估影响 在人类原代脂肪细胞系中这些途径上的DDE的表达，这是一个将不受 人类观察性研究中不受控制的混杂的可能性，这也可能发现新的 路径(目标2)。然后我们将在人类AT的代谢组和转录组图谱中测试这些途径 来自青少年实验室的研究参与者，使用分层建模方法(目标3)。最后，我们将整合 使用一种新的潜变量对人类AT和脂肪细胞系进行DDE组学分析的结果 建模框架，以确定体重减轻较少且在以下方面改善较少的青少年亚组 减肥手术后的胰岛素抵抗，基于他们的DDE暴露和AT的多组学资料(AIM 4)。 这项拟议的研究将是第一项研究DDE对人体AT毒性机制的人体研究， 使用脂肪组织特异性暴露和基因组措施，以及临床相关的代谢结果，如 体重指数和胰岛素抵抗。一支强大的跨学科调查团队带来了环境方面的专业知识 流行病学、减肥外科、毒物学、组学和生物统计学。我们的研究，在体外与人类 观察性方法，有可能为研究亲脂性肥胖建立一个新的范式 这将有助于我们更好地了解环境对肥胖和2型糖尿病的影响。

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.