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

项目总结 肥胖是一个严重的公共卫生问题，很大程度上是因为肥胖和相关的疾病(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2000多亿美元 成本。目前肥胖症的临床治疗模式是能量摄入与能量消耗的对比，临床 管理层的重点是饮食和锻炼。饮食和锻炼是导致肥胖的重要因素，尤其是 能量密集的西方饮食模式，但它们并不能完全解释肥胖的流行。美国成年人是 即使在卡路里摄入量和能量消耗相当的情况下，2006年的BMI也比1988年高2.3公斤/平方米。 新出现的证据支持暴露于内分泌干扰物(EDCs)在 肥胖。我们发现三丁基锡(TBT)是一种环境“肥胖源”--一种会导致体重增加的化学物质。 在活体内。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 间充质干细胞在F1-F4中有利于成脂和引起非酒精性脂肪性肝病 雄性后代。我们在两个独立的实验中复制了这些跨代表型，并发现 当饲料脂肪增加时，F0 TBT处理组的雄性F4后代变得肥胖。这些肥肉 在动物恢复正常的低脂饮食后，持续存在。经TBT处理的动物及其后代 对禁食诱导的脂肪减少具有抵抗力，这表明这些动物不会在相同程度上调动脂肪 作为禁食期间的对照。我们发现，TBT处理过的母鼠的F4雄性后代的脂肪表现出持久性 包括重要代谢基因的区域的DNA低甲基化增加，如Lep基因 瘦素mRNA表达，血浆瘦素水平升高，以及脂肪中这些低甲基化区域较少 可在F3/F4雄性精子染色质中获得。我们提出这些动物表现出一种跨代的 “节俭表型”是由染色质结构和可及性改变引起的。我们假设TBT暴露于 在多个世代中修改表观基因组，使动物对体重增加敏感，这是一种节俭 表型“是由于膳食脂肪的增加而显露或加重的。提出了两个具体目标：1)如何 TBT暴露加剧了“完全西方饮食”导致体重增加的影响？2)TBT是如何 暴露在空气中会让动物抵抗脂肪流失吗？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。拟议中的研究将揭示哪些分子机制 可能是肥胖的影响以及西方饮食模式如何与肥胖暴露相互作用的基础。 倾向于增加肥胖，促进肥胖的跨代规划。这将极大地促进 临床医生和公众在了解个人对肥胖的易感性以及如何最好地理解肥胖方面的想法 在个人中进行治疗和预防。这项研究的成功完成将照亮分子 外来化学物质在肥胖中作用的潜在机制，并可能为深入了解 肥胖症的流行可以得到遏制。

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.