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

项目摘要 肥胖是一个严重的公共卫生问题，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）每年为美国医疗保健增加2000多亿美元 成本目前肥胖症的临床范例是能量摄入与能量消耗之一，临床上， 管理重点是饮食和锻炼。饮食和运动是肥胖的重要因素，特别是 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 2.3 2006年的体重指数比1988年高出1.5kg/m2，即使在热量摄入和能量消耗相当的情况下。 新出现的证据支持暴露于内分泌干扰化学品（EDCs）的重要作用， 肥胖我们发现三丁基锡（TBT）是一种环境“致肥剂”--一种导致体重增加的化学物质， in vivo.子宫内暴露于环境相关水平的三丁基锡化合物增加了脂肪储存重量，重新编程 间充质干细胞有利于脂肪形成的命运，并在F1-F4中引起非酒精性脂肪肝疾病 男性后代我们在两个独立的实验中复制了这些跨代表型， 当膳食脂肪增加时，F0 TBT处理动物的雄性F4后代变得肥胖。这种脂肪 在动物恢复正常的低脂肪食物后持续存在。TBT处理的动物及其后代 对禁食诱导的脂肪减少有抵抗力，表明这些动物不能在相同程度上动员脂肪 作为禁食期间的对照。我们发现，TBT处理母鼠的F4雄性后代的脂肪表现出持续的 在包含重要代谢基因（如Lep基因）的区域，DNA低甲基化增加， 瘦素mRNA表达，血浆瘦素水平升高，脂肪中这些低甲基化区域较少 在F3/F4雄性的精子染色质中可接近。我们认为这些动物表现出一种跨代的 由染色质结构和可接近性改变引起的“节俭表型”。我们假设TBT暴露 在多代中修改表观基因组，使动物对体重增加敏感，这种“节俭” 增加的膳食脂肪暴露或加剧了“表型”。提出了两个具体目标：1）如何 三丁基锡化合物暴露加剧了“完全西方饮食”的影响，导致体重增加？（2）技术性贸易壁垒如何 暴露使动物抵抗脂肪损失？探讨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。这项研究将揭示哪些分子机制 可能是肥胖的影响的基础，以及西方饮食模式如何与肥胖接触相互作用， 易患脂肪增加，并促进肥胖的跨代编程。这将极大地告知 临床医生和公众在理解个体对肥胖的易感性以及如何最好地 治疗和预防在个人。这项研究的成功完成将阐明 外源性化学物质对肥胖作用的潜在机制，并可能提供关于如何影响肥胖的见解。 肥胖症的流行是可以减少的。

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.