Endocrine disruption by organotins in obesity and diabetes

描述(申请人提供)：肥胖和相关的代谢综合征疾病已经成为一种全球性的流行病。过度摄入高热量食物和减少体力活动是普遍接受的肥胖原因。但是，环境因素会暴露先前存在的遗传差异，或者加剧饮食和锻炼的根本原因吗？“肥胖症假说”提出，环境化学物质会扰乱脂类平衡、脂肪细胞发育和脂肪组织功能。在敏感的发育窗口期暴露会导致不平衡，导致永久性变化，从而导致脂肪储存增加。我们实验室的新工作将有机锡确定为一类新的肥胖候选物质。有机锡是一类研究广泛的环境内分泌干扰剂，可对脊椎动物和无脊椎动物的发育、激素生理和性别决定产生多效性影响。我们发现，配体依赖的维甲酸X受体(RXR)和过氧化物酶体增殖物激活受体γ(PPARg)是三丁基锡(TBT)等有机锡的新的高亲和力分子靶点。RXR-PPARg信号是脊椎动物脂肪形成过程中的重要组成部分。RXR还作为许多参与脂质、代谢和发育信号通路的其他核受体的共同异二聚体伙伴发挥着更广泛的作用。我们提出，TBT对这些受体的有效作用是通过一种新的共价修饰来实现的，并且不适当的激活可能会打击脂肪组织动态平衡的核心。初步结果表明，在小鼠3T3-L1成脂模型中，TBT促进脂肪细胞分化，调节体内已知的成脂基因，并在宫内暴露后增加小鼠的肥胖度，与肥胖模型一致。我们假设TBT是一种环境致肥源，产前暴露可能会对新陈代谢产生长期影响，使暴露于肥胖和相关疾病的个体容易患上肥胖症和相关疾病。我们提出了三个具体的目标来验证这一假说：1)产前TBT暴露如何扰乱体内脂肪的动态平衡？2)哪些分子相互作用对有机锡诱导的成脂表型至关重要？3)有机锡与RXRs-PPARg之间的分子相互作用是什么？这一假说的验证将使我们对肥胖相关基因-环境相互作用的评估从分子水平转变到整个动物水平。由于中心性肥胖在增加人类人群中代谢综合征疾病的风险方面起着关键作用，拟议中的研究一种新的致病机制与当前的公共卫生问题高度相关。

DESCRIPTION (provided by applicant): Obesity and associated metabolic syndrome diseases have become an epidemic of global proportions. Excessive consumption of calorie-dense food and diminished physical activity are generally accepted causal factors for obesity. But can environmental factors expose preexisting genetic differences or exacerbate the root causes of diet and exercise? The "obesogen hypothesis" proposes that environmental chemicals can perturb lipid homeostasis, adipocyte development and adipose tissue function. Exposure during sensitive developmental windows can induce imbalances resulting in permanent changes that result in increased fat storage. New work from our laboratory has identified organotins as a novel class of obesogen candidates. Organotins are a well-studied group of environmental endocrine disrupting agents demonstrated to cause pleiotropic effects on development, hormonal physiology and sex determination in vertebrates and invertebrates. We found that the ligand dependent retinoid X receptors (RXR) and peroxisome proliferator activated receptor gamma (PPARg) are novel high-affinity molecular targets of the organotins such as tributyltin (TBT). RXR-PPARg signaling is a critical component in vertebrate adipogenesis. RXR also serves a broader role as the common heterodimeric partner to many additional nuclear receptors involved in lipid, metabolic and developmental signaling pathways. We have proposed that the potent effects by TBT on these receptors occurs via a novel covalent modification and that inappropriate activation has the potential to strike at the heart of adipose tissue homeostasis. Initial results show that TBT promotes adipocyte differentiation in the murine 3T3-L1 adipogenic model, modulates known adipogenic genes in vivo, and increases adiposity in mice after in utero exposure, consistent with an obesogen model. We hypothesize that TBT acts as an environmental obesogen and that prenatal exposure can lead to long-term effects on metabolism, predisposing exposed individuals to obesity and related disorders. We propose three specific aims to test this hypothesis: 1) How does prenatal TBT exposure perturb adipose homeostasis, in vivo? 2) Which molecular interactions are critical for the organotin elicited adipogenic phenotype? 3) What are the molecular interactions between organotins and RXRs-PPARg? Validation of this hypothesis will provide a paradigm shift in our evaluation of obesity related gene-environment interactions from the molecular to the whole animal level. Since central adiposity plays a pivotal role in increasing the risk of metabolic syndrome diseases in human populations, the proposed research studying a novel contributing mechanism is highly relevant to current public health concerns.