Endocrine disruption by organotins in obesity and diabetes

描述（由申请人提供）：肥胖和相关代谢综合征疾病已成为全球范围的流行病。过度食用高热量食物和减少体力活动是普遍接受的肥胖症的原因。但环境因素是否会暴露出先前存在的遗传差异，或加剧饮食和运动的根本原因？“致肥假说”提出环境化学物质可扰乱脂质稳态、脂肪细胞发育和脂肪组织功能。在敏感的发育窗口期暴露可引起失衡，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已经将有机锡确定为一类新的肥胖候选物。有机锡是一组经过充分研究的环境内分泌干扰剂，被证明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，配体依赖性维甲酸X受体（RXR）和过氧化物酶体增殖物激活受体γ（PPARg）是有机锡如三丁基锡（TBT）的新的高亲和力分子靶点。RXR-PPARg信号传导是脊椎动物脂肪形成的关键组分。RXR还作为参与脂质、代谢和发育信号传导途径的许多其他核受体的共同异二聚体伴侣发挥更广泛的作用。我们已经提出，TBT对这些受体的有效作用是通过一种新的共价修饰发生的，并且不适当的激活有可能打击脂肪组织稳态的核心。初步结果表明，三丁基锡化合物在小鼠3 T3-L1脂肪形成模型中促进脂肪细胞分化，在体内调节已知的脂肪形成基因，并在子宫内暴露后增加小鼠的肥胖，与肥胖模型一致。我们假设三丁基锡化合物作为一种环境致肥剂，产前暴露可导致对新陈代谢的长期影响，使暴露个体易患肥胖和相关疾病。我们提出了三个具体的目标来验证这一假设：1）产前TBT暴露如何扰乱体内脂肪稳态？ 2)哪些分子相互作用对有机锡诱导的脂肪形成表型至关重要？ 3)有机锡和RXRs-PPARg之间的分子相互作用是什么？验证这一假设将提供一个范式转变，我们的评估肥胖相关的基因-环境相互作用从分子到整个动物水平。由于中心性肥胖在增加人群中代谢综合征疾病的风险方面起着关键作用，因此研究新的促成机制的拟议研究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.