引发饮食过量的环境性肥胖原的鉴别及分子研究

Obesity is a global epidemic with rising trends in Asian countries, including China and Hong Kong. Because obesity is closely associated with chronic diseases, such as type 2 diabetes and cardiovascular diseases, the increase in obesity corresponds to a rise in mortality rates. There is growing epidemiological evidence indicating a positive correlation between the exposure of human population to endocrine-disrupting chemicals (EDCs, chemicals that affect hormone systems) and body weight, suggesting a possible role of EDCs in increasing obesity rates. The “obesogen hypothesis” proposes that exposure to a subset of these chemicals (obesogens) disrupts the body’s weight-control mechanisms and ultimately increases obesity. To date, most of the widely known obesogens are those that directly increase adipogenesis and lipid accumulation, while the ones which contribute to overeating (a major non-genetic cause of obesity) are understudied. .Leptin is an adipocyte-derived hormone that plays a key role in regulating food intake and inhibits appetite by decreasing the activity of the orexigenic NPY/AgRP/GABA neurons and increasing the activity of the anorexigenic POMC/CART neurons in the hypothalamus. Leptin action is exerted through its binding to the leptin receptor (OB-R) expressed on the surface of these neurons. Interestingly, chronically elevated leptin levels in “non-genetic obesity” individuals fail to cause appetite inhibition. This apparent leptin ineffectiveness (leptin resistance) is considered an important predisposing factor for diet-induced obesity (DIO). Although the concept of leptin resistance is widely accepted, its underlying mechanisms remain elusive. However, mounting evidence suggests that defective leptin transport across the blood-brain barrier (BBB) and disrupted hypothalamic leptin signaling are the potential causes for leptin resistance. Because leptin receptor (OB-R) plays an important role in regulating leptin transport and leptin signaling, it is highly likely that any disruption in OB-R activation will lead to leptin resistance. We hypothesize that certain environmental chemicals could act as leptin antagonists to enhance or promote obesity (as a result of leptin resistance) by the disruption of OB-R activity. .This study aims to conduct a screening program against a chemical library of representative environmental compounds (using biophysical and cell-based assays) to identify environmental chemicals that act as leptin antagonists. Chemicals identified by the screening program will be further tested in zebrafish to determine whether early developmental exposures to these chemicals could potentially lead to leptin resistance and DIO in adult life. We anticipate that the results of the proposed study will provide important new insights into the role of exposure to environmental chemicals in the development of obesity and thereby open new perspectives for the formulation of effective preventive strategies against obesity.

肥胖是一种全球性流行疾病，近年来有发病率上升的趋势。肥胖与慢性疾病密切相关，其发生率增加可引起公众死亡率上升。流行病学证据表明，内分泌干扰物有增加肥胖发生率的可能性。瘦素可减少下丘脑中促进食欲的NPY/AbRP/GABA神经元活性和增加食欲减退的POMC/CART神经元活性，在调节食物摄取和抑制食欲中起着关键的作用。瘦素耐受被认为是饮食诱导性肥胖的重要易感因素，但潜在机制仍未明确。由于瘦素受体在调节瘦素转运和瘦素信号传导中起着重要的作用，任何受体激活过程的阻断都可能导致瘦素耐受发生。我们假设，在瘦素受体激活阻断过程中，某特定的环境化学物质可作为瘦素拮抗剂而导致瘦素耐受。本研究旨在通过高通量筛选、BRET分析和斑马鱼表型筛查逐步找出可作为瘦素拮抗剂的环境化学物质，以确定其对引发饮食诱导性肥胖的可能性。该研究将为环境暴露化学物质在肥胖发展过程的作用提供新见解，有助于预防和抑制肥胖策略的制定。

越来越多的流行病学证据表明，人类暴露于内分泌干扰物（EDCs，影响激素系统的化学物质）与体重之间存在正相关关系，这表明EDCs可能在增加肥胖率方面发挥作用。“肥胖原假说”指出，暴露于这些化学物质（肥胖原）会破坏人体的体重控制机制，最终导致肥胖。本研究分为三个阶段，目的是以海洋青鳉鱼为模型，阐明肥胖原假说的潜在分子机制。在第1阶段，我们对一个具有代表性的环境化合物的化学库（使用计算建模方法）进行了计算机筛选程序，以识别可能作为瘦素拮抗剂的环境化学品（内分泌干扰物）。瘦素是一种脂肪细胞源性激素，在食物摄取（或食欲）调节中起关键作用，并通过其与食欲素（GABA）和厌食（POMC）神经元表面表达的瘦素受体（OB-R）的结合发挥作用。在第2阶段，我们采用细胞试验（即MCF-7细胞增殖试验和STAT3试验）来测量此前已通过第1阶段计算模型验证的9种化学物质对抑制瘦素介导的信号转导的抑制作用；在STAT3试验中，只有一种化合物2-溴-α-麦角隐亭甲磺酸酯（化合物2B）能显著抑制瘦素诱导的荧光素酶活性。在第3阶段，进行海洋青鳉鱼胚胎的化合物2B暴露实验，以确定早期发育暴露于该化学物质是否可能导致成年期瘦素抵抗和饮食诱导肥胖（DIO），数据将在2020年7月或8月公布。此外，用RNA-seq对注射化合物2B的成年雄性海洋青鳉鱼（6个月龄）的性腺进行转录分析。对450个性腺差异表达基因（DEGs）的生物信息学分析表明，暴露于化合物2B改变了与调节干细胞多能性的信号途径相关的基因簇的表达，以及控制钙信号、cAMP信号和Wnt信号的途径，这些途径已知在调节脂肪代谢和潜在肥胖中起作用。

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