围产期维生素A缺乏致子代肥胖发生的分子机制研究

VitaminA deficiency and obesity are both common public health problems. The significance of vitamin A deficiency in the process of developing obesity has been gradually recognized in recent years. During the previous research, our research group has found that the serum vitamin A level of the obesity group is less than that of the normal weight group, which indicates that the lack of vitamin A is related to obesity. According to the animal experiment, when the perinatal female rats lack vitamin A, it has found that the weight of their offspring is higher than that of normal group. However, the specific mechanisms are not clear. Leptin can be the hormones which can suppresses appetite, and the resistance of the leptin in hypothalamus is the main reason of developing obesity. Our research group assumes that during perinatal period, the leptin signaling pathways of offspring’s in hypothalamus are destroyed, leading to resistance of the leptin. This phenomenon will change the activity of appetite regulation neurons in hypothalamus, leading to the imbalance of energy. In the end, obesity appears. The research will adopt to build the obesity rat model and the rats are in lack of vitamin A in perinatal period, at the same time, vitamin A also needs to be replenished. Then we begin to monitor the metabolic characteristics of each offspring group, discussing the differences between food intake and energy expenditure of each group according to the leptin responds and cold exposure experiments; then detecting the key molecular level of the leptin signaling pathways in hypothalamus of the offspring. We are gong to adopt siRNA in vitro, silencing the RXRα in nerve cells in hypothalamus, then we begin to observe the changes of signaling pathways of leptin. Our research can help people keep gaining insight into the effect of vitamin A on the organism, which will contributes to analyzing the mechanism of formation in obesity and looking for the new preventive measures.

维生素A（VA）缺乏和肥胖均为常见的公共卫生问题。近年来VA缺乏在肥胖发生中的重要性逐渐被认识。本课题组前期研究发现，肥胖人群血清VA水平低于正常体重组，提示VA缺乏与肥胖有关。动物实验发现围产期VA缺乏雌鼠所产子代的体重高于VA正常组的子代，但具体机制不明。瘦素是具有抑制食欲作用的激素，下丘脑瘦素抵抗是肥胖发生的主要原因。本课题假设围产期VA缺乏的子代下丘脑瘦素信号通路受损，产生瘦素抵抗，改变下丘脑食欲调控神经元的活性致能量平衡失调，最终引起肥胖。研究拟建立围产期VA缺乏的大鼠模型并实施VA补充，监测子代的代谢特征，从瘦素响应和冷暴露实验探讨子鼠进食量和能量支出的差异；检测子鼠下丘脑瘦素信号通路中关键分子的表达水平。体外拟采用siRNA方法沉默下丘脑神经元细胞中维甲酸X受体RXRα，观察瘦素信号通路的变化。本研究有助于深入了解VA的作用，对解析肥胖形成的机制及寻找新的预防措施有重要价值。

维生素A（VA）缺乏和肥胖是常见的公共卫生问题。近年来VA缺乏在肥胖发生中的重要性逐渐被认识。本研究主要内容是观察和探讨围产期VA缺乏对子代肥胖形成和下丘脑瘦素抵抗的影响涉及的潜在分子机制。在动物实验方面，本研究建立了围产期VA缺乏的大鼠模型并实施VA补充，监测仔鼠血清中与肥胖相关的代谢指标的变化以及子代下丘脑瘦素代谢通路的变化。研究发现仔鼠12周龄时，VAD组的TG水平>VAS组>VAN组；VAD组的HDL-C水平显著低于VAN组和VAS组，VAN组和VAS组间没有显著性差异。三组间下丘脑代谢通路中LepR、PPARγ的mRNA表达水平没有显著性差异；VAD组的RXRa、POMC的mRNA的表达水平显著低于VAN组和VAS组，VAN组和VAS组间没有显著性差异。同时，仔鼠12周龄时三组间下丘脑中VAD组的RXRa、POMC的蛋白表达水平显著低于VAN组和VAS组，VAN组和VAS组间没有显著性差异。在细胞实验方面，我们在体外培养下丘脑神经元细胞株（GT1-7细胞株）并采用 siRNA 技术沉默下丘脑神经元细胞中的维甲酸X受体RXRα（RXRα-siRNA腺病毒感染GT1-7细胞后用1μmol/L 的9-cis RA处理24h）。分为：空白对照组、9-cis RA处理组和9-cis RA+RXRα沉默组。提取不同处理组细胞总RNA和蛋白，从基因和蛋白水平检测RXRα以及瘦素信号传导相关分子LepRb、Jak2、pJak2、STAT3、pSTAT3 等的表达水平。我们发现，9-cis RA+RXRα处理组RXRα mRNA表达水平显著低于对照组和9-cis RA处理组，9-cis RA处理组的表达水平显著高于对照组；9-cis RA+RXRα沉默组的p-Jak2、LepR蛋白表达水平显著低于对照组和9-cis RA 处理组，9-cis RA 处理组与对照组之间无显著差异。9-cis RA+RXRα处理组p-STAT3的蛋白表达水平显著低于对照组和9-cis RA处理组。本研究表明围产期VA缺乏对子代肥胖形成可能机制之一是通过下丘脑RXRα蛋白表达降低使下丘脑产生瘦素抵抗导致。这有助于深入了解VA的作用，对探讨肥胖形成的机制及寻找新的预防措施具有重要价值。