氧化应激在IP-TFA影响人脂肪细胞内分泌功能中的作用及与儿童肥胖关系研究

The endocrine dysfunction of adipose tissue plays a key role in the progress of abnormal lipid metabolism, diabetes, cardiovascular disease and other complications caused by obesity. Differences of dietary composition, especially the intake of industrially produced trans fatty acids (IP-TFA), which do harm to health, have immeasurable impact on the development of obesity. But less were well understood about the specific mechanism between IP-TFA and obesity development. Since obese people are often associated with elevated levels of oxidative stress. Our previous experimental results found that, exposing human adipocytes to EA can affect endocrinal function, cause a decline in total antioxidant capacity and down-regulate the expression of Nrf2, a key transcription factor in antioxidant response in human adipocytes. Taking into account the characteristics of children and adolescents in the special period of growth and development, we make the following assumptions: IP-TFA can affect the endocrine function of the human adipocytes, and oxidative stress may play a key role in that process; sexual development might affect the antioxidant capacity of children and adolescents. We intend to verify the above hypothesis by studying in vitro experiments, the overall animal models and normal, overweight and obesity children and adolescents, and try to make new breakthroughs in the study of the mechanism of the biological effects of IP-TFA.

脂肪组织内分泌功能紊乱在肥胖所致血脂代谢异常、糖尿病、心血管疾病等各种并发症的进展中起着关键作用。膳食营养素成分差异，尤其是工业来源反式脂肪酸（IP-TFA）的摄入对人体有健康危害，在肥胖的发生发展中具有无法估量的影响。但人们对IP-TFA与肥胖发生发展的影响机制了解较少。由于肥胖患者常伴随机体氧化应激水平升高。我们前期实验结果发现，暴露于反油酸致人脂肪细胞内分泌功能受影响，引起人脂肪细胞总抗氧化能力下降，抗氧化应答关键转录因子Nrf2的表达下调。结合儿童青少年处于生长发育特殊时期的特点，我们提出如下假设：IP-TFA能够影响人脂肪细胞的内分泌功能，氧化应激机制可能在其中起到关键作用；性发育可能会对儿童青少年的抗氧化能力有影响。本项目拟以体外细胞实验、整体动物模型和正常、超重、肥胖儿童青少年人群为研究对象，对上述假说进行验证，试图在IP-TFA生物学效应的作用机制研究上取得新突破。

膳食工业来源反式脂肪酸（IP-TFA）的摄入对人体有健康危害，在肥胖的发生发展中具有无法估量的影响。本项目以氧化应激为焦点，通过体外实验、整体动物实验和现场流行病学调查的研究方法，探讨整体动物模型IP-TFA暴露的生物学效应，及氧化应激与儿童青少年肥胖之间关系，并综合评价IP-TFA暴露引发的人脂肪细胞内分泌功能失调、以及IP-TFA诱导的各器官系统氧化损伤等的可能关系。.本项目以IP-TFA的代表物反油酸（EA）作为干预物观察对人脂肪细胞内分泌功能影响并探索其可能机制。摸清EA暴露的最大安全剂量为100μmol/L，暴露24h后可影响人脂肪细胞内分泌功能，致IL-6、MCP-1这两种脂肪因子表达显著升高，SDF-1与XCL1的表达显著降低。EA暴露可引起人脂肪细胞发生氧化应激，总抗氧化能力下降。EA暴露浓度升高可造成人脂肪细胞葡萄糖摄取能力下降，内质网应激通路IRE1-α—JNK—IRS-1相关蛋白磷酸化可能起关键作用。.为更好地模拟实际生活情况，我们以植物黄油和猪油为实验材料依据文献自行配制高脂饲料开展体内研究观察膳食摄入IP-TFA对生长发育阶段机体的影响。结果发现虽然摄入不同髙脂饲料可致相同肥胖结局，外周和内脏脂肪组织呈炎性状态，但炎性因子的分泌有部位特异性，自噬相关蛋白表达也有差异。.人群调查结果显示，受调查地区儿童青少年的超重肥胖问题突出。肥胖儿童血压显著高于正常和消瘦儿童；男女童的糖脂代谢紊乱表现不一致；肥胖致机体氧化应激水平升高，肥胖女童损伤状况明显，肥胖男童突出表现为总抗氧化能力下降。超重与肥胖组儿童青少年的生活质量低于正常组，差异突出表现在社会心理功能和生活环境方面。受调查儿童家庭全人群高脂饮食、饮酒等不良生活方式调查显示，超重人群饮酒可能与会影响左心室射血功能，随着饮酒量增加患糖尿病风险增高，提升了本研究在人群健康及肥胖相关疾病预防关口前移中的重要性。