多溴联苯醚双向调节脂肪细胞分化及胰岛素敏感性的机制研究

Obesity has become a global public health problem. In cellular level obesity means the increasing of adipose cell number and volume, which is the result of abnormal adipocyte differentiation. Peroxidase body proliferation activated receptor gamma (PPAR gamma) is the key factor of the regulating adipocyte differentiation,which can promote the process of adipocyte differentiation and the style of its regulating active is two-way in u-shaped relation. PPARγcan be induced in a variety of environmental endocrine disruptors. Polybrominated diphenyl ethers (PBDEs), a new type of environmental endocrine disruptors, in recent years have been found that in the early development of organisms PBDEs exposure was associated with birth weight, but the related direction has not yet been determined. To clarify whether PBDEs has a two-way adjustment function of adipocyte differentiation and insulin sensitivity and the mechanism through PPAR gamma, the multiple concentration gradient of BDE-47, BDE-153 and BDE-183 will be chosen to treat the PPAR gamma knockout mice and wild-type mice and 3T3-L1 cells to provide theoretical basis for the prevention and intervention on the onset of obesity and insulin resistance and related diseases.

肥胖已成为全球公共卫生问题。细胞水平上肥胖是脂肪细胞数目增多和体积增大，即脂肪细胞异常分化的结果。过氧化物酶体增殖子激活受体γ（PPARγ）是调节脂肪细胞分化的关键因子，可促进脂肪细胞的增值和分化，其活性与脂肪细胞分化及胰岛素抵抗呈双向调节的U型关系，并可被多种环境内分泌干扰物诱导。多溴联苯醚（PBDEs）是新型环境内分泌干扰物，近年多项研究发现生物体发育早期暴露PBDEs与出生体重相关，但两者相关方向却没有定论。为阐明PBDEs是否通过PPARγ介导具有双向调节脂肪细胞分化及胰岛素敏感性的作用和机制，选用多个浓度梯度BDE-47、BDE-153和BDE-183，应用PPARγ基因敲除型小鼠及同窝野生型小鼠模型和小鼠3T3-L1前脂肪细胞为研究对象，从体内和体外两个层面，探讨PBDEs对脂肪细胞分化及胰岛素敏感性的作用规律和机制，为肥胖和胰岛素抵抗及其相关疾病的发病和预防干预提供理论依据。

超重和肥胖是全球重大公共卫生挑战。与治疗已发生的肥胖相比，预防体重的过度增加是花费更少、更加高效的方法。细胞水平上肥胖是脂肪细胞异常分化的结果，阐明脂肪细胞的分化与增殖机理，可达到对脂肪沉积的预防调控。过氧化物酶体增殖子激活受体γ（PPARγ）是调节脂肪细胞分化的关键因子，可促进脂肪细胞的增值和分化，其活性与脂肪细胞分化及胰岛素抵抗呈双向调节的U型关系，并可被多种环境内分泌干扰物诱导。近年来多项研究发现生物体发育早期暴露多溴联苯醚（PBDEs）与出生体重相关，但两者相关方向却没有定论。为阐明PBDEs是否通过PPARγ介导发挥双向调节脂肪细胞分化及胰岛素敏感性的作用和机制，本研究选用生物体含量最多的BDE-47、BDE-153和BDE-209为代表性受试物，设计多个浓度梯度，应用C57BL/6小鼠模型和小鼠3T3-L1前脂肪细胞为研究对象，从体内和体外两个层面进行探索，结果发现PBDEs能够诱导脂肪细胞分化异常分化、脂肪细胞因子分泌异常，胰岛素敏感性下降，并从分子生物学及生物信息学角度初步阐明了PBDEs可能通过激活PPAR-γ活性、AMPK 等代谢通路相关基因发挥毒性作用；同时发现不同剂量PBDEs诱导脂肪细胞分化及PPAR-γ表达存在非线性的“U”型关系。这些研究成果为阐释PBDEs对生物体的一系列毒性作用机制和相关代谢性疾病的预防与治疗提供了新的思路与依据。