脂肪组织LBP通过PPARγ调节胰岛素抵抗的作用和机制研究

Inflammation plays a critical role in the pathology of obesity-associated metabolic disturbances. Lipopolysaccharide-binding protein (LBP) could bind to lipopolysaccharide (LPS) thereby initiating an innate host response. Elevated circulating LBP have previously been reported to be associated with obesity and related disorders though the mechanism is far from clarified. In our previous studies, we found that adipose is the main source of variation in the concentration of circulating LBP after high-fat feeding. And the expression of LBP and peroxisome proliferator activated receptors gamma (PPARγ) were inversely correlated in adipose tissue. In vitro, treatment with LPS led to an increase in LBP in 3T3-L1 cells in parallel with decrease expression of PPARγ and phosphorylation of mammalian target of rapamycin (mTOR). Based on our previous findings, we assumed that decreased LBP would result in improvement of adipocyte function and insulin resistance (IR), by regulating the AMPK- and PI3K-mTOR-PPARγ signaling pathways. In the present study, in vitro we would like to adopt the 3T3-L1 preadipocytes and in vivo to use obese and insulin resistant mice models induced by high fat diet, using the biochemical and immunological methods, to see whether the decreased LBP in adipose tissue could play a key role in the improvement of insulin sensitivity, and try to find a new molecular target for protecting against obesity and IR.

炎症在肥胖及其相关的代谢性疾病的发生、发展中发挥了重要的作用。脂多糖结合蛋白（LBP）可通过与脂多糖（LPS）结合来调控炎症反应。既往研究证实，LBP 与肥胖及代谢异常密切相关，但其机制目前尚不十分清楚。而我们的前期研究进一步表明，在高脂喂养后，LBP分泌的变化主要来源于脂肪组织。且在脂肪组织中LBP和过氧化物酶增殖物活化受体γ（PPARγ）的表达呈负相关。而在体外研究中予LPS刺激脂肪细胞后，LBP表达升高，伴随着PPARγ的表达及哺乳动物雷帕霉素靶蛋白（mTOR）磷酸化下降。由此我们提出，抑制脂肪组织LBP能够通过激活mTOR通路，增高PPARγ的表达和活性而增加机体代谢进而改善胰岛素抵抗（IR）。本研究拟利用3T3-L1细胞及高脂饮食诱导的肥胖小鼠模型，借助生物化学、免疫学等技术，观察脂肪组织LBP水平的改变在改善IR方面的作用及其机制，以期为肥胖、IR寻找到有力的干预靶点。

我们基本完成了本项目的各项研究目标和研究内容，也获得了原创性的成果，所取得的研究成果简述如下，该项目研究内容已基本完成撰稿，正待投稿：.项目的主要研究目标：.炎症在肥胖及其相关的代谢性疾病的发生、发展中发挥了重要的作用。脂多糖结合蛋白（LBP）可通过与脂多糖（LPS）结合来调控炎症反应。本研究拟明确脂肪组织LBP水平的改变在改善胰岛素抵抗（IR）方面的作用及其机制，以期为肥胖、IR寻找到有力的干预靶点。.发现的重要研究成果：.在3T3-L1或小鼠脂肪组织中特异性敲低LBP，可以激活PI3K/Akt，抑制AMPK，进而激活 mTOR 通路，增加 PPARγ 的表达和活性，提高糖脂代谢、葡萄糖利用及胰岛素敏感性。而予mTOR抑制剂雷帕霉素、PPARγ 的选择性抑制剂 GW9662处理3T3-L1细胞后敲低LBP对脂肪代谢活性的改善作用消失。.研究结论：.抑制脂肪组织 LBP 能够通过激活 mTOR 通路，增高 PPARγ 的表达和活性，从而改善肥胖。