基于AT1R-CFTR蛋白复合体内化研究AngII调控内脏脂肪细胞分化的新机制

Abnormal visceral fat differentiation is an important risk factor for metabolic diseases. AngII inhibits visceral fat cell differentiation through AT1R, but its downstream mechanism is still unclear. The pre-experiment results showed that the expression of CFTR was down-regulated in the visceral adipose tissue (VAT) of obese mice, and the overexpression of CFTR promoted the differentiation of preadipocytes. AngII reduces CFTR activity/expression which can be reversed by AT1R inhibitor. AngII promote the internalization of CFTR, and CFTR and AT1R combined together. Therefore, our hypothesis is that CFTR will be internalized under the stimulation of AngII by forming AT1R-CFTR protein complex, and then mediate the inhibitory effect of AngII on the differentiation of visceral adipocytes. Based on the above, this project intends to apply pre-adipocyte-specific CFTR transgenic mice and CFTR agonists to clarify the role of CFTR in regulating VAT adipocyte differentiation, and clarify AngII promotes CFTR internalization through AT1R-CFTR protein complex and thus regulate its expression and activity. This study will systematically evaluate the role of CFTR in the differentiation of visceral adipose cells regulated by AngII, so as to provide laboratory evidence for finding new targets for the prevention and treatment of metabolic diseases caused by central obesity.

内脏脂肪分化异常是代谢相关疾病的重要危险因素，AngII通过AT1R抑制内脏脂肪细胞分化，但其下游机制尚不清楚。预实验结果发现CFTR在肥胖小鼠内脏脂肪组织（VAT）表达下调，过表达CFTR促进前脂肪细胞分化；AngII降低CFTR活性/表达且可被AT1R抑制剂逆转；CFTR与AT1R相互结合且AngII可引起CFTR内化。因此提出假设，CFTR通过形成AT1R-CFTR蛋白复合体，在AngII刺激下发生内化，进而介导AngII对内脏脂肪细胞分化的抑制作用。在上述基础上，本课题拟应用前脂肪细胞特异性CFTR转基因小鼠和CFTR激动剂明确CFTR调控VAT脂肪细胞分化的作用，并阐明AngII通过AT1R-CFTR蛋白复合体促进CFTR内化以调控其表达及活性。本研究将系统评估CFTR在AngII调控的内脏脂肪细胞分化中的作用，为寻找防治中心性肥胖引起的代谢性疾病的新靶点提供实验室证据。

内脏脂肪分化异常和脂肪炎症是代谢相关疾病的重要危险因素，AngII通过AT1R抑制内脏脂肪细胞分化，但其下游机制尚不清楚。本研究实验发现CFTR在肥胖小鼠内脏脂肪组织(VAT)表达下调，过表达CFTR促进前脂肪细胞分化，AngII降低CFTR活性/表达且可被AT1R抑制剂逆转，CFTR与AT1R相互结合且AngII可引起CFTR内化，阐明了CFTR通过形成AT1R-CFTR蛋白复合体，在AngII刺激下发生内化进而介导AngII对内脏脂肪细胞分化的抑制作用，明确了CFTR参与内脏前脂肪细胞分化并初步揭示其机制。在此基础上，进一步从脂肪炎症角度探索了CFTR通过TLR-4/MyD88/IRAK4信号通路参与脂肪炎症信号转导机制，为寻找防治中心性肥胖引起的代谢性疾病的新靶点提供实验室证据。

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