核受体FXR调节脂肪分化的关键信号通路的发现及调控机理研究

Over-accumulation of white fat tissue can cause obesity, diabetes, cardiovascular diseases and other problems. Inhibiting the differentiation of white adipocytes and inducing white-to-brown fat conversion could antagonize obesity, and improve glucose tolerance and insulin sensitivity. In addition to the important roles in glucose and lipid metabolism, nuclear receptor FXR also plays important roles in adipocyte differentiation. However, the mechanism how FXR regulates the differentiation of adipocyte is still not clear. FXR agonist or overexpression of FXR can reduce the levels of blood glucose, lipids, and also body weight. But it's confusing that the body weight and epididymal fat pad of FXR knockout mice were significantly lower than those of wild type mice. In our preliminary study, we found a novel gene whose expression can be suppressed by nuclear receptor FXR. In the FXR knock-out mice, the expression of this novel gene in both brown and white adipose tissues was significantly elevated, accompanied by obvious body weight loss and reduced epididymal white fat pads. Knock down the expression of this gene can inhibit the differentiation of adipocytes and also the expression of series of brown fat cells markers. Therefore, we gave it the name FRAD (FXR target gene regulating adipocyte differentiation). In this project, we will focus on studying the novel gene FRAD, from its physiological functions in vivo, to the functional mechanism starting from the upstream of the signaling pathway of FRAD regulated by FXR, to the downstream of adipocyte differentiation and the conversion of white fat cells to brown fat cells regulated by FRAD. Furthermore, we will also study the function of FRAD in obesity mouse models. The study in this project will reveal a new pathway and mechanism for adipocytes differentiation, and also provide a new therapeutic target for obesity and related diseases.

体内白色脂肪积累过多会导致肥胖症、糖尿病、心脑血管疾病等系列问题。抑制白色脂肪细胞的分化和促进白色脂肪的褐色化，能拮抗肥胖、提高糖耐受性和胰岛素的敏感性。除在糖脂代谢中的重要作用外，核受体FXR与脂肪细胞的分化还存在密切的联系，但FXR是如何调控脂肪的分化，机理尚不明确。本课题前期研究发现了一个尚未命名的FXR新靶基因，该基因能被FXR抑制表达，敲低该基因表达能抑制脂肪细胞的分化，并显著下调褐色脂肪标志基因的表达，还能抑制PPARγ诱导的脂肪分化，我们给它命名为脂肪分化调节基因（FRAD）。本项目将以FRAD为研究对象，从研究FRAD在小鼠体内的生理功能开始，对FRAD的上游如何被FXR调控、下游如何调控脂肪分化和褐色化的信号转导机理进行系统的研究，并探索FRAD在肥胖症小鼠中的治疗功能。本研究将为脂肪的分化或褐色化机理的研究开辟新的信号通路，并为肥胖及相关疾病的治疗提供新的药物靶点。

核受体FXR (Farnesoid X Receptor)参与机体生长发育、新陈代谢等许多生理过程，与系列重大疾病如肥胖症、糖尿病、肿瘤、炎症、心血管疾病等有关。FXR的过表达或者FXR的激活剂能下调体内脂肪肝和血脂含量，FXR的激活剂处理肥胖症小鼠会减轻肥胖症小鼠的体重，降低血糖，降低血脂，降低体内脂肪/体重比，但是FXR调节脂肪分化的机理仍不明确。通过本课题的研究，我们发现了一个新的FXR靶基因孕酮诱导的蜕膜蛋白DEPP（Decidual protein induced by progesterone）。我们发现在FXR敲除鼠的白色脂肪组织与褐色脂肪组织中DEPP的表达明显高于野生型小鼠。本研究确定了DEPP是核受体FXR的靶基因。从DEPP与PPARγ、去乙酰化修饰酶的相互作用、翻译后修饰的调节等方面研究FXR调控的DEPP的功能分子机理。制备了DEPP基因敲除小鼠模型。并分析了该小鼠的各种生理指标。利用前白色脂肪细胞、原代前褐色脂肪细胞和DEPP基因敲除小鼠模型，研究了体外和体内脂肪细胞中白色脂肪标志基因和褐色脂肪标志基因的水平，以及DEPP缺失后白色脂肪分化或褐色化、原代褐色脂肪细胞的分化过程等分子机理，明确了DEPP与PRDM16、UCP1、PGC1α、PPARγ等控制脂肪细胞分化关键成员如何相互调控的信号通路分子机理。分别利用高脂诱导和低温刺激研究了DEPP在脂肪组织分化、脂肪积累和代谢、胰岛素敏感性、机体产热耗能方面的功能和分子机理。同时，还从中草药天然产物中发现了几种萜类化合物能通过结合FXR调节脂肪代谢功能。发现现有地平类抗高血压药物、以及一种临床二期试验阶段的抗炎药物vidofludimus也能通过结合FXR调节脂肪代谢。研究了这些新型FXR配体与靶标FXR结合的结构机理，并研究了它们在体内通过靶标FXR调节DEPP功能以及脂肪代谢和炎症反应的生理病理功能和分子机理。本项目通过对这个FXR新的靶基因DEPP的功能及机理研究，为阐明FXR对脂肪细胞的分化或褐色化机理的研究开辟新的通路，并为肥胖及相关疾病的治疗提供新的药物靶点。