肠道转录活化因子4（ATF4）调控机体代谢稳态的新功能及机制研究

Obesity and its associated metabolic diseases is highly popular in the whole world, while gut microbiota has a close relationship with body metabolism homeostasis, it may be new targets to prevent and treat obesity and its related metabolic diseases by regulating gut microbiota. Our previous study showed that leucine deficiency regulated glucose and lipid metabolism and improved insulin sensitivity associated with activated amino acid sensor proteins. The functions and underlying mechanisms of amino acid sensor proteins on regulating gut microbiota, however, has not been elucidated. Our previous work suggested that leucine deficiency significantly altered the structure of gut microbiota in mice, and the expression of ATF4 was also significantly increased in the gut of mice treated by leucine deficiency, these data implied that gut ATF4 may participate in regulating gut micribiota to influence metabolism homeostasis. However, the role of gut ATF4 in regulating microbiota has not been reported before. The aim of our current study is to elucidate the regulation role of gut ATF4 on microbiota and metabolism homeostasis by using gut ATF4 knock out mice, and to explain the underlying mechanisms based on the analysis of 16S rRNA sequencing technology, what’s more, we will further explore the pathway which is responsible for the expression of ATF4 in gut. Taken together, our work will demonstrate a novel function of gut ATF4 in regulating metabolism homeostasis, and provide new insights for the understanding of the molecular mechanisms and potential treatment targets for obesity and its related metabolic diseases.

肥胖等代谢性疾病在全球高度流行，肠道菌群与宿主的互作与机体代谢密切相关，调节肠道菌群有可能成为预防和治疗肥胖及相关代谢疾病的新型靶点。课题组前期研究发现亮氨酸缺乏调控脂代谢和改善胰岛素敏感性并激活氨基酸感应蛋白信号。目前氨基酸感应蛋白调控肠道菌群的作用及机制并不清楚。前期研究表明亮氨酸缺乏饮食明显改变小鼠肠道菌群结构，而感应蛋白ATF4在氨基酸缺乏模型小鼠肠道中表达显著增加，提示ATF4可能参与调控肠道菌群进而调控代谢稳态。目前肠道ATF4在调控机体代谢中的作用及机制还没有报道。本项目拟采用ATF4肠道特异敲除小鼠为模型，利用细菌16S rRNA测序深入分析ATF4对肠道菌群的调控，并利用不同营养条件的小鼠模型探讨ATF4的上游调控信号及生理意义，对肠道ATF4调节代谢稳态的作用与机制进行深入的研究。该项目将阐明肠道ATF4调控机体代谢稳态的新功能，为预防及治疗肥胖及代谢疾病提供新策略。

肠道菌群与机体代谢稳态密切相关，但分子机制尚不清楚。探究菌群变化及调控机制对改变机体的代谢稳态及治疗相关代谢性疾病具有非常重要的意义。课题组前期研究发现亮氨酸缺乏激活氨基酸感应蛋白转录活化因子4（ATF4），调控全身代谢稳态。研究表明ATF4参与多个组织的糖脂代谢和能量代谢调控，但肠道ATF4调控机体代谢稳态的作用及机制以及对肠道菌群的调控作用尚无报道。本项目研究发现，短期亮氨酸缺乏饮食处理的小鼠回肠和结肠中ATF4表达显著上调，且小鼠肠道中菌群分布及构成发生了显著的变化，并发现和体重脂肪变化正相关和负相关的菌群门类的变化。肠上皮细胞特异性敲除ATF4的小鼠体重显著降低，皮下脂肪，附睾脂肪和褐色脂肪重量均显著减少。另外，ATF4肠上皮敲除小鼠的血清甘油三酯水平显著降低，血糖水平也显著降低。进一步研究发现，ATF4肠上皮敲除小鼠脂肪降低是由于脂肪合成减少，脂质分解增加导致的。另外，敲除小鼠血清氨基酸水平变化显著，下丘脑神经肽的差异变化可能也是导致小鼠代谢表型变化的原因。除此之外，研究发现ATF4肠上皮敲除小鼠具有肠炎的症状。此项目明确了肠道ATF4调控机体代谢稳态的新功能，为预防和治疗肥胖等代谢性疾病提供新策略。