ATF4调控脂肪细胞分化及糖脂代谢的作用及机制研究

Obesity is a worldwide health problem and finding effective strategies in the preventiaon and treatment of obesity has been a long-term goal in life science research. Adipocyte differentiation has been shown to play a significant role in the development of obesity and adequate control of this process is very important in the prevention of obesity, however, mechanisms underlying adipocyte differentiation is still largely unknown. Our previous work have shown that deletion of activating transcription factor (ATF)4 in mice substantially reduces adipocyte cell volume and decreases expression of adipogenesis genes including fatty acid synthase and stearoyl-CoA desaturase 1. Furthermore, knocking down expression of ATF4 significantly inhibits the ability to differentiate into mature adipocyte in mouse embryonic fibroblasts and several other preadipocyte cell lines including 3T3-L1. Based on these results, we hypothesized that ATF4 plays a key role in the regulation of adipocyte differentiation. To test this possibility, global and tissue specific ATF4 deletion mice and multiple preadipocyte cell lines, as well as adenovirus-mediated gene overexpression and knockdown techniques, will be used in current study. We will also investigate the metabolic phenotypes resulting from deletion of ATF4 in adipose tissues and elucidate underlying mechanisms. Identifying a role of ATF4 in the regulation of adipocyte differentiation and metabolism is not only important for the understanding of regulation of lipid and glucose metabolism, but also might provide important hints for the prevention and treatment of obesity and associated metbolic diseases.

肥胖在全球呈流行趋势，如何有效预防和治疗肥胖已成为生命科学领域的关键问题。而脂肪细胞分化在肥胖发生过程中扮演重要角色，控制脂肪细胞的分化对于预防肥胖具有非常重要的意义，然而, 人们对脂肪细胞的分化机制还知之甚少。申请人前期工作发现ATF4全身基因敲除可显著减少小鼠脂肪细胞面积并降低FAS、SCD1等生脂基因的表达；此外敲除ATF4基因还可以显著抑制MEF、3T3-L1等前体脂肪细胞系的脂肪分化能力，提示ATF4可能在脂肪分化中扮演着重要角色。为验证该可能性并阐明分子机制，本项目拟利用ATF4全身及脂肪组织特异性基因敲除小鼠及多种前体脂肪细胞模型，结合腺病毒基因过表达和敲除技术等手段，对ATF4调节脂肪分化和糖脂代谢的生物学作用与分子机制进行系统深入研究。这些工作成果将深化人们对ATF4调节脂肪细胞分化机制的理解，拓展糖脂能量代谢基础理论的内涵与外延，并为预防和治疗肥胖提供坚实的理论依据。

肥胖在全球呈流行趋势，如何有效预防和治疗肥胖已成为生命科学领域的关键问题。脂肪细胞分化在肥胖发生过程中扮演重要角色，控制脂肪细胞的分化对于预防肥胖具有非常重要的意义，然而人们对脂肪细胞的分化机制并不十分清楚。申请人前期工作发现ATF4全身基因敲除可显著减少小鼠脂肪细胞面积并降低FAS,SCD1等生脂基因的表达，提示ATF4可能在脂肪分化中扮演着重要角色。本项目利用多种细胞系和组织特异性敲除小鼠对这一可能性进行了验证并阐明其机制。我们研究发现，3T3-L1前脂肪细胞分化过程中ATF4表达发生变化；过表达ATF4能够显著促进3T3-L1前脂肪细胞的分化；敲除ATF4将显著抑制3T3-L1前脂肪细胞的分化；ATF4影响脂肪细胞的分化是通过调节Wnt10b表达来实现的。此外，我们还探讨了ATF4在脂肪组织、下丘脑和肝脏中调控能量稳态和糖脂代谢的新功能及分子机理。这些工作成果将深化人们对ATF4生理功能的理解，拓展糖脂能量代谢基础理论的内涵与外延，并为预防和治疗肥胖提供坚实的理论依据。