热休克蛋白 70（HSP-70）在肥胖发生中的作用和机制研究

Obesity is a systemic chronic inflammatory state with a high level of oxidative stress. Under a stress condition, HSP-70 was found to be translocated from the cytoplasm to the lipid droplet surface in fat cells in in-vitro experiments. Animal studies also showed that HSP-70 was able to fight against fat accumulation. However, it remains unclear whether HSP-70 could affect the development of obesity through regulating fat metabolism and/or preadipocyte proliferation directly. To understand the role and mechanisms of HSP-70 in the regulation of obesity, we.first explore how HSP-70 affects and regualtes preadipocyte proliferation, adipogenesis and lipolysis using small interfering RNA and plasmid overexpression in in-vitro experiments; then, we further confirm the role of HSP-70 in the development of obesity induced by high fat diet and explore the potential mechanism in animal experiments. Based on the evidence obtained from both in-vitro and in-vivo experiments, we aim to uncover the role and mechanisms of HSP-70 in regulating fat metabolism and affecting the occurrence of obesity, providing a theoretical basis and a new target for the prevention and treatment of obesity.

肥胖严重危害着人类健康，已成为全球性的公共卫生问题。肥胖被认为是一种慢性炎症、氧化应激状态。研究发现，应激能使脂肪细胞内的热休克蛋白70 (HSP-70)从胞浆转位到脂滴表面；而HSP-70过表达能显著降低小鼠脂肪含量，提示HSP-70的转位可能参与调控了脂滴代谢。然而，HSP-70在细胞增殖中的重要作用提示HSP-70也可能通过调控脂肪细胞数量进而影响脂肪堆积。因此，迄今仍不清楚HSP-70究竟是通过调控脂滴代谢（细胞体积）或/与前脂肪细胞增殖（细胞数量），进而影响肥胖的发生。鉴于此，本项目拟通过siRNA和质粒过表达等手段澄清HSP-70在脂滴代谢及在脂肪细胞增殖中的作用及机制；进而，基于基因敲除及过表达小鼠模型，验证HSP-70在高脂诱导肥胖过程中的作用，深入诠释HSP-70对肥胖发生的作用和机制。项目的开展将有助于阐明HSP-70影响肥胖发生的机理，同时可能为肥胖防治提供新的靶点。

随着社会经济的发展，肥胖对健康的危害已成为备受关注的全球性公共卫生问题，它是胰岛素抵抗、糖尿病、血脂异常和高血压等慢性疾病发生的重要独立危险因素。肥胖者的机体处于一种氧化应激以及“慢性低度炎症”状态，二者相辅相成，共同促发肥胖相关代谢综合征，严重危害着人类健康，给社会造成严重过的经济和医疗负担。本项目通过体外细胞实验和人群研究，我们得到以下结果：（1）热休克蛋白基因HSPA1A和HSPA6在脂肪分化过程中上调，敲降HSPA1A和HSPA6可以显著抑制脂肪调控关键基因的表达表达；（2）HSPA1A和HSPA6通过抑制细胞周期蛋白可以显著影响前脂肪细胞的细胞周期；（3）低体重人群 血液白细胞HSPA6 基因表达水平显著降低。这些结果提示热休克蛋白对脂肪代谢的关键作用， 表明HSP-70的关键靶点。该项目根据研究计划和研究内容顺利开展并完成既定目标，受该项目的资助，已经发表学术论文8篇，培养研究生4名。