双水杨酸酯作用骨髓间充质干细胞NF-κB改善高脂饮食诱导肥胖对小鼠骨髓造血的影响

Obesity is now considered as low-grade chronic inflammatory disease associated with increased levels of pro-inflammatory cytokines. The effect of metabolic stress on the bone marrow niche is poorly defined. Our previous results indicated that high fat diet-induced obesity (DIO) increased inflammatory cytokines (TNF-α and IL-1β) in bone and disrupted hematopoiesis by affecting quiescence and differentiation of hematopoietic stem cell (HSC), shifted lymphoid to myeloid cell differentiation. Bone marrow mesenchymal stem cells (BMSC), which are involved in hematopoietic niche, can be affected by inflammatory cytokines, resulting from induction of NF-κB. Recent clinical trials demonstrated that salsalate, an old anti-inflammatory agent, can lower glucose as well as inflammatory cytokines in obesity and diabetes through regulation of NF-κB pathway. Therefore, it will have great significance to investigate whether salsalate can palliate the obesity associated disruption of hematopoiesis and how it affect BMSC and bone marrow niche by targeting NF-κB. In this project, we will establish the model of DIO mice in vivo and palmitic acid induced lipid injury of BMSC in vitro, to evaluate the effects of salsalate on hematopoiesis and BMSC disrupted by high fat diet and lipid burden, and explore the possibility of salsalate targeting NF-κB in BMSC rescue disruption of hematopoiesis by DIO using flow cytometry, RT-PCR, Western blot and cell culture etc. The research will provide theoretical and experimental foundation for the treatment of obesity, type 2 diabetes and cardiovascular diseases using salsalate.

肥胖是一种慢性低度炎症性疾病。前期发现高脂饮食诱导的肥胖（DIO）可上调小鼠骨组织炎症细胞因子（TNF-α和IL-1β）的表达，影响骨髓造血。肥胖可激活骨髓间充质干细胞（BMSC）中NF-κB，导致骨髓炎症反应。而双水杨酸酯具有抑制NF-κB信号激活的抗炎作用。故而提出双水杨酸酯或可通过抑制BMSC中的NF-κB的活化，减轻炎症反应，而逆转DIO诱导的炎性微环境的假说。拟以DIO小鼠和棕榈酸诱导的BMSC高脂损伤为模型，采用流式细胞仪、蛋白印迹、PCR等技术证实双水杨酸酯作用于BMSC 中的NF-κB发挥抗炎作用，从而逆转DIO介导的骨髓造血的破坏作用，改善DIO所致的免疫紊乱。研究结果有望为双水杨酸酯用于肥胖、2型糖尿病及心血管疾病等的治疗提供新的理论依据。

目前，肥胖被认为是一种慢性、低度炎症性疾病，是胰岛素抵抗及相关疾病发生的关键因素。我们前期研究结果表明，高脂诱导肥胖促进小鼠骨髓造血干细胞、祖细胞的扩增。肥胖小鼠外周血白细胞计数明显升高，骨髓脂肪细胞计数在肥胖小鼠中明显增多，而在成年机体中，所有的血细胞和免疫细胞均起源于造血干细胞。研究通过双水杨酸酯对肥胖小鼠进行干预，结果显示双水杨酸酯可通过抑制骨髓间充质干细胞（bone marrow mesenchymal stem cell，BMSC ）中核转录因子NF-κB，减轻炎症反应，使得肥胖小鼠外周血白细胞计数恢复正常，降低肥胖小鼠骨髓中脂肪细胞计数，逆转肥胖对骨髓微环境的破坏，同时减轻肥胖小鼠体重和胰岛素抵抗。研究结果为双水杨酸酯用于肥胖、2型糖尿病及心血管疾病等的治疗提供新的理论依据。