棕色脂肪激活对机体正常和异常造血的影响

The Effects of Brown Fat Activation on Normal and Abnormal Hematopoiesis

激活棕色脂肪组织(BAT)可以抑制实体肿瘤生长,然而其对正常或异常造血细胞的影响仍然不清楚。因此,该研究采用β3-肾上腺素受体激动剂米拉贝隆分别激活野生型和白血病小鼠BAT,观察和分析其对正常造血细胞以及白血病细胞的影响。通过流式分析了不同时间点米拉贝隆治疗组和对照组小鼠骨髓、脾脏、肝脏和外周血中白血病细胞的比例,以及骨髓中造血干/祖及成熟细胞的比例、数目、细胞周期、凋亡和集落形成能力;验证了脂肪组织的激活程度;通过手术移除BAT来检测米拉贝隆激活BAT在白血病中的作用。研究结果显示,米拉贝隆治疗组显著激活了BAT,减少了急性白血病小鼠的骨髓、脾脏、肝脏和外周血中白血病细胞的比例,延长了小鼠生存期。米拉贝隆对正常C57小鼠的成熟免疫细胞和骨髓造血干/祖细胞的比例和数量没有明显影响,但在白血病小鼠中治疗组骨髓中各类成熟免疫细胞的比例和绝对数均显著高于对照组,造血干/祖细胞的比例和绝对数均显著增加,细胞凋亡减少,集落形成能力增强。手术切除BAT阻断了米拉贝隆介导的抗白血病作用。研究结果表明,通过米拉贝隆预给药可以激活棕色脂肪组织,抑制白血病细胞的增殖,促进白血病小鼠正常造血干/祖细胞的增殖分化和存活,延长小鼠生存期,为今后白血病的临床治疗提供了一种新的策略。

Activation of BAT(brown adipose tissue)can inhibit solid tumor growth,but its effect on normal or abnormal hematopoietic cells remains unclear.Therefore,in this study,theβ3-adrenergic receptor agonist mirabegron was used to activate BAT in wild-type and leukemia mice,and the effects on normal hematopoietic cells and leukemia cells were observed and analyzed.The proportion of leukemia cells in bone marrow,spleen,liver,and peripheral blood of mice treated with mirabegron and control mice was analyzed at various time points.The proportion,number,cell cycle,apoptosis and colony formation ability of HS/PCs(hematopoietic stem/progenitor cells)and mature hematopoietic cells in the bone marrow of leukemia mice were analyzed.The activation degree of adipose tissue was verified.The role of BAT activation by mirabegron in leukemia was examined by surgical removal of BAT.The results showed that mirabegron treatment significantly activated BAT,reduced the proportion of leukemia cells in the bone marrow,spleen,liver and peripheral blood of acute leukemia mice,and prolonged the survival time.Mirabegron treatment had no significant effect on the proportion and number of mature immune cells and HS/PCs in the bone marrow of normal C57 mice,but in the leukemia mice,the proportion and absolute number of various mature immune cells in the bone marrow of the treatment group were significantly higher than those of the control group,the proportion and absolute number of HS/PCs in the bone marrow of the treatment group were significantly increased,the apoptosis of the cells was decreased,and the ability of colony formation was enhanced.Surgical removal of BAT blocked mirabegron-mediated anti-leukemic effects.Overall,these findings demonstrate that pretreatment with mirabegron can activate brown adipose tissue,suppress the proliferation of leukemia cells,enhance the proliferation,differentiation,and survival of normal hematopoietic stem/progenitor cells in leukemia mice,and extend the lifespan of mice.This offers a novel approach for future clinical management of leukemia.