Lee Yonggu, Song Yi-Sun, Fang Cheng-Hu, So Byung-Im, Park Jun-Young, Joo Hyun-Woo, Park In-Hwa, Shen Guang-Yin, Shin Jeong-Hun, Kim Hyuck, Ahn You-Heon, Kim Kyung-Soo
Division of Cardiology, Department of Internal Medicine, Hanyang University College of Medicine, Seoul, South Korea; Department of Cardiology, Sung-Ae Hospital, Seoul, South Korea.
Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, South Korea.
PLoS One. 2014 Aug 21;9(8):e105603. doi: 10.1371/journal.pone.0105603. eCollection 2014.
Granulocyte-colony stimulating factor (G-CSF) has molecular structures and intracellular signaling pathways that are similar to those of leptin and ciliary neurotropic factor (CNTF). It also has immune-modulatory properties. Given that leptin and CNTF play important roles in energy homeostasis and that obesity is an inflammatory condition in adipose tissue, we hypothesized that G-CSF could also play a role in energy homeostasis. We treated 12 38-week-old male Otsuka-Long-Evans-Tokushima fatty rats (OLETF, diabetic) and 12 age-matched male Long-Evans-Tokushima rats (LETO, healthy) with 200 µg/day G-CSF or saline for 5 consecutive days. Body weight reduction was greater in G-CSF-treated OLETF (G-CSF/OLETF) than saline-treated OLETF (saline/OLETF) following 8 weeks of treatment (-6.9±1.6% vs. -3.1±2.2%, p<0.05). G-CSF treatment had no effect on body weight in LETO or on food intake in either OLETF or LETO. Body fat in G-CSF/OLETF was more reduced than in saline/OLETF (-32.2±3.1% vs. -20.8±6.2%, p<0.05). Energy expenditure was higher in G-CSF/OLETF from 4 weeks after the treatments than in saline/OLETF. Serum levels of cholesterol, triglyceride, interleukin-6 and tumor necrosis factor-α were lower in G-CSF/OLETF than in saline/OLETF. Uncoupling protein-1 (UCP-1) expression in brown adipose tissue (BAT) was higher in G-CSF/OLETF than in saline/OLETF, but was unaffected in LETO. Immunofluorescence staining and PCR results revealed that G-CSF receptors were expressed in BAT. In vitro experiments using brown adipocyte primary culture revealed that G-CSF enhanced UCP-1 expression from mature brown adipocytes via p38 mitogen-activated protein kinase pathway. In conclusion, G-CSF treatment reduced body weight and increased energy expenditure in a diabetic model, and enhanced UCP-1 expression and decreased inflammatory cytokine levels may be associated with the effects of G-CSF treatment.
粒细胞集落刺激因子（G-CSF）具有与瘦素和睫状神经营养因子（CNTF）相似的分子结构和细胞内信号通路。它还具有免疫调节特性。鉴于瘦素和CNTF在能量稳态中起重要作用，且肥胖是脂肪组织中的一种炎症状态，我们推测G-CSF也可能在能量稳态中发挥作用。我们用200μg/天的G-CSF或生理盐水连续5天处理12只38周龄的雄性大冢-朗-伊文斯-德岛肥胖大鼠（OLETF，糖尿病大鼠）和12只年龄匹配的雄性朗-伊文斯-德岛大鼠（LETO，健康大鼠）。治疗8周后，G-CSF处理的OLETF（G-CSF/OLETF）体重减轻幅度大于生理盐水处理的OLETF（生理盐水/OLETF）（-6.9±1.6%对-3.1±2.2%，p<0.05）。G-CSF处理对LETO的体重或OLETF和LETO的食物摄入量均无影响。G-CSF/OLETF的体脂减少幅度大于生理盐水/OLETF（-32.2±3.1%对-20.8±6.2%，p<0.05）。治疗4周后，G-CSF/OLETF的能量消耗高于生理盐水/OLETF。G-CSF/OLETF的血清胆固醇、甘油三酯、白细胞介素-6和肿瘤坏死因子-α水平低于生理盐水/OLETF。G-CSF/OLETF棕色脂肪组织（BAT）中解偶联蛋白-1（UCP-1）的表达高于生理盐水/OLETF，但在LETO中未受影响。免疫荧光染色和PCR结果显示G-CSF受体在BAT中表达。使用棕色脂肪细胞原代培养的体外实验表明，G-CSF通过p38丝裂原活化蛋白激酶途径增强成熟棕色脂肪细胞中UCP-1的表达。总之，在糖尿病模型中，G-CSF治疗可减轻体重并增加能量消耗，UCP-1表达增强和炎症细胞因子水平降低可能与G-CSF治疗的效果有关。
