Obesity-related upregulation of monocyte chemotactic factors in adipocytes: involvement of nuclear factor-kappaB and c-Jun NH2-terminal kinase pathways.
Obesity-related upregulation of monocyte chemotactic factors in adipocytes: involvement of nuclear factor-kappaB and c-Jun NH2-terminal kinase pathways.
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DOI：
10.2337/db07-1344
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发表时间：
2009-01
期刊：
影响因子：
7.7
通讯作者：
Xu, Haiyan
中科院分区：
文献类型：
--
作者：
Jiao, Ping;Chen, Qiu;Shah, Suketu;Du, Jing;Tao, Bo;Tzameli, Iphigenia;Yan, Weiqun;Xu, Haiyan
我们试图评估所有单核细胞趋化因子的全貌，这些趋化因子可能导致肥胖症患者脂肪组织巨噬细胞积聚。研究设计和方法--在肥胖小鼠和瘦小鼠的脂肪组织和分离的脂肪细胞中评价整个趋化因子超家族成员的表达和调节。脂肪组织巨噬细胞浸润的动力学特征在于荧光激活细胞分选。研究了脂肪酸对脂肪细胞中趋化因子表达的刺激作用及其机制。首次发现6种单核细胞趋化因子在肥胖小鼠的分离脂肪细胞与基质血管细胞中主要上调，尽管其中大多数先前报道在整个脂肪组织中上调。在饮食诱导的肥胖小鼠中，脂肪组织增大、脂肪细胞数量增加和多种趋化因子表达升高先于巨噬细胞浸润的开始。发现游离脂肪酸（FFA）是上调3 T3-L1脂肪细胞中这些趋化因子的诱导剂，并且这种作用可以通过减少Toll样受体4表达而部分减弱。游离脂肪酸通过转录依赖和非依赖机制诱导脂肪细胞中单核细胞趋化因子的表达。与报道的JNK作为FFA诱导的巨噬细胞中单核细胞趋化蛋白-1（MCP-1）表达的唯一介导者的作用相反，我们显示了κB激酶-β（IKKβ）抑制剂在介导FFA诱导的所有六种趋化因子上调中的新作用，以及JNK在FFA诱导的MCP-1和MCP-3上调中的作用。结论：脂肪细胞来源的多种趋化因子可能与肥胖相关的WAT巨噬细胞浸润有关，FFA是潜在的触发因子，并参与IKKβ和JNK途径。
OBJECTIVE—We sought to evaluate the entire picture of all monocyte chemotactic factors that potentially contribute to adipose tissue macrophage accumulation in obesity. RESEARCH DESIGN AND METHODS—Expression and regulation of members in the entire chemokine superfamily were evaluated in adipose tissue and isolated adipocytes of obese versus lean mice. Kinetics of adipose tissue macrophage infiltration was characterized by fluorescence-activated cell sorting. The effects of fatty acids on stimulation of chemokine expression in adipocytes and underlying mechanisms were investigated. RESULTS—Six monocyte chemotactic factors were found to be predominantly upregulated in isolated adipocytes versus stromal vascular cells in obese mice for the first time, although most of them were previously reported to be upregulated in whole adipose tissue. In diet-induced obese mice, adipose tissue enlargement, increase of adipocyte number, and elevation of multiple chemokine expression precede the initiation of macrophage infiltration. Free fatty acids (FFAs) are found to be inducers for upregulating these chemokines in 3T3-L1 adipocytes, and this effect can be partially blunted by reducing Toll-like receptor 4 expression. FFAs induce expression of monocyte chemotactic factors in adipocytes via both transcription-dependent and -independent mechanisms. In contrast to the reported role of JNK as the exclusive mediator of FFA-induced monocyte chemoattractant protein-1 (MCP-1) expression in macrophages, we show a novel role of inhibitor of κB kinase-β (IKKβ) in mediating FFA-induced upregulation of all six chemokines and a role of JNK in FFA-induced upregulation of MCP-1 and MCP-3. CONCLUSIONS—Multiple chemokines derived from adipocytes might contribute to obesity-related WAT macrophage infiltration with FFAs as potential triggers and involvement of both IKKβ and JNK pathways.
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