Adipocyte-derived Th2 cytokines and myeloid PPARδ regulate macrophage polarization and insulin sensitivity
Adipocyte-derived Th2 cytokines and myeloid PPARδ regulate macrophage polarization and insulin sensitivity
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DOI：
10.1016/j.cmet.2008.04.002
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发表时间：
2008-06-01
期刊：
影响因子：
29
通讯作者：
Lee, Chih-Hao
中科院分区：
文献类型：
--
作者：
Kang, Kihwa;Reilly, Shannon M.;Lee, Chih-Hao
脂肪组织驻留的巨噬细胞偏向交替激活的、抗炎的M2表型，被认为可以改善胰岛素敏感性。然而，控制组织巨噬细胞激活的机制仍不清楚。在这里，我们发现脂肪细胞是Th2细胞因子的来源，包括IL-13和IL-4，IL-4通过其启动子上的STAT6结合位点诱导巨噬细胞PPAR Delta/beta(Ppard/b)表达，以激活替代激活。共培养研究表明，Ppard消融使巨噬细胞不能转变为M2表型，进而导致脂肪细胞的炎症和代谢紊乱。值得注意的是，肝细胞来源的Th2细胞因子和巨噬细胞PPAR Delta对肝脏脂质代谢的调控机制相似。这种旁分泌途径在髓系特异性PPAR Delta(-/-)小鼠中被证明具有生理学意义，这些小鼠发展为胰岛素抵抗，并表现出脂肪细胞脂解增加和严重的肝骨病。这些发现为调节组织驻留巨噬细胞激活和胰岛素敏感性提供了分子基础。
The polarization of adipose tissue-resident macrophages toward the alternatively activated, anti-inflammatory M2 phenotype is believed to improve insulin sensitivity. However, the mechanisms controlling tissue macrophage activation remain unclear. Here we show that adipocytes are a source of Th2 cytokines, including IL-13 and to a lesser extent IL-4, which induce macrophage PPAR delta/beta (Ppard/b) expression through a STAT6 binding site on its promoter to activate alternative activation. Coculture studies indicate that Ppard ablation renders macrophages incapable of transition to the M2 phenotype, which in turns causes inflammation and metabolic derangement in adipocytes. Remarkably, a similar regulatory mechanism by hepatocyte-derived Th2 cytokines and macrophage PPAR delta is found to control hepatic lipid metabolism. The physiological relevance of this paracrine pathway is demonstrated in myeloid-specific PPAR delta(-/-) mice, which develop insulin resistance and show increased adipocyte lipolysis and severe hepatosteatosis. These findings provide a molecular basis to modulate tissue-resident macrophage activation and insulin sensitivity.