Odegaard Justin I, Ricardo-Gonzalez Roberto R, Goforth Matthew H, Morel Christine R, Subramanian Vidya, Mukundan Lata, Red Eagle Alex, Vats Divya, Brombacher Frank, Ferrante Anthony W, Chawla Ajay
Division of Endocrinology, Metabolism and Gerontology, Department of Medicine, Stanford University School of Medicine, Stanford, California 94305-5103, USA.
Nature. 2007 Jun 28;447(7148):1116-20. doi: 10.1038/nature05894. Epub 2007 May 21.
Obesity and insulin resistance, the cardinal features of metabolic syndrome, are closely associated with a state of low-grade inflammation. In adipose tissue chronic overnutrition leads to macrophage infiltration, resulting in local inflammation that potentiates insulin resistance. For instance, transgenic expression of Mcp1 (also known as chemokine ligand 2, Ccl2) in adipose tissue increases macrophage infiltration, inflammation and insulin resistance. Conversely, disruption of Mcp1 or its receptor Ccr2 impairs migration of macrophages into adipose tissue, thereby lowering adipose tissue inflammation and improving insulin sensitivity. These findings together suggest a correlation between macrophage content in adipose tissue and insulin resistance. However, resident macrophages in tissues display tremendous heterogeneity in their activities and functions, primarily reflecting their local metabolic and immune microenvironment. While Mcp1 directs recruitment of pro-inflammatory classically activated macrophages to sites of tissue damage, resident macrophages, such as those present in the adipose tissue of lean mice, display the alternatively activated phenotype. Despite their higher capacity to repair tissue, the precise role of alternatively activated macrophages in obesity-induced insulin resistance remains unknown. Using mice with macrophage-specific deletion of the peroxisome proliferator activated receptor-gamma (PPARgamma), we show here that PPARgamma is required for maturation of alternatively activated macrophages. Disruption of PPARgamma in myeloid cells impairs alternative macrophage activation, and predisposes these animals to development of diet-induced obesity, insulin resistance, and glucose intolerance. Furthermore, gene expression profiling revealed that downregulation of oxidative phosphorylation gene expression in skeletal muscle and liver leads to decreased insulin sensitivity in these tissues. Together, our findings suggest that resident alternatively activated macrophages have a beneficial role in regulating nutrient homeostasis and suggest that macrophage polarization towards the alternative state might be a useful strategy for treating type 2 diabetes.
肥胖和胰岛素抵抗是代谢综合征的主要特征，与低度炎症状态密切相关。在脂肪组织中，慢性营养过剩会导致巨噬细胞浸润，从而引发局部炎症，增强胰岛素抵抗。例如，脂肪组织中Mcp1（也称为趋化因子配体2，Ccl2）的转基因表达会增加巨噬细胞浸润、炎症和胰岛素抵抗。相反，Mcp1或其受体Ccr2的破坏会损害巨噬细胞向脂肪组织的迁移，从而降低脂肪组织炎症并改善胰岛素敏感性。这些发现共同表明脂肪组织中巨噬细胞含量与胰岛素抵抗之间存在关联。然而，组织中的驻留巨噬细胞在其活性和功能上表现出极大的异质性，主要反映了它们局部的代谢和免疫微环境。虽然Mcp1指导促炎性经典活化巨噬细胞募集到组织损伤部位，但驻留巨噬细胞，如瘦小鼠脂肪组织中的巨噬细胞，表现出替代性活化表型。尽管它们具有更高的组织修复能力，但替代性活化巨噬细胞在肥胖诱导的胰岛素抵抗中的精确作用仍然未知。通过使用巨噬细胞特异性缺失过氧化物酶体增殖物激活受体γ（PPARγ）的小鼠，我们在此表明PPARγ是替代性活化巨噬细胞成熟所必需的。髓系细胞中PPARγ的破坏会损害替代性巨噬细胞活化，并使这些动物易患饮食诱导的肥胖、胰岛素抵抗和葡萄糖不耐受。此外，基因表达谱分析显示骨骼肌和肝脏中氧化磷酸化基因表达的下调导致这些组织中胰岛素敏感性降低。总之，我们的发现表明驻留的替代性活化巨噬细胞在调节营养稳态中具有有益作用，并表明巨噬细胞向替代状态的极化可能是治疗2型糖尿病的有用策略。
