Kanda Hajime, Tateya Sanshiro, Tamori Yoshikazu, Kotani Ko, Hiasa Ken-ichi, Kitazawa Riko, Kitazawa Sohei, Miyachi Hitoshi, Maeda Sakan, Egashira Kensuke, Kasuga Masato
Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
J Clin Invest. 2006 Jun;116(6):1494-505. doi: 10.1172/JCI26498. Epub 2006 May 11.
Adipocytes secrete a variety of bioactive molecules that affect the insulin sensitivity of other tissues. We now show that the abundance of monocyte chemoattractant protein-1 (MCP-1) mRNA in adipose tissue and the plasma concentration of MCP-1 were increased both in genetically obese diabetic (db/db) mice and in WT mice with obesity induced by a high-fat diet. Mice engineered to express an MCP-1 transgene in adipose tissue under the control of the aP2 gene promoter exhibited insulin resistance, macrophage infiltration into adipose tissue, and increased hepatic triglyceride content. Furthermore, insulin resistance, hepatic steatosis, and macrophage accumulation in adipose tissue induced by a high-fat diet were reduced extensively in MCP-1 homozygous KO mice compared with WT animals. Finally, acute expression of a dominant-negative mutant of MCP-1 ameliorated insulin resistance in db/db mice and in WT mice fed a high-fat diet. These findings suggest that an increase in MCP-1 expression in adipose tissue contributes to the macrophage infiltration into this tissue, insulin resistance, and hepatic steatosis associated with obesity in mice.
脂肪细胞分泌多种生物活性分子，这些分子会影响其他组织的胰岛素敏感性。我们现在发现，在遗传性肥胖糖尿病（db/db）小鼠以及高脂饮食诱导肥胖的野生型（WT）小鼠中，脂肪组织中单核细胞趋化蛋白-1（MCP-1）mRNA的丰度和血浆中MCP-1的浓度均升高。在aP2基因启动子控制下，经基因工程改造在脂肪组织中表达MCP-1转基因的小鼠表现出胰岛素抵抗、巨噬细胞浸润至脂肪组织以及肝脏甘油三酯含量增加。此外，与野生型动物相比，MCP-1纯合敲除（KO）小鼠中由高脂饮食诱导的胰岛素抵抗、肝脏脂肪变性和脂肪组织中的巨噬细胞积累大幅减少。最后，MCP-1显性负性突变体的急性表达改善了db/db小鼠以及高脂饮食喂养的野生型小鼠的胰岛素抵抗。这些发现表明，脂肪组织中MCP-1表达的增加导致巨噬细胞浸润至该组织、胰岛素抵抗以及与小鼠肥胖相关联的肝脏脂肪变性。
