Strissel Katherine J, Stancheva Zlatina, Miyoshi Hideaki, Perfield James W, DeFuria Jason, Jick Zoe, Greenberg Andrew S, Obin Martin S
Obesity and Metabolism Laboratory, Jean Mayer-U.S. Department of Agriculture Human Nutrition Research Center on Aging (JM-USDA HNRCA) at Tufts University, Boston, MA, USA.
Diabetes. 2007 Dec;56(12):2910-8. doi: 10.2337/db07-0767. Epub 2007 Sep 11.
We sought to determine the role of adipocyte death in obesity-induced adipose tissue (AT) inflammation and obesity complications.
Male C57BL/6 mice were fed a high-fat diet for 20 weeks to induce obesity. Every 4 weeks, insulin resistance was assessed by intraperitoneal insulin tolerance tests, and epididymal (eAT) and inguinal subcutaneous AT (iAT) and livers were harvested for histological, immunohistochemical, and gene expression analyses.
Frequency of adipocyte death in eAT increased from <0.1% at baseline to 16% at week 12, coincident with increases in 1) depot weight; 2) AT macrophages (ATM Phi s) expressing F4/80 and CD11c; 3) mRNA for tumor necrosis factor (TNF)-alpha, monocyte chemotactic protein (MCP)-1, and interleukin (IL)-10; and 4) insulin resistance. ATM Phi s in crown-like structures surrounding dead adipocytes expressed TNF-alpha and IL-6 proteins. Adipocyte number began to decline at week 12. At week 16, adipocyte death reached approximately 80%, coincident with maximal expression of CD11c and inflammatory genes, loss (40%) of eAT mass, widespread collagen deposition, and accelerated hepatic macrosteatosis. By week 20, adipocyte number was restored with small adipocytes, coincident with reduced adipocyte death (fourfold), CD11c and MCP-1 gene expression (twofold), and insulin resistance (35%). eAT weight did not increase at week 20 and was inversely correlated with liver weight after week 12 (r = -0. 85, P < 0.001). In iAT, adipocyte death was first detected at week 12 and remained <or=3%.
These results implicate depot-selective adipocyte death and M Phi-mediated AT remodeling in inflammatory and metabolic complications of murine obesity.
我们试图确定脂肪细胞死亡在肥胖诱导的脂肪组织（AT）炎症和肥胖并发症中的作用。
雄性C57BL/6小鼠喂食高脂饮食20周以诱导肥胖。每4周通过腹腔内胰岛素耐量试验评估胰岛素抵抗，并采集附睾（eAT）、腹股沟皮下脂肪组织（iAT）和肝脏进行组织学、免疫组织化学和基因表达分析。
eAT中脂肪细胞死亡频率从基线时的<0.1%增加到第12周时的16%，同时伴随着以下各项增加：1）脂肪库重量；2）表达F4/80和CD11c的AT巨噬细胞（ATM Phi s）；3）肿瘤坏死因子（TNF）-α、单核细胞趋化蛋白（MCP）-1和白细胞介素（IL）-10的mRNA；4）胰岛素抵抗。围绕死亡脂肪细胞的冠状结构中的ATM Phi s表达TNF-α和IL-6蛋白。脂肪细胞数量在第12周开始下降。在第16周，脂肪细胞死亡达到约80%，同时CD11c和炎症基因表达达到最大值，eAT质量损失（40%），广泛的胶原沉积，以及肝脏大脂肪变性加速。到第20周，脂肪细胞数量恢复为小脂肪细胞，同时脂肪细胞死亡减少（四倍），CD11c和MCP-1基因表达减少（两倍），胰岛素抵抗降低（35%）。第20周时eAT重量未增加，且在第12周后与肝脏重量呈负相关（r = -0.85，P < 0.001）。在iAT中，脂肪细胞死亡在第12周首次检测到，且仍≤3%。
这些结果表明，在小鼠肥胖的炎症和代谢并发症中，存在脂肪库选择性脂肪细胞死亡和M Phi介导的AT重塑。
