The ATP-P2X7 signaling axis is dispensable for obesity-associated inflammasome activation in adipose tissue

Inflammasome activation in adipose tissue has been implicated in obesity-associated insulin resistance and type 2 diabetes. However, when and how inflammasome is activated in adipose tissue remains speculative. Here we test the hypothesis that extracellular ATP, a potent stimulus of inflammasome in macrophages via purinergic receptor P2X, ligand-gated ion channel, 7 (P2X7), may play a role in inflammasome activation in adipose tissue in obesity. Our data show that inflammasome is activated in adipose tissue upon 8-week feeding of 60% HFD, coinciding with the onset of hyperglycemia and hyperinsulinemia as well as the induction of P2X7 in adipose tissue. Unexpectedly, P2X7-deficient animals on HFD exhibit no changes in metabolic phenotypes, nor in inflammatory responses or inflammasome activation when compared to the wildtype controls. Similar observations have been obtained in hematopoietic cell-specific P2X7-deficient animals generated by bone marrow transplantation. Thus, we conclude that inflammasome activation in adipose tissue in obesity coincides with the onset of hyperglycemia and hyperinsulinemia, but unexpectedly, is not mediated by the ATP-P2X7 signaling axis. The nature of the inflammasome-activating danger signal(s) in adipose tissue in obesity remains to be characterized. Wild type and P2X7 knockout mice were fed a low fat diet (chow) or high fat diet for 12 weeks. After the diet intervention period, the animals were killed and epididymal white adipose tissue was removed. Total RNA was isolated and subjected to gene expression profiling.

脂肪组织中的炎性小体（inflammasome）激活与肥胖相关的胰岛素抵抗及2型糖尿病密切相关。然而，脂肪组织中炎性小体的激活时机与具体机制仍有待阐明。本研究验证了下述假说：细胞外ATP作为巨噬细胞中通过嘌呤能受体P2X配体门控离子通道7（P2X7）激活炎性小体的强效刺激物，可能在肥胖状态下的脂肪组织炎性小体激活过程中发挥作用。
我们的实验数据显示，在喂食60%脂肪含量的高脂饮食（HFD）8周后，脂肪组织中出现炎性小体激活现象，该过程与高血糖症、高胰岛素血症的发病以及脂肪组织中P2X7的表达上调同步发生。
出乎意料的是，与野生型对照组相比，喂食高脂饮食的P2X7基因敲除小鼠并未出现代谢表型的显著改变，炎症反应或炎性小体激活情况也无明显差异。通过骨髓移植构建的造血细胞特异性P2X7敲除小鼠也得到了一致的实验结果。
综上，本研究得出结论：肥胖状态下脂肪组织中的炎性小体激活与高血糖症、高胰岛素血症的发病同步发生，但令人意外的是，该过程并非由ATP-P2X7信号轴介导。肥胖状态下脂肪组织中激活炎性小体的危险信号本质仍有待进一步研究阐明。
本研究将野生型及P2X7敲除小鼠分别喂食低脂标准饲料（chow）或高脂饮食，干预周期为12周。饮食干预结束后，处死实验动物并摘取附睾白色脂肪组织。提取总RNA并开展基因表达谱分析。