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 (P2X(7)), 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% high-fat diet (HFD), coinciding with the onset of hyperglycemia and hyperinsulinemia as well as the induction of P2X(7) in adipose tissue. Unexpectedly, P2X(7)-deficient animals on HFD exhibit no changes in metabolic phenotypes, inflammatory responses, or inflammasome activation when compared with the wild-type controls. Similar observations have been obtained in hematopoietic cell-specific P2X(7)-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-P2X(7) signaling axis. The nature of the inflammasome-activating danger signal(s) in adipose tissue in obesity remains to be characterized.