A body of research has strongly implicated inflammation in the genesis of obesity-associated diseases such as type 2 diabetes and cardiovascular disease. An outstanding issue is how obesity-induced metabolic signals are translated into an inflammatory response. In this issue of Science Translational Medicine, Kishore et al. demonstrate that the action of free fatty acids on adipose tissue macrophages dynamically regulates the expression of plasminogen activator inhibitor-1, a serine protease inhibitor that suppresses the breakdown of blood clots. Their data suggest that these macrophages sit in a specialized microenvironment that senses metabolic signals from fat cells and the circulation and integrates them to produce an inflammatory signal.