PI3Kγ activity in leukocytes promotes adipose tissue inflammation and early-onset insulin resistance during obesity.

The phosphoinositide 3-kinase g (PI3K gamma) plays a major role in leukocyte recruitment during acute inflammation and has been proposed to inhibit classical macrophage activation by driving immunosuppressive gene expression. PI3K gamma plays an important role in diet-induced obesity and insulin resistance. In seeking to determine the underlying molecular mechanisms, we showed that PI3K gamma action in high-fat diet-induced inflammation and insulin resistance depended largely on its role in the control of adiposity, which was due to PI3K gamma activity in a nonhematopoietic cell type. However, PI3K gamma activity in leukocytes was required for efficient neutrophil recruitment to adipose tissue. Neutrophil recruitment was correlated with proinflammatory gene expression in macrophages in adipose tissue, which triggered insulin resistance early during the development of obesity. Our data challenge the concept that PI3K gamma is a general suppressor of classical macrophage activation and indicate that PI3K gamma controls macrophage gene expression by non-cell-autonomous mechanisms, the outcome of which is context-dependent.