PI3Kg activity in leukocytes promotes adipose tissue inflammation and early-onset insulin resistance during obesity

Abstract

The phosphoinositide 3-kinase g (PI3Kg) plays a major role in leukocyte recruitment during acute inflammation and has been proposed to inhibit classical macrophage activation by driving immunosuppressive gene expression. PI3Kg plays an important role in diet-induced obesity and insulin resistance. In seeking to determine the underlying molecular mechanisms, we showed that PI3Kg action in high-fat diet-induced inflammation and insulin resistance depended largely on its role in the control of adiposity, which was due to PI3Kg activity in a nonhematopoietic cell type. However, PI3Kg 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 PI3Kg is a general suppressor of classical macrophage activation and indicate that PI3Kg controls macrophage gene expression by non-cell-Autonomous mechanisms, the outcome of which is context-dependent.