The impact of myeloid cell-restricted insulin receptor deficiency on obesity-induced insulin resistance

A major component of obesity-related insulin resistance is the establishment of a chronic inflammatory state with invasion of white adipose tissue by mononuclear cells. This results in release of pro-inflammatory cytokines, which in turn leads to insulin resistance in target tissues such as skeletal muscle and liver. To determine the role of insulin action in macrophages and monocytes in obesity-associated insulin resistance, we have conditionally inactivated the insulin receptor (IR) gene in myeloid cells of mice (IRΔmyel mice). While these animals exhibit unaltered glucose metabolism on a normal diet, they are protected from the development of obesity-associated insulin resistance upon high fat feeding. Euglycemic-hyperinsulinemic clamp studies demonstrate that this results from decreased basal hepatic glucose production and from increased insulin-stimulated glucose disposal in skeletal muscle. Furthermore, IRΔmyel mice exhibit decreased concentration of circulating tumor necrosis factor (TNF) α and reduced c-jun N-terminal kinase (JNK) activity in skeletal muscle, reflecting a drastic reduction of the chronic and systemic lowgrade inflammatory state associated with obesity. This arises from reduced inflammatory recruitment of macrophages to white adipose tissue. Cell-autonomously, insulin receptordeficient macrophages are prone to lipid-induced apoptosis and exhibit reduced proinflammatory gene transcription. Additionally, these cells show a pronounced impairment of lipid-induced matrix metalloproteinase (MMP) 9 expression and decreased motility in response to macrophage chemoattractant protein (MCP) 1. These data indicate that insulin action in myeloid cells plays an unexpected, critical role in the regulation of macrophage invasion into white adipose tissue and the development of obesity-associated insulin resistance.