Myeloid Cell-Restricted Insulin Receptor Deficiency Protects Against Obesity-Induced Inflammation and Systemic Insulin Resistance

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Abstract
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 the 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 conditionally inactivated the insulin receptor (IR) gene in myeloid lineage cells in 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 concentrations of circulating tumor necrosis factor (TNF) α and thus reduced c-Jun N-terminal kinase (JNK) activity in skeletal muscle upon high fat feeding, reflecting a dramatic reduction of the chronic and systemic low-grade inflammatory state associated with obesity. This is paralleled by a reduced accumulation of macrophages in white adipose tissue due to a pronounced impairment of matrix metalloproteinase (MMP) 9 expression and activity in these cells. 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 in the development of obesity-associated insulin resistance. Obesity represents a major health burden with steadily increasing incidence. While it is associated with numerous co-morbidities, type 2 diabetes mellitus represents one of the major life-threatening, obesity-related conditions. Over the last years, it has become clear that during the course of obesity development not only does fat mass increase, but also fat composition changes qualitatively, leading to an influx of inflammatory cells, such as macrophages, into adipose tissue. Macrophages in turn secrete inflammatory mediators, which inhibit insulin action in skeletal muscle, liver, and even the central nervous system to ultimately cause insulin-resistant diabetes mellitus. However, the effect of insulin action and resistance in these inflammatory cell types themselves has not been addressed. To this end, we have generated and analyzed mice with inactivation of the insulin receptor specifically in myeloid cell-derived, inflammatory cells. Surprisingly, these animals are protected from the development of obesity-associated deterioration of glucose metabolism, thereby defining insulin action in inflammatory cells as a novel and promising target for therapeutic intervention against obesity-associated diabetes mellitus.