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

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.

Insulin Inhibits IL-10–Mediated Regulatory T Cell Function: Implications for Obesity

“…In both settings, Tregs encountered high levels of insulin, and in both, Tregs acquired a specific defect in IL-10 production, whereas retaining normal expression of other proteins associated with Treg function. Thus, our data suggest a possible pathological effect of insulin on Tregs in the setting of obesity, similar to an observation previously made in myeloid cells (49), where insulin receptor expression has been shown to contribute to the development of obesity-associated inflammation. In conclusion, Tregs become phenotypically altered in conditions of hyperinsulinemia, and the loss of IL-10 production and gain of IFN-g could contribute to the immune dysregulation that ensues in VAT during obesity.…”

Adipose tissue inflammation: a cause or consequence of obesity-related insulin resistance?

“…Against this hypothesis, we did not find evidence for increased immune cell filtration into adipose tissue from mice with an adipose tissue selective knockout of the insulin receptor [54]. On the other hand, a conditional inactivation of insulin action in monocytes and macrophages [IR(Deltamyel)-mice] displayed significantly reduced accumulation of macrophages in white adipose tissue, decreased levels of circulating TNF-α and protection against high fat diet induced insulin resistance [55]. These data shed light on the relevance of intact insulin signalling in immune cells in the regulation of macrophage invasion into adipose tissue.…”

Applications of myeloid-specific promoters in transgenic mice support in vivo imaging and functional genomics but do not support the concept of distinct macrophage and dendritic cell lineages or roles in immunity

“…Other genes that have been conditionally deleted using the lysM-cre mouse are summarized in Table 1; they include IKK [34], mineralocorticoid receptor [35], IL-4R␣ [36 -38], the feedback regulator SOCS1 [39], the adenosine A2a receptor [40], IB␣ [41], GRK-2 [42], tissue factor [43,44], and the leptin receptor [45]. A recent study used lysM-cre to delete the insulin receptor in myeloid cells, thereby revealing an unexpected role in the control of glucose metabolism and obesity [46]. Mortier et al [47] used the absence of lysM-cre-mediated deletion in CD11c-positive "DC" to argue that IL-15R function in macrophages, as opposed to DC, was required for T cell maturation and memory cell formation.…”