NOD1: An Interface Between Innate Immunity and Insulin Resistance

Abstract

Insulin resistance is driven, in part, by activation of the innate immune system. We have discussed the evidence linking nucleotide-binding oligomerization domain (NOD)1, an intracellular pattern recognition receptor, to the onset and progression of obesity-induced insulin resistance. On a molecular level, crosstalk between downstream NOD1 effectors and the insulin receptor pathway inhibits insulin signaling, potentially through reduced insulin receptor substrate action. In vivo studies have demonstrated that NOD1 activation induces peripheral, hepatic, and whole-body insulin resistance. Also, NOD1-deficient models are protected from high-fat diet (HFD)-induced insulin resistance. Moreover, hematopoietic NOD1 deficiency prevented HFD-induced changes in proinflammatory macrophage polarization status, thus protecting against the development of metabolic inflammation and insulin resistance. Serum from HFD-fed mice activated NOD1 signaling ex vivo; however, the molecular identity of the activating factors remains unclear. Many have proposed that an HFD changes the gut permeability, resulting in increased translocation of bacterial fragments and increased circulating NOD1 ligands. In contrast, others have suggested that NOD1 ligands are endogenous and potentially lipid-derived metabolites produced during states of nutrient overload. Nevertheless, that NOD1 contributes to the development of insulin resistance, and that NOD1-based therapy might provide benefit, is an exciting advancement in metabolic research.

Figure 1.

Proposed sources of NOD1 activation and corresponding physiologic, endocrine, and cell tissue communication events leading to insulin resistance in different tissues. Generic NOD1 activation by bacterial peptidoglycans (PAMPs) or metabolites (DAMPs) initiate a downstream inflammatory signal cascade in which the adaptor protein, RIPK2, interacts with NOD1 via its caspase recruitment domain (CARD) motif. Subsequent recruitment and activation of TAK1 enhances MAPK and NF-κB signaling. Crosstalk between the insulin receptor pathway and both NF-κB and MAPK signaling can occur through inhibitory inputs of IKKβ and JNK on IRS1,2 phosphorylation, reducing insulin signaling and, thus, contributing to insulin resistance. Circulating proinflammatory cytokines—NF-κB signaling promoted proinflammatory cytokine gene and protein expression, establishing a feed-forward cascade in which cytokines can bind to their respective receptors and propagate downstream inflammatory signaling on the same, neighbor, or distal cell. Enhanced inflammation in target cells attenuates insulin receptor signaling, thereby participating in the onset of whole-body insulin resistance. NOD1 signaling in cells of hematopoietic origin amplifies peripheral inflammation and insulin resistance—NOD1 activation in hematopoietic cells promotes changes in macrophage polarization, converting anti-inflammatory macrophages to a proinflammatory state. Elevated proinflammatory cytokine secretion and increased proinflammatory macrophage infiltration in adipose and peripheral tissues results in heightened inflammation in target tissues and corresponding reductions in insulin signaling. The NOD1-dependent influx in proinflammatory macrophages is accompanied by an increase in neutrophil infiltration, which together are thought to participate in inflammation-mediated insulin resistance. NOD1 signaling in adipose tissue stimulates lipolysis and reduces insulin-stimulated glucose uptake—increased inflammation and cytokine secretion in adipose tissue as a result of autonomous activation of NOD1 and infiltration of immune cells collectively dampen insulin receptor signaling. Loss of phosphatidylinositol 3-kinase (PI3K)/AKT activity translates to reduced GLUT4 membrane translocation, thereby decreasing insulin-stimulated glucose uptake. NOD1-induced inflammation also enhances adipose lipolysis via proposed NF-κB/PKA– and ERK-dependent pathways, increasing hormone sensitive lipase (HSL) activity. Elevated circulating FFAs travel to, and accumulate in, metabolically active tissues, where they can convert into lipid metabolites and stimulate PKC isoforms. Enhanced PKC signaling in the liver and muscle mediates changes in local insulin receptor signaling, contributing to the onset of hepatic and peripheral insulin resistance, respectively. However, NOD1 activation might also occur directly in liver and skeletal muscle.