Mechanisms of obesity-induced inflammation and insulin resistance: insights into the emerging role of nutritional strategies

Abstract

Obesity and associated chronic inflammation initiate a state of insulin resistance (IR). The secretion of chemoattractants such as MCP-1 and MIF and of cytokines IL-6, TNF-α, and IL-1β, draw immune cells including dendritic cells, T cells, and macrophages into adipose tissue (AT). Dysfunctional AT lipid metabolism leads to increased circulating free fatty acids, initiating inflammatory signaling cascades in the population of infiltrating cells. A feedback loop of pro-inflammatory cytokines exacerbates this pathological state, driving further immune cell infiltration and cytokine secretion and disrupts the insulin signaling cascade. Disruption of normal AT function is causative of defects in hepatic and skeletal muscle glucose homeostasis, resulting in systemic IR and ultimately the development of type 2 diabetes. Pharmaceutical strategies that target the inflammatory milieu may have some potential; however there are a number of safety concerns surrounding such pharmaceutical approaches. Nutritional anti-inflammatory interventions could offer a more suitable long-term alternative; whilst they may be less potent than some pharmaceutical anti-inflammatory agents, this may be advantageous for long-term therapy. This review will investigate obese AT biology, initiation of the inflammatory, and insulin resistant environment; and the mechanisms through which dietary anti-inflammatory components/functional nutrients may be beneficial.

Keywords: PUFA; immune cell infiltration; inflammation; insulin resistance; nutrient sensing; obesity.

Figure 1

Metabolic tissues implicated in obesity-induced insulin resistance. Adipose tissue, liver, and skeletal muscle are involved in glucose uptake, glucose production, and glucose processing. These tissues therefore are paramount in obesity and the progression of insulin resistance. A combination of defective fatty acid storage and metabolism together with immune cell infiltration and a pro-inflammatory tissue milieu result in dysregulation of insulin signaling.

Figure 2

Obese adipose tissue expansion – resultant inflammation and metabolic dysregulation. Excess energy leads to adipose expansion with hypertrophic adipocytes that secrete chemoattractants such as MCP-1, drawing immune cells into the tissue. Secretion of pro-inflammatory mediators such as TNF-α, IL-1β, and IL-6 by adipocytes, pre-adipocytes, and infiltrating immune cells results in polarization of macrophages to a pro-inflammatory M1 phenotype, and drive an inflammatory T cell population. Augmented lipolysis leads to increased levels of FFAs. This environment negatively impacts on the insulin signaling pathway and a state of insulin resistance results. Additionally hypertrophic adipocytes are also linked with hypoxia.

Figure 3

Major cell types involved in obesity-induced inflammation and insulin resistance; adipocytes, pre-adipocytes, dendritic cells, T cells, and macrophages.

Figure 4

Cross-talk between insulin and inflammatory signaling pathways. Inflammatory signaling pathways activated by SFA or by pro-inflammatory cytokines IL-1β, IL-6, and TNF-α initiate a cascade of events that promote the release of further inflammatory mediators. These signaling events converge at the NF-κB and MAPK pathways, resulting in the translocation of transcription factors to the nucleus, transcriptional activation, and cytokine production. The inflammasome is activated through a two-hit process; with obesity the first hit occurs when TLR4 is activated by SFAs and this results in pro-IL-1β production, ATP or ceramides then provide the second hit. The NLRP3 inflammasome acts on pro-caspase-1 causing the release of caspase-1; caspase-1 then acts upon pro-IL-1β cleaving this precursor to the active IL-1β form. Insulin signaling promotes glucose uptake by promoting the translocation of GLUT4 to the cell surface plasma membrane. Inflammatory signaling pathways can alter the phosphorylation status of IRS-1. IRS-1 is crucial in the insulin signaling pathway, tyrosine phosphorylation is associated with an insulin sensitive state. IKKβ and JNK can promote serine phosphorylation of IRS-1 and this phosphorylation state is linked to insulin resistance and reduced glucose uptake.

Figure 5

Activation and propagation of inflammation and insulin resistance in obese adipose tissue. Adipocyte hypertrophy results in elevated circulation of FFAs (A) and increased secretion of adipokines (B). These in turn result in immune cell infiltration and the activation of pro-inflammatory signaling pathways, driving further infiltration and the polarization of adipose tissue macrophages and T cells toward a pro-inflammatory phenotype. This environment then drives further adipokine secretions (C) and hampers adipogenesis, resulting in greater numbers of pre-adipocytes that in turn secrete pro-inflammatory mediators. Together these events lead to defective insulin signaling and ultimately to an insulin resistant state.