The role of the immune system in obesity and insulin resistance

Abstract

The innate immune system provides organisms with rapid and well-coordinated protection from foreign pathogens. However, under certain conditions of metabolic dysfunction, components of the innate immune system may be activated in the absence of external pathogens, leading to pathologic consequences. Indeed, there appears to be an intimate relationship between metabolic diseases and immune dysfunction; for example, macrophages are prime players in the initiation of a chronic inflammatory state in obesity which leads to insulin resistance. In response to increases in free fatty acid release from obese adipose depots, M1-polarized macrophages infiltrate adipose tissues. These M1 macrophages trigger inflammatory signaling and stress responses within cells that signal through JNK or IKK β pathways, leading to insulin resistance. If overnutrition persists, mechanisms that counteract inflammation (such as M2 macrophages and PPAR signaling) are suppressed, and the inflammation becomes chronic. Although macrophages are a principal constituent of obese adipose tissue inflammation, other components of the immune system such as lymphocytes and mast cells also contribute to the inflammatory cascade. Thus it is not merely an increased mass of adipose tissue that directly leads to attenuation of insulin action, but rather adipose tissue inflammation activated by the immune system in obese individuals that leads to insulin resistance.

Figures

Figure 1

Role of the immune system in lean versus obese adipose tissue. In lean adipose tissue, T-helper type 2 (TH2) cells produce anti-inflammatory cytokines such as interleukin (IL)-4, 10, and 13 which promote alternatively activated M2 macrophage polarization. M2 polarization is also induced by regulatory T cells (Tregs) and eosinophils via IL-4. M2 macrophages secrete other anti-inflammatory signals such as IL-10 which maintain insulin sensitivity within lean adipose tissue. Conversely, TH1 type cytokines such as interferon (IFN)-γ stimulate M1 macrophage polarization in obese adipose tissue. Other immune cells are also increased in obese adipose tissue which contribute to insulin resistance including mast cells, B cells, and immunoglobulins (Igs). CD8(+) T cells promote ATM accumulation and proinflammatory gene expression and are also increased as well. Macrophages are not homogenously distributed throughout obese adipose tissue but rather aggregated around dead adipocytes forming crown-like structures (CLS). M1 macrophages are proinflammatory, secreting cytokines such as TNF-α and IL-1β. Macrophages are bone-marrow-derived myeloid cells hence both M1 and M2 macrophages express the myeloid cell surface markers F4/80 and CD11b. However, only the M1 population expresses the marker CD11c.

Figure 2

Various signaling pathways promoting or inhibiting inflammatory signaling (green arrows represent activation, and red arrows represent inhibition). Jun N-terminal kinase-1 (JNK1) and inhibitor of kB kinase (IKKβ) are inflammatory signaling pathways which promote insulin resistance. Activation of either pathway leads to serine phosphorylation of insulin receptor substrate protein-1 (IRS-1), causing attenuation of insulin action. IKKβ also phosphorylates inhibitor of nuclear factor-κB (IκB) which essentially frees nuclear factor-κB (NF-κB), allowing it to translocate to the nucleus, bind to DNA, and activate inflammatory mediators. JNK1 can also stimulate transcription of inflammatory genes in association with transcription factor activator protein 1 (AP1). Toll-like receptor 4 (TLR4) activation, which normally binds lipopolysaccharides (LPS) and saturated fatty acids (FA), results in activation of JNK and IKKβ. Endoplasmic reticulum (ER) stress, stimulated by FA, nutrient excess, and microhypoxia, leads to the unfolded protein response (UPR). UPR comprises three main pathways: inositol-requiring enzyme (IRE)-1, protein kinase-like ER kinase (PERK), and activating transcription factor (ATF)α which all lead to activation of JNK1 and IKKβ. Hypoxia also activates the transcription factor hypoxia-inducible factor-1α (HIF-1α), which induces expression of various target genes. Conversely, insulin sensitivity is promoted by activation of the omega-3 fatty acid receptor (GRP120) which inhibits JNK1 and IKKβ. PPARγ also promotes insulin sensitivity by interfering with the NF-κB and AP1 signaling pathways and subsequent expression of inflammatory genes.