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Review
. 2016 Dec 12:7:157.
doi: 10.3389/fendo.2016.00157. eCollection 2016.

Obesity: An Immunometabolic Perspective

Indrani Ray  1 , Sushil K Mahata  2 , Rajat K De  1
Affiliations
Review

Obesity: An Immunometabolic Perspective

Indrani Ray et al. Front Endocrinol (Lausanne). .

Abstract

Obesity, characterized by chronic activation of inflammatory pathways, is a critical factor contributing to insulin resistance (IR) and type 2 diabetes (T2D). Free fatty acids (FFAs) are increased in obesity and are implicated as proximate causes of IR and induction of inflammatory signaling in adipose, liver, muscle, and pancreas. Cells of the innate immune system produce cytokines, and other factors that affect insulin signaling and result in the development of IR. In the lean state, adipose tissue is populated by adipose tissue macrophage of the anti-inflammatory M2 type (ATM2) and natural killer (NK) cells; this maintains the insulin-sensitive phenotype because ATM2 cells secrete IL10. In contrast, obesity induces lipolysis and release of pro-inflammatory FFAs and factors, such as chemokine (C-C motif) ligand 2 (CCL2) and tumor necrosis factor alpha (TNF-α), which recruit blood monocytes in adipose tissue, where they are converted to macrophages of the highly pro-inflammatory M1-type (ATM1). Activated ATM1 produce large amounts of pro-inflammatory mediators such as TNF-α, interleukin-1β, IL-6, leukotriene B4, nitric oxide (NO), and resistin that work in a paracrine fashion and cause IR in adipose tissue. In the liver, both pro-inflammatory Kupffer cells (M1-KCs) and recruited hepatic macrophages (Ly6Chigh) contribute to decreased hepatic insulin sensitivity. The present mini-review will update the bidirectional interaction between the immune system and obesity-induced changes in metabolism in adipose tissue and liver and the metabolic consequences thereof.

Keywords: ER stress; insulin resistance; macrophages; non-alcoholic fatty liver diseases; obesity; reactive oxygen species; type 2 diabetes.

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Figures

Figure 1
Figure 1
Molecular events that connect inflammation to insulin resistance in obesity. Saturated fatty acids (SFAs) bind to Fetuin-A, an endogenous ligand of toll-like receptor 4 (TLR4) and TLR2, and initiate transcription of interferon regulatory factor 3 (IRF3) in a myeloid differentiation primary response protein 88 (MyD88)–TIR-domain-containing adapter-inducing interferon-β-dependent pathway. Activated IRF3 then translocates to the nucleus and binds to target DNA sequences. Tumor necrosis factor (TNF) protein binds to its receptor and initiates inhibitor of κB (IκB)–NF-κB signaling pathway leading to translocation of NF-κB to the nucleus where it binds to AP-1 DNA sequences. Stimulation leukotriene B4 receptor 1 (LTB41) activates the c-Jun N-terminal kinase pathway, leading to phosphorylation and binding of the c-Jun–c-Fos heterodimer to target genes. NF-κB, c-Jun–c-Fos, and IRF3 induce expression of inflammatory factors such as cytokines, chemokines, and components of the inflammasome. When inflammasome is assembled, pro-caspase-1 is converted to caspase-1, which then converts pro-interleukin-1β (IL-1β) and pro-IL-18 to IL-1β and IL-18, respectively. I, insulin; insulin receptor; IRS, insulin receptor substrate.
Figure 2
Figure 2
Schematic diagram showing obesity-induced inflammation in peripheral organs including adipose tissue, the liver, skeletal muscle, and the pancreas to cause dysbiosis in the intestine. In adipose tissue, pro-inflammatory signaling induces lipolysis and release of free fatty acids eventuating in the development of insulin resistance. In the liver, obesity induces pro-inflammatory cytokine production and M1 macrophage recruitment, resulting in insulin resistance and steatosis. In skeletal muscle of obese rodents, accumulations of lipid and pro-inflammatory macrophage inhibit insulin signaling, which result in the development of insulin resistance. In the pancreas, obesity induces macrophage infiltration, interleukin-1β secretion, and decreases insulin secretion. Because of the change in the composition of the microbial population, dysbiosis occurs in the intestine. AC, adipocyte; KC, Kupffer cell; L, lipid droplets; M1Φ, classically activated macrophages/pro-inflammatory macrophages; M2Φ, alternatively activated macrophages/anti-inflammatory macrophages; NK, natural killer cell; PMN, polymorphonuclear neutrophil; WAT, white adipose tissue.
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