Diabetes 2013 July-24

 

The role of innate immune cells in obese adipose tissue inflammation and development of insulin resistance

Thromb Haemost. 2013 Mar 5;109(3):399-406.

Jindrich Chmelar,1, 2, Kyoung-Jin Chung,1, Triantafyllos Chavakis 1

1 on Vascular Inflammation, Diabetes and Kidney, Department of Medicine, University Clinic Carl-Gustav-Carus, Technical University Dresden, Fetscherstrasse 74, 01307 Dresden, Germany

2 Institute of Parasitology, Biology Centre, ASCR, Branišovská 31, 370 05 České Budějovice, Czech Republic

 

BACKGROUND: Obesity is characterized by a chronic state of low grade inflammation in different tissues including the vasculature. There is a causal link between adipose tissue inflammation and obesity-related metabolic complications, such as the development of insulin resistance and subsequently of type 2 diabetes. Many immune cell types were found to be involved in the development and promotion of these metabolic complications. For several years, however, the focus was aimed mainly at adipose tissue macrophages and T-cell subpopulations. Several recent major works showed that other leukocyte populations of innate branch of immunity, i.e. dendritic cells, mast cells, neutrophils, natural killer cells and eosinophils are also important in the obesity, having specific roles.

DESIGN: In this review we overviewed thoroughly the state of knowledge about the role of various innate immune cells in obesity and related metabolic disorders.

RESULTS: Several recent works revealed the importance of innate immune cells -apart from macrophages- in obesity: Dendritic cells seem to positively affect the infiltration of pro-inflammatory M1 macrophages into adipose tissue 1, neutrophils can promote macrophages infiltration, but also influence insulin resistance directly by the secretion of elastase 2. Eosinophils were found to sustain the presence of antiinflammatory M2 macrophages in white adipose tissue by secreting IL-4 and IL-13, thus keeping normal physiological state in the lean adipose tissue 3. Mast cells are important inflammatory modulators, resident in various tissues including white adipose tissue.  Mast cell deficiency or prevention from degranulation leads to protection from obesity and from metabolic dysregulation in mice 4. This is just a brief summary, which is in graphical form described in the figure 1.

CONCLUSION: Other leukocyte populations, aside macrophages, have been neglected in obesity and diabetes research for some time, but recent findings showed that all immune cell types play some role in the development of obesity related complications.

 

  1. Stefanovic-Racic M, Yang X, Turner MS, et al. Dendritic cells promote macrophage infiltration and comprise a substantial proportion of obesity-associated increases in CD11c+ cells in adipose tissue and liver. Diabetes. Sep 2012;61(9):2330-2339.
  2. Talukdar S, Oh DY, Bandyopadhyay G, et al. Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase. Nat Med. Aug 5 2012.
  3. Wu D, Molofsky AB, Liang HE, et al. Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science. Apr 8 2011;332(6026):243-247.
  4. Liu J, Divoux A, Sun J, et al. Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice. Nat Med. Aug 2009;15(8):940-945.

 

Supplementary information:

Jindrich Chmelar-2

Figure 1. The function of innate immune cells in the white adipose tissue (WAT). The healthy lean WAT (homeostasis) contains eosinophils that promote the presence of M2 macrophages in the WAT via IL-4 and IL-13 secretion. Caloric excess induces the accumulation of neutrophils, pro-inflammatory M1 macrophages and mast cells in the WAT. Neutrophils secrete elastase, which contributes to M1-polarization of macrophages via TLR-4. Activated M1 macrophages further contribute to insulin resistance in WAT by releasing pro-inflammatory cytokines, mainly TNF and IL-6. Neutrophil elastase-driven degradation of IRS-1 leads to lower insulin sensitivity in the obese WAT and liver. The increased mast cells number in the obese WAT also correlates with impaired insulin sensitivity. Mast cells-derived cytokines may affect M1-polarization in the obese AT, whereas mast cells-derived prostaglandins regulate WAT derived PPAR-γ, which in turn is a major regulator of insulin sensitivity. Dendritic cells contribute to M1 macrophage accumulation in the obese WAT and can affect liver steatosis and insulin resistance in both the liver and the AT.

 

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