Diabetes Metab J.  2013 Jun;37(3):165-172. 10.4093/dmj.2013.37.3.165.

Chemokine Systems Link Obesity to Insulin Resistance

• Ota T

• KMID: 2174289
• DOI: http://doi.org/10.4093/dmj.2013.37.3.165

Abstract

Obesity is a state of chronic low-grade systemic inflammation. This chronic inflammation is deeply involved in insulin resistance, which is the underlying condition of type 2 diabetes and metabolic syndrome. A significant advance in our understanding of obesity-associated inflammation and insulin resistance has been recognition of the critical role of adipose tissue macrophages (ATMs). Chemokines are small proteins that direct the trafficking of immune cells to sites of inflammation. In addition, chemokines activate the production and secretion of inflammatory cytokines through specific G protein-coupled receptors. ATM accumulation through C-C motif chemokine receptor 2 and its ligand monocyte chemoattractant protein-1 is considered pivotal in the development of insulin resistance. However, chemokine systems appear to exhibit a high degree of functional redundancy. Currently, more than 50 chemokines and 18 chemokine receptors exhibiting various physiological and pathological properties have been discovered. Therefore, additional, unidentified chemokine/chemokine receptor pathways that may play significant roles in ATM recruitment and insulin sensitivity remain to be fully identified. This review focuses on some of the latest findings on chemokine systems linking obesity to inflammation and subsequent development of insulin resistance.

Keyword

Adipokines; Adipose tissue macrophage; C-C motif chemokine receptor 2; C-C motif chemokine receptor 5; Chemokine CCL2; Chemokines; Diabetes mellitus, type 2; Inflammation; Insulin resistance; Macrophage polarization

MeSH Terms

Adipokines
Adipose Tissue
Aluminum Hydroxide
Carbonates
Chemokine CCL2
Chemokines
Cytokines
Diabetes Mellitus, Type 2
Inflammation
Insulin
Insulin Resistance
Macrophages
Obesity
Proteins
Receptors, Chemokine
Adipokines
Aluminum Hydroxide
Carbonates
Chemokine CCL2
Chemokines
Cytokines
Insulin
Proteins
Receptors, Chemokine

Figure

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  Fig. 1 C-C motif chemokine receptor 5 (CCR5) promotes obesity-induced inflammation and insulin resistance. Kitade et al. [33] recently identified and characterized a role for CCR5, a CC chemokine receptor, and made several important observations. First, expression of CCR5 and its ligands is significantly increased and is equal to that of CCR2 and its ligands in white adipose tissue (WAT) of obese mice. Second, CCR5+ adipose tissue macrophages (ATMs) accumulate in WAT of obese mice. Third, Ccr5-/- mice are protected from insulin resistance and diabetes through both reduction in ATM accumulation and induction of an alternatively activated, M2 dominant shift in ATM. Taken together, these data indicate that CCR5 provides a novel link between obesity, adipose tissue inflammation, and insulin resistance. TNF, tumor necrosis factor; IL, interleukin; MCP, monocyte chemoattractant protein.

• 

  Fig. 2 Hypothetical role of C-C motif chemokine receptor 5 (CCR5) and monocyte chemoattractant protein (MCP)-1-CCR2 in the development of adipose tissue inflammation and insulin resistance in obesity. Obesity causes both the recruitment and proiflammatory activation of adipose tissue macrophages (ATMs). Adipocytes or preadipocytes begin to secrete MCP-1 as well as other chemokines, such as MIP1α, MIP1β, and RANSTES (ligands for CCR5) in obesity. Thereafter, CCR2+ and/or CCR5+ macrophages accumulate and presumably maintain the inflammation as M1 or classically activated macrophages in obese adipose tissue. Ly6Chi monocytes exit the bone marrow in a CCR2-dependent manner and are recruited to inflamed tissues. CCR5 may also regulate recruitment of Ly6Chi and Ly6C- monocytes and their fate as M1/M2 ATMs. Once these ATMs are present and active, cytokines (tumor necrosis factor [TNF]-α, interleukin [IL]-6, and IL-1β) are produced. Therefore, CCR5, independently from and/or cooperatively with CCR2, could play an important role in the induction and maintenance of obesity-induced inflammation and insulin resistance.

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