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Chemotactic Cytokines, Obesity and Type 2 Diabetes: in Vivo and in Vitro

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Chemotactic Cytokines, Obesity and Type 2 Diabetes: in Vivo and in Vitro Proceedings of the Nutrition Society (2009), 68, 378–384 doi:10.1017/S0029665109990218 g The Authors 2009 First published online 24 August 2009 A Meeting of the Nutrition Society, hosted by the Scottish Section, was held at the Royal Society of Edinburgh, Edinburgh on 7 and 8 April 2009 Symposium on ‘Frontiers in adipose tissue biology’ Chemotactic cytokines, obesity and type 2 diabetes: in vivo and in vitro evidence for a possible causal correlation? Henrike Sell and Ju¨rgen Eckel* Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Du¨sseldorf, Germany A strong causal link between increased adipose tissue mass and insulin resistance in tissues such as liver and skeletal muscle exists in obesity-related disorders such as type 2 diabetes. Increased adipose tissue mass in obese patients and patients with diabetes is associated with altered secretion of adipokines, which also includes chemotactic proteins. Adipose tissue releases a wide range of chemotactic proteins including many chemokines and chemerin, which are interesting targets for adipose tissue biology and for biomedical research in obesity and obesity-related diseases. This class of adipokines may be directly linked to a chronic state of low-grade inflammation and macrophage infiltration in adipose tissue, a concept intensively studied in adipose tissue biology in recent years. The inflammatory state of adipose tissue in obese patients may be the most important factor linking increased adipose tissue mass to insulin resistance. Furthermore, chemoattractant adipokines may play an important role in this situation, as many of these proteins possess biological activity beyond the recruitment of immune cells including effects on adipogenesis and glucose homeostasis in insulin-sensitive tissues. The present review provides a summary of experimental evidence of the role of adipose tissue-derived chemotactic cytokines and their function in insulin resistance in vivo and in vitro. Chemokine: Chemerin: Insulin resistance: Adipose tissue: Obesity Proceedings of the Nutrition Society Obesity with increased adipose tissue mass is associated adipokines. Increased adipose tissue mass in obese patients with insulin resistance, hyperglycaemia, dyslipidaemia, and patients with diabetes has been found to be associated hypertension and other components of the metabolic syn- with altered secretion of adipokines, the most important of drome(1,2). Type 2 diabetes has markedly increased in which are TNFa, IL-6 and adiponectin(7). Adipose tissue prevalence; 50% of men and 70% of women with diabetes also releases a wide range of chemotactic proteins includ- are obese and obesity predisposes strongly to diabetes(3). ing many chemokines, which are becoming increasingly Furthermore, type 2 diabetes is becoming a serious health interesting in relation to adipose tissue biology as well as issue in overweight or obese children and adolescents(4). biomedical research in obesity and obesity-related dis- Indeed, there is clearly a strong causal link between eases. This class of adipokines may be directly linked to a increased adipose tissue mass and insulin resistance in chronic state of low-grade inflammation and macrophage tissues such as liver and skeletal muscle in patients with infiltration in adipose tissue, a concept that has been diabetes(5,6). intensively studied in adipose tissue biology in recent Adipocytes, the predominant cell type in adipose tissue, years. The inflammatory state of adipose tissue in obese are insulin-sensitive cells that store TAG, but in addition patients may be the most important factor linking increased to their storage function they are also active endocrine adipose tissue mass to insulin resistance, and chemo- cells that produce and release various proteins termed attractant adipokines might play an important role in this Abbreviations: CCR, chemokine CC motif receptor; CMKLR1, chemokine-like receptor 1; CXCL, chemokine CXC motif ligand; MCP, monocyte chemoattractant protein. *Corresponding author: Professor Ju¨rgen Eckel, fax + 49 211 3382697, email [email protected] Downloaded from https://www.cambridge.org/core. IP address: 170.106.33.19, on 29 Sep 2021 at 12:17:59, subject to the Cambridge Core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/10.1017/S0029665109990218 Chemotactic cytokines, obesity and type 2 diabetes 379 Table 1. Clinical data showing the association between chemotactic cytokines and obesity and type 2 diabetes Chemotactic cytokine Clinical data related to obesity and type 2 diabetes References MCP-1 (CCL2) Increased in obesity and diabetes Christiansen et al.(11), Kim et al.(12), Herder et al.(13), Malavazos et al.(14), Huber et al.(15), Piemonti et al.(16), Simeoni et al.(17) RANTES (CCL5) Associated with diabetes Herder et al.(26) MCP-3 (CCL7) Elevated in obesity Jiao et al.(25) MCP-2 (CCL8) Elevated in obesity Huber et al.(15), Murdolo et al.(24) Eotaxin (CCL11) Increased in obesity but not associated with Hashimoto et al.(23), Vasudevan et al.(27) insulin resistance MCP-4 (CCL13) Elevated in obesity Hashimoto et al.(23) CXCL5 Linking obesity and insulin resistance Chavey et al.(32) IL-8 (CXCL8) Increased in obesity and diabetes Kim et al.(12), Herder et al.(13) IP-10 (CXCL10) Increased in obesity but not associated with Herder et al.(26,31) insulin resistance Chemerin Increased in obesity but not related to Bozaoglu et al.(9) type 2 diabetes MCP, monocyte chemoattractant protein; CCL, chemokine CC motif ligand; CXCL, chemokine CXC motif ligand; IP-10, 10 kDa interferon g-induced protein. scenario. The present review provides a summary of tissue such as visceral, subcutaneous and epicardial adi- experimental evidence of the role of adipose tissue-derived pose tissue show increased expression of MCP-1(14,15). chemoattractant proteins and their function in insulin resis- Clinical data provide good evidence for a relationship tance in vivo and in vitro. The aim is to provide an overview between serum MCP-1 levels and insulin resistance, as of known relationships between the chemokines and chemo- well as type 2 diabetes. Several studies have demonstrated tactic cytokines being released from adipose tissue and that patients with type 2 diabetes display elevated MCP-1 obesity and type 2 diabetes. Mechanisms of obesity-related levels(13,16,17). High MCP-1 levels have been shown to disorders that underlie adipose tissue inflammation and that contribute to diabetes risk independently of previously- may be related to chemotactic cytokines are also discussed. described clinical, metabolic and immunological risk factors(13). Conversely, diabetes treatments such as exer- cise(18), pioglitazone(19) and weight loss(20), all of which improve insulin sensitivity in obese patients, reduce MCP-1 Chemotactic proteins in obesity and type 2 diabetes plasma concentrations. Expression of MCP-1 has been Chemotactic proteins, particularly those of the chemokine found to be higher in visceral adipose tissue than in sub- family, have been shown to be related in vivo to the cutaneous tissue and is closely related to the number of metabolic syndrome, obesity and type 2 diabetes (Table 1) resident macrophages(21). Conversely, obese patients that and to be adipokines secreted from adipocytes or other cell lose weight after bariatric surgery show decreased levels of types residing in adipose tissue. Chemokines are small MCP-1(20), probably in parallel with lower macrophage proteins that attract various immune cells such as mono- infiltration in adipose tissue(22). Proceedings of the Nutritioncytes, Society neutrophils, T lymphocytes, basophils or eosinophils Fewer data are available for other MCP such as MCP-2, (each chemokine activating one or more target cell -3 and -4 but it is clear that these adipokines are elevated types)(8). Chemokines are characterized by the presence of in obese patients(15,23–25). Measurement of these factors in four highly-conserved cysteine residues. CXC chemokines adipose tissue has shown a marked increase in expression have two amino-terminal cysteine residues separated by together with an increased expression of the corresponding only one amino acid. In CC chemokines, the other main receptors in obese patients(15). subfamily of chemokines, the amino-terminal cysteine Other CC chemokines such as RANTES (or chemokine residues are adjacent(8). In addition, other chemoattractant CC motif ligand 5) and eotaxin (or chemokine CC motif proteins such as chemerin, which has been shown to attract ligand 11) are also elevated in the serum of obese patients macrophages and dendritic cells but is not structurally as compared with lean controls(23,26,27). Eotaxin is over- related to any chemokine family, comprise the adipokines expressed in visceral adipose tissue of obese patients as and factors shown to be involved in obesity and obesity- compared with lean controls and subcutaneous fat. While related pathologies(9). RANTES has also been found to be associated with type 2 Monocyte chemoattractant protein (MCP)-1 is a chemo- diabetes in a large German study cohort, eotaxin is not kine and a member of the small inducible cytokine family associated with insulin resistance(26). that plays a role in the recruitment of monocytes and T IL-8 and 10 kDa interferon g-induced protein (or chemo- lymphocytes to sites of injury and infection(10). Its main kine CXC motif ligand (CXCL) 10) are CXC chemokines. receptor is the chemokine CC motif receptor (CCR) 2. IL-8 is secreted from adipose tissue and its plasma levels Plasma MCP-1 levels are markedly higher in obese are increased in obesity(28–30). However, a correlation patients(11,12) and patients with diabetes(13), and in relation between higher levels of IL-8 in obesity and increased to these pathologies MCP-1 is one of the most studied insulin resistance has not yet been fully established, as the chemokines. In obese patients different depots of adipose association between IL-8 and diabetes(13) is attenuated by Downloaded from https://www.cambridge.org/core. IP address: 170.106.33.19, on 29 Sep 2021 at 12:17:59, subject to the Cambridge Core terms of use, available at https://www.cambridge.org/core/terms.
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