*2.3.3. LTB4 and BLT-1*

LTB4 is a kind of proinflammatory lipid mediator generated from arachidonic acid [59, 60]. LTB4 is rapidly produced by activated leukocytes, it promotes leukocyte chemotaxis, and regulates proinflammatory cytokines [59, 61]. The biological actions of LTB4 are mediated by an interaction with a G protein-coupled receptor termed BLT-1 [61]. Although the LTB4/BLT-1 axis plays a critical role in host defense during acute infection, chronic activation of this pathway provides continuous inflammation, which is feature of inflammatory pathologies such as atherosclerosis and arthritis [62-67]. Moreover, LTB4 levels increased in adipose tissue of both mice and rats consuming a HFD [67-69]. Spite et al. reported that deficiency of BLT-1 protects against the progression of insulin resistance in DIO by regulating ATM accumulation and inflammation in peripheral tissues [70].

## *2.3.4. Fractalkine (CX3CL1) and CX3CR1*

CX3CL1, a chemokine that binds to a single known receptor (CX3CR1), is involved in the recruitment and adhesion of both monocytes and T cells in atherosclerosis and rheumatologic disorders [71]. CX3CR1 is a G-protein-coupled receptor expressed in many leukocyte subtypes [72, 73] and promotes leukocyte activation and survival [74]. To develop macrophage-rich atherosclerotic lesions, CX3CR1 is required for monocyte recruitment. [75, 76]. Digby et al. suggested that adipocytes also expressed CX3CL1 and that CX3CR1 signaling in macrophages was inhibited by PPARγ agonists [77]. Moreover, modulation of the CX3CL1/CX3CR1 system can regulate chronic inflammatory diseases, including atherosclerosis, independent of CCL2/ CCR2 [78], which indicates that this also occur in adipose tissue inflammation and its related complications. Recently, Shah et al. found that CX3CL1 is one of markedly upregulated genes in human adipose tissue through *in vivo* inflammation by using a microarray of adipose tissue mRNA during experimental endotoxemia [79, 80].

## *2.3.5. CXCL14*

CXCL14 (originally designated as BRAK, BMAC, or Mip-2g) is expressed in WAT, brown adipose tissue (BAT), and skeletal muscle, which indicates that it may have a role in adipogenesis, myogenesis, and metabolic complications. CXCL14, as a chemoattractant, is

required for activated tissue macrophages and dendritic cells [81-87]. Nara et al. generat‐ ed *Cxcl14* deficient mice and described that CXCL14 is involved in the obesity-induced infiltration of macrophages into WAT, serum adipokine levels, hepatic steatosis, and attenuation of insulin signaling in skeletal muscle; thereby, contributing to systemic insulin resistance in DIO mice [88].

## *2.3.6. Osteopontin*

CCL5 production in fibroblasts, platelets, and monocytes/macrophages is a known feature of inflammatory disorders [56]. In atherosclerosis, CCL5, via CCR1 and CCR5, contributes to

Kitade et al. revealed that CCR5 plays a crucial role in the regulation of adipose tissue inflammation in obesity and the development of insulin resistance [58]. Expression of CCR5 and its ligands is highly increased in WAT of both *ob/ob* and DIO mice. FACS analysis clearly

improved obesity-induced insulin resistance in mice. Both *Ccr5-/-*mice fed a HFD and mice deficient in *Ccr5* bone marrow-derived cells showed ameliorated insulin sensitivity and protection from obesity-induced insulin resistance via reduction of ATM accumulation.

LTB4 is a kind of proinflammatory lipid mediator generated from arachidonic acid [59, 60]. LTB4 is rapidly produced by activated leukocytes, it promotes leukocyte chemotaxis, and regulates proinflammatory cytokines [59, 61]. The biological actions of LTB4 are mediated by an interaction with a G protein-coupled receptor termed BLT-1 [61]. Although the LTB4/BLT-1 axis plays a critical role in host defense during acute infection, chronic activation of this pathway provides continuous inflammation, which is feature of inflammatory pathologies such as atherosclerosis and arthritis [62-67]. Moreover, LTB4 levels increased in adipose tissue of both mice and rats consuming a HFD [67-69]. Spite et al. reported that deficiency of BLT-1 protects against the progression of insulin resistance in DIO by regulating ATM accumulation

CX3CL1, a chemokine that binds to a single known receptor (CX3CR1), is involved in the recruitment and adhesion of both monocytes and T cells in atherosclerosis and rheumatologic disorders [71]. CX3CR1 is a G-protein-coupled receptor expressed in many leukocyte subtypes [72, 73] and promotes leukocyte activation and survival [74]. To develop macrophage-rich atherosclerotic lesions, CX3CR1 is required for monocyte recruitment. [75, 76]. Digby et al. suggested that adipocytes also expressed CX3CL1 and that CX3CR1 signaling in macrophages was inhibited by PPARγ agonists [77]. Moreover, modulation of the CX3CL1/CX3CR1 system can regulate chronic inflammatory diseases, including atherosclerosis, independent of CCL2/ CCR2 [78], which indicates that this also occur in adipose tissue inflammation and its related complications. Recently, Shah et al. found that CX3CL1 is one of markedly upregulated genes in human adipose tissue through *in vivo* inflammation by using a microarray of adipose tissue

CXCL14 (originally designated as BRAK, BMAC, or Mip-2g) is expressed in WAT, brown adipose tissue (BAT), and skeletal muscle, which indicates that it may have a role in adipogenesis, myogenesis, and metabolic complications. CXCL14, as a chemoattractant, is

macrophages accumulate in WAT of obese mice. The loss of CCR5

transmigration of monocytes and T cells in atherogenic lesions [57].

demonstrated that CCR5+

140 Glucose Homeostasis

*2.3.3. LTB4 and BLT-1*

and inflammation in peripheral tissues [70].

mRNA during experimental endotoxemia [79, 80].

*2.3.5. CXCL14*

*2.3.4. Fractalkine (CX3CL1) and CX3CR1*

Osteopontin (OPN) is a secreted matrix glycoprotein and proinflammatory cytokine that has previously been reported as a major element of cell-mediated immunity [89]. Many studies have provided evidence that OPN is secreted by macrophages at sites of inflammation where it mediates monocyte adhesion [90], migration [91], differentiation [92], and phagocytosis [93]. OPN play a role in the development of atherosclerosis. OPN induces chemotaxis of monocytes and elevates cellular migration through a direct interaction with its receptors [94, 95]. No‐ miyama et al. demonstrated that OPN secretion is upregulated during obesity and greatly expressed in ATMs of DIO mice, characterizing OPN as an adipokine. OPN deficiency attenuated ATM accumulation, adipose tissue inflammation and improved whole body insulin resistance [96].

#### *2.3.7. Apoptosis inhibitor of macrophage (AIM/CD5L)*

AIM [97] is incorporated into adipocytes via CD36-associated endocytosis, and it mediated lipolysis by suppressing the activity of fatty acid synthase (FAS) [98]. AIM is a member of the scavenger receptor cysteine-rich superfamily and was initially characterized as an apoptosis inhibitor that supports the survival of macrophages against apoptosis-inducing stimuli [97]. AIM is a direct target for regulation by nuclear receptor liver X receptor/retinoid X receptor (LXR/RXR) heterodimers [99, 100], and it is exclusively produced by tissue macrophages. As a secreted molecule, AIM is found in both human and mouse blood [97, 100-103] and increases in blood with the progression of obesity in DIO mice [98]. AIM-associated lipolysis is respon‐ sible for the obesity-induced recruitment of ATMs. Kurokawa et al. demonstrated the role of AIM in the initiation of adipose tissue inflammation that links obesity and insulin resistance [104]. Firstly, AIM-induced lipolysis is required for macrophage recruitment into obese adipose tissues. Increased blood AIM levels induce dynamic lipolysis in obese adipose tissues, augmenting local extracellular fatty acid concentrations to a level sufficient for the stimulation of TLR4, which promotes chemokine production by adipocytes and macrophage infiltration. Secondly, an increase in blood AIM is required as well as adipocyte hypertrophy for the initiation of macrophage recruitment. In *AIM* deficient mice, although the level of AIMindependent lipolysis escalated in line with adipocyte hypertrophy [98], it may not reach a level sufficient for macrophage infiltration. Thirdly, crosstalk between adipocytes and macrophages within adipose tissue establishes a vicious circle that accelerates inflammation; saturated fatty acids brought about by lipolysis activated TLR4 to induce TNFα, which in turn activated the TNFα receptor to produce inflammatory cytokines [105]. This response induces a further progression of inflammation, lipolysis, and macrophage recruitment.

#### *2.3.8. Macrophage migration inhibitory factor (MIF)*

MIF is a multifunctional proinflammatory cytokine which is responsible for inflammatory processes. The primary source and target of MIF have been identified as macrophages [106]. MIF is rapidly released in response to inflammatory stimuli such as lipopolysaccharide, TNFα, and IFN-γ. MIF can have both paracrine and autocrine effects [106-108]. MIF elevates adipose tissue inflammation through amplification of migration, recruitment, and activation of leukocytes at the site of inflammation through upregulation of adhesion molecules such as ICAM-1 and MCP-1 [109-111]. MIF can utilize its chemotactic properties via CXCR2 and CXCR4 in macrophages and T cells, respectively [111]. The interaction of MIF with CXCR4 on the surface of fibroblasts and T cells induced CXCL8 secretion [112]. Interestingly, the alter‐ native MIF receptor CD74, which is traditionally involved in the activation of the mitogenactivated protein kinases pathway, has recently been demonstrated to also mediate macrophage chemotactic responses [113, 114]. Although these roles in macrophage recruit‐ ment have been demonstrated, a recent study showed MIF-/-mice did not exhibit significant changes in ATM content compared to WT mice when fed a HFD [115].

**Author details**

Stockholm, Sweden

**References**

, Jong Hyuk Yoon1

Pohang, Gyeongbuk, Republic of Korea

Pubmed Central PMCID: 3104761.

PMID: 17875176.

Jun;65(6):1774-82. PubMed PMID: 9174472.

23307735. Pubmed Central PMCID: 3725457.

21252989. Pubmed Central PMCID: 3518031.

Pubmed Central PMCID: 3725458.

Pubmed Central PMCID: 296998.

\*Address all correspondence to: sungho@postech.ac.kr

, Jaeyoon Kim2

1 Department of Life Sciences, Pohang University of Science and Technology (POSTECH),

2 The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet,

[1] Sun K, Kusminski CM, Scherer PE. Adipose tissue remodeling and obesity. The Jour‐ nal of clinical investigation. 2011 Jun;121(6):2094-101. PubMed PMID: 21633177.

[2] Aarsland A, Chinkes D, Wolfe RR. Hepatic and whole-body fat synthesis in humans during carbohydrate overfeeding. The American journal of clinical nutrition. 1997

[3] Henry BA, Clarke IJ. Adipose tissue hormones and the regulation of food intake. Journal of neuroendocrinology. 2008 Jun;20(6):842-9. PubMed PMID: 18601708.

[4] Ferrante AW, Jr. Obesity-induced inflammation: a metabolic dialogue in the lan‐ guage of inflammation. Journal of internal medicine. 2007 Oct;262(4):408-14. PubMed

[5] Odegaard JI, Chawla A. Pleiotropic actions of insulin resistance and inflammation in metabolic homeostasis. Science. 2013 Jan 11;339(6116):172-7. PubMed PMID:

[6] Ouchi N, Parker JL, Lugus JJ, Walsh K. Adipokines in inflammation and metabolic disease. Nature reviews Immunology. 2011 Feb;11(2):85-97. PubMed PMID:

[7] Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature. 2013 Apr 25;496(7446):445-55. PubMed PMID: 23619691.

[8] Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. The Journal of clinical investigation. 2003 Dec;112(12):1821-30. PubMed PMID: 14679177.

and Sung Ho Ryu1\*

Adipokines Involved in Macrophage Recruitment

http://dx.doi.org/10.5772/57558

143

Dayea Kim1
