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Role of anti-inflammatory adipokines in obesity-related diseases Koji Ohashi1, Rei Shibata2, Toyoaki Murohara2, and Noriyuki Ouchi1 1 2

Department of Molecular Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-Ku, Nagoya, Japan Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-Ku, Nagoya, Japan

Obesity results in many health complications. Accumulating evidence indicates that the obese state is characterized by chronic low-grade inflammation, thereby leading to the initiation and progression of obesity-related disorders such as type 2 diabetes, hypertension, cardiovascular disease, and atherosclerosis. Fat tissue releases numerous bioactive molecules, called adipokines, which affect whole-body homeostasis. Most adipokines are proinflammatory, whereas a small number of anti-inflammatory adipokines including adiponectin exert beneficial actions on obese complications. The dysregulated production of adipokines seen in obesity is linked to the pathogenesis of various disease processes. In this review we focus on the role of the anti-inflammatory adipokines that are of current interest in the setting of obesity-linked metabolic and cardiovascular diseases. Introduction Obesity is a pandemic social problem worldwide. Excess fat accumulation is causally linked with various metabolic risk factors including type 2 diabetes, hypertension, and dyslipidemia, finally leading to the development of cardiovascular disease [1,2]. It is well established that obesity, in particular, visceral fat accumulation causes chronic lowgrade inflammation, which contributes to the initiation and progression of metabolic disorders [3–5]. Adipose tissue is an active endocrine organ and secretes a variety of bioactive molecules known as adipokines [3,6,7]. The adipokines comprise a large number of proinflammatory mediators, including tumor necrosis factor (TNF)-a, monocyte chemoattractant protein (MCP)-1, and interleukin (IL)-6, that promote disease progression. By contrast, a small number of anti-inflammatory adipokines, which are downregulated by obese states, seem to protect against the development of obese complications [3,7–9]. In this review we discuss recent progress in our understanding of the action of anti-inflammatory adipokines in the context of metabolism and cardiovascular disease. Adiponectin Adiponectin, also referred to as ACRP30 (adipocyte complement-related 30 kDa protein), is an adipocyte-specific Corresponding authors: Shibata, R. ([email protected]); Ouchi, N. ([email protected]). Keywords: adiponectin; CTRP3; CTRP9; adipolin; omentin-1. 1043-2760/ ß 2014 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.tem.2014.03.009

adipokine found in human plasma at concentrations ranging from 3 to 30 mg/ml [10,11]. Adiponectin contains a collagen-repeat domain and a globular domain with a sequence homology to complement factor C1q. It is well established that adiponectin levels in plasma are negatively associated with the accumulation of body fat, particularly visceral fat [12], and that plasma adiponectin levels are low in obese individuals. Clinical studies indicate a close association of low adiponectin levels with many obesity-related disorders [13–15]. In addition, plasma levels of C-reactive protein (CRP), an acute-phase protein that is elevated in inflammation, and IL-6 levels are both negatively correlated with plasma adiponectin levels [16,17]. Bodyweight reduction in obese women through lifestyle changes is associated with a reduction in various inflammatory markers, including CRP and IL-6, as well as an increase in adiponectin [17]. Furthermore, CRP expression is observed in human adipose tissue, and CRP transcript expression inversely correlates with adiponectin mRNA levels in human adipose tissue [16]. Thus, the reciprocal association of adiponectin and the inflammatory mediators may participate in the development of obese complications. Consistent with these clinical findings, several experimental studies indicate a protective anti-inflammatory Glossary AMP-activated protein kinase (AMPK): AMPK acts as an energy sensor in response to low AMP concentration. AMPK promotes glucose uptake, glycolysis, and fatty acid oxidation, and inhibits the synthesis of glucose and fatty acids. AMPK is also activated by various hormonal signals including adiponectin and leptin. In addition to metabolic functions, AMPK signaling exerts many protective functions against cardiovascular disorders. Apolipoprotein E (ApoE): ApoE is a major apolipoprotein which acts as a ligand for the low-density lipoprotein (LDL) and very low density lipoprotein (VLDL) receptors in the liver. ApoE deficient mice show remarkable hypercholesterolemia and severe atherosclerosis. Inflammatory cytokines: in the obese state, many inflammatory cytokines such as TNF-a, IL-6, monocyte chemotactic protein (MCP)-1, macrophage, migration inhibitory factor (MIF), and CCL4 are increased in systemic organs, thereby leading to insulin resistance, hypertension, and cardiovascular disease. Kru¨ppel-like factor (KLF): a family of zinc-finger transcription factors that recognize GC-rich elements and CACCC boxes. KLF family proteins are ubiquitously expressed and modulate several obesity-related inflammatory states and metabolic dysfunction. Ob/ob mice: mice that lack leptin, a fat-derived anorexigenic hormone that controls appetite via its action in the hypothalamus. Ob/ob mice are severely obese and insulin resistant, and are used as an animal model for the study of type 2 diabetes. 3T3-L1 adipocytes: cells derived from mouse fibroblast clones, which are able to differentiate into adipocytes when treated with insulin, 1-methyl-3-isobutylxanthine, and dexamethasone. 3T3-L1 adipocytes are widely used as cultured adipocytes in in vitro studies. Trends in Endocrinology and Metabolism xx (2014) 1–8

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Figure 1. Anti-inflammatory actions of adiponectin. Adiponectin exerts anti-inflammatory actions on macrophages, endothelial cells, cardiomyocytes, and fibroblasts. Adiponectin attenuates foam cell transformation of macrophages and reduces the expression of tumor necrosis factor (TNF)-a and matrix metalloproteinase (MMP)-12 in macrophages. Adiponectin promotes the phenotypic change of macrophages from inflammatory M1 to anti-inflammatory M2, and enhances clearance of early apoptotic cells. In endothelial cells, adiponectin also reduces the expression of adhesion molecules including vascular cell adhesion molecule (VCAM)-1 and intercellular cell adhesion molecule (ICAM)-1, and also reduces interleukin (IL)-6 expression. Furthermore, adiponectin attenuates TNF-a expression in cardiomyocytes and fibroblasts. Therefore, adiponectin displays a protective action on various organs including heart, vasculature, and lung.

role of adiponectin in obese complications. In vitro experiments showed that treatment with adiponectin protein decreases lipopolysaccharide (LPS)-induced expression of TNF-a in cultured macrophages through inhibition of NFkB signaling [18,19] (Figure 1). Adiponectin also reduces the expression of class A scavenger receptor (SR)-A in human monocyte-derived macrophages and prevents macrophage foam cell formation [20] (Figure 1). In vivo experidemonstrated that adenovirus-mediated ments overexpression of adiponectin attenuates the progression of atherosclerotic lesions in apolipoprotein E (ApoE; see Glossary) knockout (KO) mice, with an accompanying decrease in TNF-a and SR-A expression [21] (Figure 1). Of importance, ApoE/adiponectin (APN) double-KO mice show accelerated atherogenesis, accompanied by increased T lymphocyte accumulation in atherosclerotic lesions, compared to ApoE KO mice [22]. Adiponectin treatment also reduces the infiltration of CD4+ T lymphocytes into atherosclerotic lesions via the suppression of T lymphocyte chemoattractants in macrophages, including the interferon (IFN)-inducible protein, I-TAC (IFN-inducible T cell a chemoattractant and monokine; also known as CXCl11) [22]. After LPS administration the endothelial expression levels of vascular cell adhesion molecule (VCAM)-1 and intercellular cell adhesion molecule (ICAM)-1 are much higher in APN KO mice than in wild type (WT) mice [23]. Thus, it is conceivable that adiponectin protects against atherogenesis, at least in part, by attenuating the inflammatory response in vascular walls. Adiponectin also appears to modulate the inflammatory response in other organs. APN KO mice show increased expression of TNF-a and metalloproteinase (MMP)-12 in lung, and display an emphysema-like phenotype [24]. 2

Treatment of cultured alveolar macrophages with adiponectin reduces TNF-a and MMP-12 expression in response to LPS stimulation. Exaggeration of lung injury and inflammation is observed in APN KO mice after intratracheal injection of LPS. Endothelial cells isolated from lung digests in APN KO mice after LPS administration have increased expression of proinflammatory cytokines including IL-6 compared to WT mice [25]. Furthermore, myocardial ischemia–reperfusion in APN KO mice results in an increase in cardiac infarct size, apoptosis, and TNF-a expression [26]. Conversely, supplementation of adiponectin diminishes infarct size following ischemia–reperfusion in APN KO and WT mice, with accompanying reductions in myocyte apoptosis and TNF-a production. Treatment of cultured cardiac myocytes or fibroblasts with adiponectin also leads to reduced apoptosis and TNF-a production. It has also been shown that adiponectin reduces cardiomyocyte apoptosis by increasing the production of sphingosine1-phosphate through stimulation of ceramidase activity involving its receptors, Adipo R1 and Adipo R2, indicating the possible involvement of sphingolipid metabolism as a mechanism for cardioprotection by this adipokine [27]. Furthermore, adiponectin exerts a protective action on myocardial ischemia–reperfusion damage through reduction of oxidative/nitrative stress [28]. In addition, intracoronary administration of adiponectin protein improves cardiac injury and function, and attenuates inflammatory response after ischemia–reperfusion, in a preclinical pig model [29]. Thus, adiponectin is protective against acute injury of lung or heart by suppressing inflammatory responses in its target cells. In this context, development of an adiponectin-like drug or agonist to adiponectin signals or receptors may be useful for the treatment of acute

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Review tissue injury because AdipoRon, the recently identified agonist of Adipo R1 and Adipo R2, has been shown to improve obesity-related metabolic diseases [30]. Recent reports indicate that adiponectin acts as a modulator of macrophage phenotypes. It was shown that adiponectin switches the phenotype from the proinflammatory classically activated macrophage (M1) to an antiinflammatory alternatively activated macrophage (M2) [31] (Figure 1). Generally, obese adipose tissue is inclined to M1 polarization, which causes exacerbation of inflammation and tissue destruction [32]. By contrast, M2 polarized macrophages exert an anti-inflammatory action and protect against obesity-related metabolic disorders [33]. APN KO mice exhibit increased expression levels of M1related genes, such as TNF-a, IL-6 and MCP-1, in peritoneal macrophages and stromal vascular fractions (SVFs) compared to WT mice [31]. By contrast, treatment of WT mice with adiponectin stimulates the expression of M2related genes, including arginase-1, IL-10, and macrophage galactose N-acetyl-galactosamine specific lectin-1, in peritoneal macrophages and SVFs [31]. Adiponectin also promotes the phenotypic conversion of human monocytederived macrophages into M2 through a peroxisome proliferator-activated receptor (PPAR)-a-dependent mechanism [34]. It has been shown that adiponectin polarizes Kupffer cells and RAW264.7 macrophages to M2 through a mechanism involving the adiponectin receptor AdipoR2 [35]. Thus, these data suggest that adiponectin exhibits anti-inflammatory effects via direct modulation of macrophage phenotype. Of importance, adiponectin enhances the ability of macrophage to remove early apoptotic bodies, which is crucial in preventing inflammation and immune system dysfunction [36]. Ablation of adiponectin leads to impaired clearance of early apoptotic bodies by peritoneal macrophages, and this is associated with increased inflammatory responses such as elevation of TNF-a production [36]. Adiponectin also promotes the removal of apoptotic cells and improves systemic inflammation and the features of autoimmunity in lpr (lymphoproliferation) mice, a valuable model of systemic lupus erythematosus. In cultured macrophages, adiponectin treatment enhances the clearance of apoptotic debris in vitro [36]. Moreover, adiponectin promotes the removal of apoptotic bodies by macrophages through the calreticulin/CD91 system on the cell surface of macrophages [36] (Figure 1). Collectively, adiponectin can switch the function and phenotype of macrophages towards an anti-inflammatory state, and reduce chronic inflammation in target organs including the vasculature, lung, and heart, thereby leading to protection against various obesity-related disorders. C1q/TNF-related protein (CTRP) family A highly conserved family of adiponectin paralogs known as C1q/TNF-related proteins [37], the CTRP family has common structural domains: a signal sequence, a collagenous domain, and a C1q-like globular domain. Similarly to adiponectin, some CTRPs such as CTRP6, CTRP9, and CTRP12 are mainly expressed in adipose tissue [38–40]. Furthermore, several CTRPs have glucose-lowering effects and anti-inflammatory functions.

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CTRP3 CTRP3, also referred to as C1q/TNF-related protein-3, CORS-26, cartducin, or cartonectin, was cloned as a factor induced by transforming growth factor (TGF)-b1 [41]. The protein exists in two alternatively spliced isoforms, CTRP3A and CTRP3B, which differ in length and glycosylation [42]. CTRP3 is synthesized by adipocytes and produced by mesenteric adipose tissue [43,44]. It inhibits LPS-induced expression of macrophage migration inhibitory factor (MIF), MCP-1, and C-C motif chemokine ligand4 (CCL4) in human monocyte-derived macrophages [45], and suppresses chemokine production in response to lauric acid, LPS, or Toll-like receptor (TLR) stimulation in macrophages and adipocytes [44]. Interestingly, CTRP3 stimulates the expression of adiponectin in primary human adipocytes and cultured 3T3-L1 adipocytes [46]. Ablation of CTRP3 by small interfering RNA (siRNA) increases the expression of proinflammatory adipokines including CCL2 and decreases adiponectin expression in preadipocytes [44]. Therefore, CTRP3 may act as an anti-inflammatory adipokine in vitro. It has also been reported that supplementation of exogenous CTRP3 improves post-ischemic cardiac function and remodeling in mice through its ability to promote revascularization and reduce apoptosis in ischemic heart [47]. Future research will be required to clarify the in vivo role of CTRP3 in controlling inflammation and obese complications. CTRP6 Another member of the family is CTRP6, which is abundantly expressed in adipose tissue. CTRP6 exists in the blood as homo-trimers, oligomers, or heteromers with CTRP1 [38]. Obese ob/ob mice and APN KO mice exhibit higher plasma levels of CTRP6 [38]. CTRP6 increases the expression of anti-inflammatory cytokine IL-10 in human monocyte-derived macrophages through the p42/44 mitogen-activated protein kinase (MAPK)-dependent pathway [48]. It also stimulates activation of AMP-activated protein kinase (AMPK) and enhances fatty acid oxidation in skeletal muscle cells [49]. Thus, CTRP6 may affect metabolic function and inflammatory states under conditions of obesity, but this will require future investigation. CTRP9 CTRP9 is the closest paralog of adiponectin among CTRPs and acts as an adipokine that is abundantly expressed in adipose tissue [39]. Plasma CTRP9 levels are decreased in mouse models of obesity [40]. In addition, CTRP9 forms heterotrimers with adiponectin, and shares the receptor Adipo R1 with adiponectin in vascular endothelial cells and cardiac myocytes [39,40,50]. An initial report indicates that CTRP9 has favorable actions on obesity-related metabolic disorders. Systemic delivery of CTRP9 by adenovirus systems attenuates blood glucose levels in genetic obese ob/ob mice [39]. In cultured myocytes, CTRP9 protein activates phosphorylation by signaling molecules including AMPK and Akt (protein kinase B), and promotes glucose uptake induced by insulin [39]. A recent report also demonstrated that CTRP9 transgenic mice show dramatic resistance to diet-induced weight gain and have decreased insulin resistance and hepatic steatosis, with 3

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Figure 2. Regulation and function of adipolin. Kru¨ppel-like factor (KLF)15 transcriptionally increases, whereas KLF3 suppresses, the expression of adipolin. Adipolin is cleaved between amino acids 91-K and 92-S (KK/SR) by furin. Adipolin suppresses the inflammatory response in macrophages. Adipolin enhances glucose uptake in adipocytes and suppresses gluconeogenesis in hepatocytes. The full-length form of adipolin more effectively enhances insulin-stimulated glucose uptake in adipocytes. Abbreviation: SP, signal peptide.

enhanced AMPK activation and fat oxidation in skeletal muscle [51]. These results suggest that CTRP9 may prevent metabolic dysfunction under conditions of obesity via activation of AMPK in muscle. Several reports indicate that CTRP9 exerts beneficial effects on the cardiovascular system. It increases endothelium-dependent vasorelaxation in aortic rings [50], a vasorelaxative effect mediated through its ability to activate the AdipoR1/AMPK/endothelial nitric oxide synthase (eNOS) signaling pathway. Recently, it was demonstrated that systemic delivery of CTRP9 reduces the pathological remodeling of vascular walls in a mouse wire injury model [52]. CTRP9 attenuates vascular smooth-muscle cell (VSMC) proliferation through a cAMP–protein kinase A (PKA)dependent mechanism. Of note, CTRP9-mediated suppression of VSMC growth is independent of AdipoR1 or AMPK signaling. Thus, CTRP9 exerts a vascular protective action via at least two pathways including AMPK and PKA. It was previously shown that intravenous administration of CTRP9 to WT mice reduces myocardial infarct size and cardiomyocyte apoptosis after ischemia–reperfusion [40]. Treatment of cardiac myocytes with CTRP9 protein reduces apoptosis in response to hypoxia–reoxygenation stress via activation of AMPK. In addition, CTRP9 administration to diabetic mice reduces myocardial infarct size and apoptosis, and improves cardiac function after ischemia–reperfusion, by inhibiting oxidative stress signaling [53]. A recent study demonstrated that continuous 4

infusion of CTRP9 protein improves cardiac function, apoptosis, and fibrosis in mice after myocardial infarction (MI) [54]. The cardioprotective action of CTRP9 in vitro is dependent on the PKA signaling pathway. Therefore, both AMPK and PKA pathways mediate the cardiovascular protection by CTRP9. Interestingly, CTRP9 levels decline in plasma and adipose tissue after myocardial ischemia–reperfusion and MI [40,54]. Plasma concentrations of free fatty acid (FFA) and mRNA levels of oxidative stress markers in adipose tissue are elevated after myocardial ischemia–reperfusion [40]. Treatment of 3T3-L1 adipocytes with palmitic acid or an inducer of oxidative stress significantly reduces CTRP9 expression [40], and an excess of fatty acids has been reported to stimulate oxidative stress in adipocytes. These data indicate that increased levels of FFA caused by myocardial ischemia could reduce CTRP9 levels in adipose tissue and blood via enhancement of adipose oxidative stress. Taken together, CTRP9 protects against the development of obesity-linked metabolic dysfunction and cardiovascular disorders. However, further research is needed to dissect the precise mechanism by which CTRP9 regulates metabolic and cardiovascular homeostasis. Adipolin/CTRP12 Recently, CTRP12 was identified as a novel insulinsensitizing adipokine that is abundantly expressed in fat tissue, and was designated adipolin (adipose-derived

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Figure 3. Protective function of omentin-1 in the vasculature. Omentin-1 exerts anti-inflammatory and anti-atherogenic functions in endothelial cells and smooth-muscle cells. Omentin-1 attenuates monocyte adhesion to endothelial cells by decreasing the expression of vascular cell adhesion molecule (VCAM)-1 and intercellular cell adhesion molecule (ICAM)-1 through suppression of extracellular signal-regulated kinase (ERK)/nuclear factor (NF)-kB signaling within endothelial cells. Omentin-1 promotes vasodilation and endothelial cell differentiation and survival through activation of the AMP activated protein kinase (AMPK)/endothelial nitric oxide synthase (eNOS) pathway. Omentin-1 inhibits inflammation in endothelial cells by suppressing c-Jun N-terminal kinase (JNK) activation through an AMPK/eNOS-dependent pathway. Omentin-1 also attenuates monocyte adhesion to smooth-muscle cells by reducing expression of VCAM-1 and ICAM-1 through suppression of p38/JNK signaling.

insulin-sensitizing factor) [9]. Adipolin has comparatively less homology with adiponectin than other CTRPs [9,55]. Adipolin expression in fat tissue is decreased in rodent models of obesity. Systemic delivery of adipolin improves glucose tolerance and insulin sensitivity in diet-induced obese mice. Administration of adipolin also attenuates macrophage infiltration and proinflammatory gene expression in adipose tissue of obese mice. In vitro experiment suggests that adipolin suppresses the expression of proinflammatory cytokines including TNFa, IL-1b, and MCP-1 in cultured macrophages. Thus, it is conceivable that adipolin can ameliorate insulin resistance, at least in part, via suppression of inflammatory response of macrophages in adipose tissue (Figure 2). Consistent with these data, it has been reported that adipolin ameliorates insulin sensitivity in obese mice through activation of insulin signaling in the liver and adipose tissue [55]. Treatment of cultured hepatocytes and adipocytes with adipolin protein activates the Akt signaling pathway, leading to suppression of gluconeogenesis and enhancement of glucose uptake [55] (Figure 2). Therefore, in addition to anti-inflammatory effects, adipolin can modulate glucose homeostasis in adipocytes and hepatocytes, thereby leading to resolution of insulin resistance. Circulating adipolin levels are reduced both in genetic obese ob/ob mice and in diet-induced obese mice [9]. Obese conditions promote inflammatory response and endoplasmic reticulum and oxidative stress in adipocytes. In this regard, treatment of 3T3-L1 adipocytes with inducers of inflammation or endoplasmic reticulum stress significantly reduces expression of adipolin [9]. A recent clinical report demonstrated that patients with polycystic ovary syndrome (PCOS), who exhibit obesity and type 2 diabetes, have lower levels of adipolin in plasma and adipose tissue compared to control subjects [56]. Serum adipolin concentrations

negatively correlate with body mass index (BMI), waistto-hip ratio, and glucose levels. Thus, it is tempting to speculate that circulating adipolin may associate with obese or diabetic states in humans. However, future clinical studies are necessary to clarify the association of adipolin with obesity-linked disorders. Recent studies indicate that adipolin expression is both transcriptionally and post-transcriptionally regulated [57,58]. It has been shown that Kru¨ppel-like factor (KLF) 3 negatively regulates adipolin expression [59] (Figure 2). KLF3 KO mice are protected from diet-induced obesity and glucose intolerance, and display robustly increased adipolin expression [59]. KLF3 directly binds to the promoter region of adipolin and represses its activity [59] (Figure 2). Thus, KLF3 may represent a target molecule for manipulation of insulin resistance via modulation of adipolin transcript. It was recently shown that KLF15 positively regulates adipolin expression in adipocytes [60] (Figure 2). KLF15 expression is reduced in adipose tissue in obese mice. TNF-a treatment reduces mRNA levels of KLF15 and adipolin in cultured adipocytes via a c-Jun Nterminal kinase (JNK)-dependent mechanism. Overexpression of KLF15 reversed TNF-a-induced reduction of adipolin expression in adipocytes. KLF15 also enhances the adipolin promoter activity. Furthermore, siRNA-mediated ablation of KLF15 significantly reduces adipolin expression in adipocytes [60]. These data suggest that obese conditions (e.g., adipose inflammation) suppress adipolin expression in part via JNK-dependent downregulation of KLF15 in adipocytes. Collectively, approaches to enhance adipolin production by targeting KLF3 or KLF15 could be valuable for the treatment of metabolic dysfunction in obesity. A recent report showed that adipolin protein is cleaved at Lys (91) by the endopeptidase furin in adipocytes, resulting in the production of a cleaved form of circulating 5

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Review adipolin [57] (Figure 2). Diet-induced obese mice display a significant reduction of plasma levels of full-length and total (full and cleaved) adipolin compared to control mice, leading to an increase in the ratio of cleaved to full-length isoform [58]. Furin expression is elevated in adipose tissue of obese mice. In addition, treatment of adipocytes with TNF-a increases furin expression. These results suggest that obese states facilitate the cleavage of adipolin, presumably through upregulation of furin in adipose tissue. It has been shown that the full-length form of adipolin is more effective in enhancing insulin-stimulated glucose uptake in adipocytes than the cleaved form [57]. Collectively, therapeutic strategies to increase expression of adipolin, in particular the full-length isoform, at both the transcriptional and post-translational levels could be useful for the treatment or prevention of obesity-related metabolic disorders. Omentin-1 Omentin-1, also referred to as intelectin-1, was originally identified as a soluble galactofuranose-binding lectin [61]. Human omentin-1 forms a disulfide-linked and N-glycosylated trimer [61]. It has been reported that human omentin-1 is abundantly expressed in visceral fat tissue [62]. Omentin-1 is detectable in human blood, and circulating omentin-1 levels are decreased in obese individuals [63]. By contrast, omentin-1 concentrations are increased in obese subjects after weight reduction [64]. Reduced levels of omentin-1 are also observed in patients with impaired glucose tolerance and type 2 diabetes, and in overweight insulin-resistant women with polycystic ovary syndrome [65,66]. Furthermore, circulating omentin-1 levels negatively correlate with a multiplicity of metabolic risk factors such as increased waist circumstance, dyslipidemia, elevated blood pressure, and glucose intolerance [67]. In agreement with these clinical observations, it has been shown that omentin-1 stimulates glucose uptake in response to insulin in cultured adipocytes in vitro [62]. Thus, reduced levels of omentin-1 are associated with obesityrelated metabolic dysfunction. Recently, several clinical studies show an association between omentin-1 concentrations and the clinical manifestations of carotid atherosclerosis and coronary artery disease (CAD). Omentin-1 levels are independently correlated with carotid intima media thickness (IMT) in apparently healthy men [68]. In addition, serum omentin-1 levels are negatively correlated with arterial stiffness and carotid IMT in type 2 diabetic patients [69]. Low levels of plasma omentin-1 are observed in patients with CAD [70]. Omentin-1 levels are also inversely associated with the presence and angiographic severity of CAD in patients with metabolic syndrome and in postmenopausal women [71]. These data suggest that omentin-1 acts as a useful biomarker for obesity-associated metabolic and cardiovascular diseases. Increasing evidence from experimental studies indicates that omentin-1 exerts favorable effects on the development of cardiovascular disease. It has been reported that omentin-1 protein enhances vasodilation in isolated blood vessels through endothelium-derived NO [72] (Figure 3). It was shown that treatment with 6

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omentin-1 leads to enhancement of endothelial cell differentiation and reduction of endothelial cell apoptosis through an AMPK/eNOS-dependent mechanism [73] (Figure 3). Systemic administration of omentin-1 to WT mice results in a significant increase in bloodflow recovery and capillary density in ischemic limbs [73]. Of importance, the stimulatory effects of omentin-1 on bloodflow recovery are dependent of its ability to activate eNOS in ischemic limb. Thus, the beneficial actions of omentin-1 on endothelial cell function are mediated, at least in part, though its ability to activate AMPK/eNOS pathways. It has been shown that omentin-1 suppresses inflammatory responses in cultured endothelial cells via suppression of JNK activation through the AMPK/eNOS signaling pathway [74] (Figure 3). In addition, treatment with omentin-1 protein inhibits TNF-a-induced adhesion of THP-1 monocytes to human umbilical vein endothelial cells [75] (Figure 3). Omentin-1 also inhibits TNF-a-induced expression of intracellular adhesion molecule-1 and VCAM-1 in endothelial cells via suppression of the ERK/NF-kB pathway (Figure 3). Moreover, omentin-1 inhibits TNF-a-induced adhesion of U937 monocytes to isolated rat VSMCs [76] (Figure 3). Omentin-1 inhibits TNF-a-induced expression of VCAM-1 in VSMCs via suppression of p38 and JNK pathways (Figure 3). Thus, omentin-1 functions as an adipokine that attenuates vascular inflammation. Taken together, omentin-1 may modulate obesity-related metabolic and cardiovascular disorders via an anti-inflammatory mechanism. Additional studies are necessary to clarify the receptor-mediated signaling events that mediate omentin1’s cardiovascular protection, and the in vivo role of omentin1 in the regulation of obese complications using mouse genetic models. Concluding remarks It has been increasingly recognized that imbalance of proinflammatory and anti-inflammatory adipokines contributes to the development of obesity-linked disorders. Dysregulation of anti-inflammatory adipokines caused by fat accumulation participates in local or systemic inflammatory responses, thereby leading to the initiation or progression of metabolic and cardiovascular disorders. In this regard, resolution of the imbalance between proinflammatory and anti-inflammatory adipokines, in particular the enhanced production of anti-inflammatory adipokines, could be valuable as a potential therapeutic strategy for various obese complications. Furthermore, therapeutic approaches to enhance receptor-mediated signaling pathways for anti-inflammatory adipokines may be beneficial in obesity-inducible inflammatory states. Although much attention has been paid to identification of new adipokines, most anti-inflammatory adipokines have been discovered only in the past few years, and their functional roles in disease processes have been poorly clarified. Therefore, further elucidation of the functions, mechanisms, and regulation of anti-inflammatory adipokines discussed here, or the identification of novel adipokines that modulate inflammatory responses, will lead to a better understanding of the pathogenesis of obese complications.

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Review Acknowledgments This work was supported by a Grant-in-Aid for Scientific Research, a Grant-in-Aid for Challenging Exploratory Research, and grants from the Takeda Science Foundation, the Uehara Memorial Foundation, the Daiichi-Sankyo Foundation of Life Science, and the SENSHIN Medical Research Foundation to N.O. R.S. was supported by a Grant-in-Aid for Young Scientists B and by the Uehara Memorial Foundation. K.O. was supported by a Grant-in-Aid for Scientific Research C and by The Cardiovascular Research Fund, Tokyo, Japan.

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Role of anti-inflammatory adipokines in obesity-related diseases.

Obesity results in many health complications. Accumulating evidence indicates that the obese state is characterized by chronic low-grade inflammation,...
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