TEM-949; No.

of Pages 8

Review

Role of anti-inflammatory adipokines

in obesity-related diseases
Koji Ohashi1, Rei Shibata2, Toyoaki Murohara2, and Noriyuki Ouchi1
1
Department of Molecular Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-Ku, Nagoya, Japan
2
Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-Ku, Nagoya, Japan

Obesity results in many health complications. Accumu- adipokine found in human plasma at concentrations rang-
lating evidence indicates that the obese state is charac- ing from 3 to 30 mg/ml [10,11]. Adiponectin contains a
terized by chronic low-grade inflammation, thereby collagen-repeat domain and a globular domain with a
leading to the initiation and progression of obesity-relat- sequence homology to complement factor C1q. It is well
ed disorders such as type 2 diabetes, hypertension, car- established that adiponectin levels in plasma are negative-
diovascular disease, and atherosclerosis. Fat tissue ly associated with the accumulation of body fat, particu-
releases numerous bioactive molecules, called adipo- larly visceral fat [12], and that plasma adiponectin levels
kines, which affect whole-body homeostasis. Most adi- are low in obese individuals. Clinical studies indicate a
pokines are proinflammatory, whereas a small number of close association of low adiponectin levels with many
anti-inflammatory adipokines including adiponectin exert obesity-related disorders [13–15]. In addition, plasma
beneficial actions on obese complications. The dysregu- levels of C-reactive protein (CRP), an acute-phase protein
lated production of adipokines seen in obesity is linked to that is elevated in inflammation, and IL-6 levels are both
the pathogenesis of various disease processes. In this negatively correlated with plasma adiponectin levels
review we focus on the role of the anti-inflammatory [16,17]. Bodyweight reduction in obese women through
adipokines that are of current interest in the setting of lifestyle changes is associated with a reduction in various
obesity-linked metabolic and cardiovascular diseases. inflammatory markers, including CRP and IL-6, as well as
an increase in adiponectin [17]. Furthermore, CRP expres-
Introduction sion is observed in human adipose tissue, and CRP tran-
Obesity is a pandemic social problem worldwide. Excess fat script expression inversely correlates with adiponectin
accumulation is causally linked with various metabolic mRNA levels in human adipose tissue [16]. Thus, the
risk factors including type 2 diabetes, hypertension, and reciprocal association of adiponectin and the inflammatory
dyslipidemia, finally leading to the development of cardio- mediators may participate in the development of obese
vascular disease [1,2]. It is well established that obesity, in complications.
particular, visceral fat accumulation causes chronic low- Consistent with these clinical findings, several experi-
grade inflammation, which contributes to the initiation mental studies indicate a protective anti-inflammatory
and progression of metabolic disorders [3–5]. Adipose tis-
sue is an active endocrine organ and secretes a variety of
bioactive molecules known as adipokines [3,6,7]. The adi- Glossary
pokines comprise a large number of proinflammatory med- AMP-activated protein kinase (AMPK): AMPK acts as an energy sensor in
response to low AMP concentration. AMPK promotes glucose uptake,
iators, including tumor necrosis factor (TNF)-a, monocyte glycolysis, and fatty acid oxidation, and inhibits the synthesis of glucose and
chemoattractant protein (MCP)-1, and interleukin (IL)-6, fatty acids. AMPK is also activated by various hormonal signals including
that promote disease progression. By contrast, a small adiponectin and leptin. In addition to metabolic functions, AMPK signaling
exerts many protective functions against cardiovascular disorders.
number of anti-inflammatory adipokines, which are down- Apolipoprotein E (ApoE): ApoE is a major apolipoprotein which acts as a ligand
regulated by obese states, seem to protect against the for the low-density lipoprotein (LDL) and very low density lipoprotein (VLDL)
development of obese complications [3,7–9]. In this review receptors in the liver. ApoE deficient mice show remarkable hypercholester-
olemia and severe atherosclerosis.
we discuss recent progress in our understanding of the Inflammatory cytokines: in the obese state, many inflammatory cytokines such
action of anti-inflammatory adipokines in the context of as TNF-a, IL-6, monocyte chemotactic protein (MCP)-1, macrophage, migration
metabolism and cardiovascular disease. inhibitory factor (MIF), and CCL4 are increased in systemic organs, thereby
leading to insulin resistance, hypertension, and cardiovascular disease.
Krüppel-like factor (KLF): a family of zinc-finger transcription factors that
Adiponectin recognize GC-rich elements and CACCC boxes. KLF family proteins are
Adiponectin, also referred to as ACRP30 (adipocyte com- ubiquitously expressed and modulate several obesity-related inflammatory
states and metabolic dysfunction.
plement-related 30 kDa protein), is an adipocyte-specific 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
Corresponding authors: Shibata, R. (rshibata@med.nagoya-u.ac.jp); Ouchi, N. obese and insulin resistant, and are used as an animal model for the study of
(nouchi@med.nagoya-u.ac.jp). type 2 diabetes.
Keywords: adiponectin; CTRP3; CTRP9; adipolin; omentin-1. 3T3-L1 adipocytes: cells derived from mouse fibroblast clones, which are able
1043-2760/ to differentiate into adipocytes when treated with insulin, 1-methyl-3-isobutyl-
ß 2014 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.tem.2014.03.009 xanthine, and dexamethasone. 3T3-L1 adipocytes are widely used as cultured
adipocytes in in vitro studies.

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Adiponecn

Macrophage Endothelial cell Cardiomyocyte Fibroblast

Foam cell transformaon ↓ VCAM-1 ↓ TNF-α ↓
TNF-α ↓ TNF-α ↓
ICAM-1 ↓
MMP-12 ↓
M1 phenotypic change ↓
IL-6 ↓
M2 phenotypic change ↑
Clearance of early apoptoc cells ↑

Protecon against ssue injury (heart, vasculature, and lung)

TRENDS in Endocrinology & Metabolism

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 experi- Treatment of cultured alveolar macrophages with adipo-
ments showed that treatment with adiponectin protein nectin reduces TNF-a and MMP-12 expression in response
decreases lipopolysaccharide (LPS)-induced expression of to LPS stimulation. Exaggeration of lung injury and in-
TNF-a in cultured macrophages through inhibition of NF- flammation is observed in APN KO mice after intratra-
kB signaling [18,19] (Figure 1). Adiponectin also reduces cheal injection of LPS. Endothelial cells isolated from lung
the expression of class A scavenger receptor (SR)-A in digests in APN KO mice after LPS administration have
human monocyte-derived macrophages and prevents mac- increased expression of proinflammatory cytokines includ-
rophage foam cell formation [20] (Figure 1). In vivo experi- ing IL-6 compared to WT mice [25]. Furthermore, myocar-
ments demonstrated that adenovirus-mediated dial ischemia–reperfusion in APN KO mice results in an
overexpression of adiponectin attenuates the progression increase in cardiac infarct size, apoptosis, and TNF-a
of atherosclerotic lesions in apolipoprotein E (ApoE; see expression [26]. Conversely, supplementation of adiponec-
Glossary) knockout (KO) mice, with an accompanying tin diminishes infarct size following ischemia–reperfusion
decrease in TNF-a and SR-A expression [21] (Figure 1). in APN KO and WT mice, with accompanying reductions in
Of importance, ApoE/adiponectin (APN) double-KO mice myocyte apoptosis and TNF-a production. Treatment of
show accelerated atherogenesis, accompanied by increased cultured cardiac myocytes or fibroblasts with adiponectin
T lymphocyte accumulation in atherosclerotic lesions, com- also leads to reduced apoptosis and TNF-a production. It
pared to ApoE KO mice [22]. Adiponectin treatment also has also been shown that adiponectin reduces cardiomyo-
reduces the infiltration of CD4+ T lymphocytes into ath- cyte apoptosis by increasing the production of sphingosine-
erosclerotic lesions via the suppression of T lymphocyte 1-phosphate through stimulation of ceramidase activity
chemoattractants in macrophages, including the interfer- involving its receptors, Adipo R1 and Adipo R2, indicating
on (IFN)-inducible protein, I-TAC (IFN-inducible T cell a the possible involvement of sphingolipid metabolism as a
chemoattractant and monokine; also known as CXCl11) mechanism for cardioprotection by this adipokine [27].
[22]. After LPS administration the endothelial expression Furthermore, adiponectin exerts a protective action on
levels of vascular cell adhesion molecule (VCAM)-1 and myocardial ischemia–reperfusion damage through reduc-
intercellular cell adhesion molecule (ICAM)-1 are much tion of oxidative/nitrative stress [28]. In addition, intracor-
higher in APN KO mice than in wild type (WT) mice [23]. onary administration of adiponectin protein improves
Thus, it is conceivable that adiponectin protects against cardiac injury and function, and attenuates inflammatory
atherogenesis, at least in part, by attenuating the inflam- response after ischemia–reperfusion, in a preclinical pig
matory response in vascular walls. model [29]. Thus, adiponectin is protective against acute
Adiponectin also appears to modulate the inflammatory injury of lung or heart by suppressing inflammatory
response in other organs. APN KO mice show increased responses in its target cells. In this context, development
expression of TNF-a and metalloproteinase (MMP)-12 in of an adiponectin-like drug or agonist to adiponectin sig-
lung, and display an emphysema-like phenotype [24]. nals or receptors may be useful for the treatment of acute
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tissue injury because AdipoRon, the recently identified CTRP3

agonist of Adipo R1 and Adipo R2, has been shown to CTRP3, also referred to as C1q/TNF-related protein-3,
improve obesity-related metabolic diseases [30]. CORS-26, cartducin, or cartonectin, was cloned as a factor
Recent reports indicate that adiponectin acts as a induced by transforming growth factor (TGF)-b1 [41]. The
modulator of macrophage phenotypes. It was shown that protein exists in two alternatively spliced isoforms,
adiponectin switches the phenotype from the proinflam- CTRP3A and CTRP3B, which differ in length and glyco-
matory classically activated macrophage (M1) to an anti- sylation [42]. CTRP3 is synthesized by adipocytes and
inflammatory alternatively activated macrophage (M2) produced by mesenteric adipose tissue [43,44]. It inhibits
[31] (Figure 1). Generally, obese adipose tissue is inclined LPS-induced expression of macrophage migration inhibi-
to M1 polarization, which causes exacerbation of inflam- tory factor (MIF), MCP-1, and C-C motif chemokine ligand-
mation and tissue destruction [32]. By contrast, M2 polar- 4 (CCL4) in human monocyte-derived macrophages [45],
ized macrophages exert an anti-inflammatory action and and suppresses chemokine production in response to lauric
protect against obesity-related metabolic disorders [33]. acid, LPS, or Toll-like receptor (TLR) stimulation in macro-
APN KO mice exhibit increased expression levels of M1- phages and adipocytes [44]. Interestingly, CTRP3 stimu-
related genes, such as TNF-a, IL-6 and MCP-1, in perito- lates the expression of adiponectin in primary human
neal macrophages and stromal vascular fractions (SVFs) adipocytes and cultured 3T3-L1 adipocytes [46]. Ablation
compared to WT mice [31]. By contrast, treatment of WT of CTRP3 by small interfering RNA (siRNA) increases the
mice with adiponectin stimulates the expression of M2- expression of proinflammatory adipokines including CCL2
related genes, including arginase-1, IL-10, and macro- and decreases adiponectin expression in preadipocytes
phage galactose N-acetyl-galactosamine specific lectin-1, [44]. Therefore, CTRP3 may act as an anti-inflammatory
in peritoneal macrophages and SVFs [31]. Adiponectin also adipokine in vitro. It has also been reported that supple-
promotes the phenotypic conversion of human monocyte- mentation of exogenous CTRP3 improves post-ischemic
derived macrophages into M2 through a peroxisome pro- cardiac function and remodeling in mice through its ability
liferator-activated receptor (PPAR)-a-dependent mecha- to promote revascularization and reduce apoptosis in is-
nism [34]. It has been shown that adiponectin polarizes chemic heart [47]. Future research will be required to
Kupffer cells and RAW264.7 macrophages to M2 through a clarify the in vivo role of CTRP3 in controlling inflamma-
mechanism involving the adiponectin receptor AdipoR2 tion and obese complications.
[35]. Thus, these data suggest that adiponectin exhibits
anti-inflammatory effects via direct modulation of macro- CTRP6
phage phenotype. Another member of the family is CTRP6, which is abun-
Of importance, adiponectin enhances the ability of mac- dantly expressed in adipose tissue. CTRP6 exists in the
rophage to remove early apoptotic bodies, which is crucial blood as homo-trimers, oligomers, or heteromers with
in preventing inflammation and immune system dysfunc- CTRP1 [38]. Obese ob/ob mice and APN KO mice exhibit
tion [36]. Ablation of adiponectin leads to impaired clear- higher plasma levels of CTRP6 [38]. CTRP6 increases the
ance of early apoptotic bodies by peritoneal macrophages, expression of anti-inflammatory cytokine IL-10 in human
and this is associated with increased inflammatory monocyte-derived macrophages through the p42/44 mito-
responses such as elevation of TNF-a production [36]. gen-activated protein kinase (MAPK)-dependent pathway
Adiponectin also promotes the removal of apoptotic cells [48]. It also stimulates activation of AMP-activated protein
and improves systemic inflammation and the features of kinase (AMPK) and enhances fatty acid oxidation in skel-
autoimmunity in lpr (lymphoproliferation) mice, a valu- etal muscle cells [49]. Thus, CTRP6 may affect metabolic
able model of systemic lupus erythematosus. In cultured function and inflammatory states under conditions of obe-
macrophages, adiponectin treatment enhances the clear- sity, but this will require future investigation.
ance of apoptotic debris in vitro [36]. Moreover, adiponectin
promotes the removal of apoptotic bodies by macrophages CTRP9
through the calreticulin/CD91 system on the cell surface of CTRP9 is the closest paralog of adiponectin among CTRPs
macrophages [36] (Figure 1). Collectively, adiponectin can and acts as an adipokine that is abundantly expressed in
switch the function and phenotype of macrophages to- adipose tissue [39]. Plasma CTRP9 levels are decreased in
wards an anti-inflammatory state, and reduce chronic mouse models of obesity [40]. In addition, CTRP9 forms
inflammation in target organs including the vasculature, heterotrimers with adiponectin, and shares the receptor
lung, and heart, thereby leading to protection against Adipo R1 with adiponectin in vascular endothelial cells
various obesity-related disorders. and cardiac myocytes [39,40,50]. An initial report indicates
that CTRP9 has favorable actions on obesity-related met-
C1q/TNF-related protein (CTRP) family abolic disorders. Systemic delivery of CTRP9 by adenovi-
A highly conserved family of adiponectin paralogs known rus systems attenuates blood glucose levels in genetic
as C1q/TNF-related proteins [37], the CTRP family has obese ob/ob mice [39]. In cultured myocytes, CTRP9 protein
common structural domains: a signal sequence, a collage- activates phosphorylation by signaling molecules includ-
nous domain, and a C1q-like globular domain. Similarly to ing AMPK and Akt (protein kinase B), and promotes
adiponectin, some CTRPs such as CTRP6, CTRP9, and glucose uptake induced by insulin [39]. A recent report
CTRP12 are mainly expressed in adipose tissue [38–40]. also demonstrated that CTRP9 transgenic mice show dra-
Furthermore, several CTRPs have glucose-lowering effects matic resistance to diet-induced weight gain and have
and anti-inflammatory functions. decreased insulin resistance and hepatic steatosis, with
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KLF3 KLF15

Adipolin
Promoter

KK/SR
1 21 96 117 308
SP Collagen C1q-like globular domain

Furin
KK/SR
1 21 96 117 308
SP Collagen C1q-like globular domain

Inflammaon Glucose uptake Gluconeogenesis

Macrophage Adipocyte Liver

TRENDS in Endocrinology & Metabolism

Figure 2. Regulation and function of adipolin. Krüppel-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 infusion of CTRP9 protein improves cardiac function, apo-
muscle [51]. These results suggest that CTRP9 may pre- ptosis, and fibrosis in mice after myocardial infarction (MI)
vent metabolic dysfunction under conditions of obesity via [54]. The cardioprotective action of CTRP9 in vitro is
activation of AMPK in muscle. dependent on the PKA signaling pathway. Therefore, both
Several reports indicate that CTRP9 exerts beneficial AMPK and PKA pathways mediate the cardiovascular
effects on the cardiovascular system. It increases endothe- protection by CTRP9.
lium-dependent vasorelaxation in aortic rings [50], a vasor- Interestingly, CTRP9 levels decline in plasma and adi-
elaxative effect mediated through its ability to activate the pose tissue after myocardial ischemia–reperfusion and MI
AdipoR1/AMPK/endothelial nitric oxide synthase (eNOS) [40,54]. Plasma concentrations of free fatty acid (FFA) and
signaling pathway. Recently, it was demonstrated that mRNA levels of oxidative stress markers in adipose tissue
systemic delivery of CTRP9 reduces the pathological remo- are elevated after myocardial ischemia–reperfusion [40].
deling of vascular walls in a mouse wire injury model [52]. Treatment of 3T3-L1 adipocytes with palmitic acid or an
CTRP9 attenuates vascular smooth-muscle cell (VSMC) inducer of oxidative stress significantly reduces CTRP9
proliferation through a cAMP–protein kinase A (PKA)- expression [40], and an excess of fatty acids has been
dependent mechanism. Of note, CTRP9-mediated suppres- reported to stimulate oxidative stress in adipocytes. These
sion of VSMC growth is independent of AdipoR1 or AMPK data indicate that increased levels of FFA caused by myo-
signaling. Thus, CTRP9 exerts a vascular protective action cardial ischemia could reduce CTRP9 levels in adipose
via at least two pathways including AMPK and PKA. tissue and blood via enhancement of adipose oxidative
It was previously shown that intravenous administra- stress. Taken together, CTRP9 protects against the devel-
tion of CTRP9 to WT mice reduces myocardial infarct size opment of obesity-linked metabolic dysfunction and car-
and cardiomyocyte apoptosis after ischemia–reperfusion diovascular disorders. However, further research is needed
[40]. Treatment of cardiac myocytes with CTRP9 protein to dissect the precise mechanism by which CTRP9 regu-
reduces apoptosis in response to hypoxia–reoxygenation lates metabolic and cardiovascular homeostasis.
stress via activation of AMPK. In addition, CTRP9 admin-
istration to diabetic mice reduces myocardial infarct Adipolin/CTRP12
size and apoptosis, and improves cardiac function after Recently, CTRP12 was identified as a novel insulin-
ischemia–reperfusion, by inhibiting oxidative stress sig- sensitizing adipokine that is abundantly expressed in
naling [53]. A recent study demonstrated that continuous fat tissue, and was designated adipolin (adipose-derived
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Omenn-1

ERK/NF-κB p38/JNK

VCAM-1 ↓ eNOS AMPK/eNOS VCAM-1 ↓

ICAM-1 ↓ ICAM-1 ↓
JNK

Monocyte
↓ Vasodilaon ↑ Differenaon ↑ Inflammaon ↓ Monocyte adhesion ↓
adhesion Survival ↑

Endothelial cell Smooth-muscle cell

TRENDS in Endocrinology & Metabolism

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 comparative- negatively correlate with body mass index (BMI), waist-
ly less homology with adiponectin than other CTRPs to-hip ratio, and glucose levels. Thus, it is tempting to
[9,55]. Adipolin expression in fat tissue is decreased in speculate that circulating adipolin may associate with obese
rodent models of obesity. Systemic delivery of adipolin or diabetic states in humans. However, future clinical stud-
improves glucose tolerance and insulin sensitivity in ies are necessary to clarify the association of adipolin with
diet-induced obese mice. Administration of adipolin also obesity-linked disorders.
attenuates macrophage infiltration and proinflammatory Recent studies indicate that adipolin expression is both
gene expression in adipose tissue of obese mice. In vitro transcriptionally and post-transcriptionally regulated
experiment suggests that adipolin suppresses the ex- [57,58]. It has been shown that Krüppel-like factor
pression of proinflammatory cytokines including TNF- (KLF) 3 negatively regulates adipolin expression [59]
a, IL-1b, and MCP-1 in cultured macrophages. Thus, it is (Figure 2). KLF3 KO mice are protected from diet-induced
conceivable that adipolin can ameliorate insulin resis- obesity and glucose intolerance, and display robustly in-
tance, at least in part, via suppression of inflammatory creased adipolin expression [59]. KLF3 directly binds to
response of macrophages in adipose tissue (Figure 2). the promoter region of adipolin and represses its activity
Consistent with these data, it has been reported that [59] (Figure 2). Thus, KLF3 may represent a target mole-
adipolin ameliorates insulin sensitivity in obese mice cule for manipulation of insulin resistance via modulation
through activation of insulin signaling in the liver and of adipolin transcript. It was recently shown that KLF15
adipose tissue [55]. Treatment of cultured hepatocytes positively regulates adipolin expression in adipocytes [60]
and adipocytes with adipolin protein activates the Akt (Figure 2). KLF15 expression is reduced in adipose tissue
signaling pathway, leading to suppression of gluconeo- in obese mice. TNF-a treatment reduces mRNA levels of
genesis and enhancement of glucose uptake [55] KLF15 and adipolin in cultured adipocytes via a c-Jun N-
(Figure 2). Therefore, in addition to anti-inflammatory terminal kinase (JNK)-dependent mechanism. Overex-
effects, adipolin can modulate glucose homeostasis in pression of KLF15 reversed TNF-a-induced reduction of
adipocytes and hepatocytes, thereby leading to resolu- adipolin expression in adipocytes. KLF15 also enhances
tion of insulin resistance. the adipolin promoter activity. Furthermore, siRNA-medi-
Circulating adipolin levels are reduced both in genetic ated ablation of KLF15 significantly reduces adipolin ex-
obese ob/ob mice and in diet-induced obese mice [9]. Obese pression in adipocytes [60]. These data suggest that obese
conditions promote inflammatory response and endoplas- conditions (e.g., adipose inflammation) suppress adipolin
mic reticulum and oxidative stress in adipocytes. In this expression in part via JNK-dependent downregulation of
regard, treatment of 3T3-L1 adipocytes with inducers of KLF15 in adipocytes. Collectively, approaches to enhance
inflammation or endoplasmic reticulum stress significantly adipolin production by targeting KLF3 or KLF15 could be
reduces expression of adipolin [9]. A recent clinical report valuable for the treatment of metabolic dysfunction in
demonstrated that patients with polycystic ovary syndrome obesity.
(PCOS), who exhibit obesity and type 2 diabetes, have lower A recent report showed that adipolin protein is cleaved
levels of adipolin in plasma and adipose tissue compared at Lys (91) by the endopeptidase furin in adipocytes,
to control subjects [56]. Serum adipolin concentrations resulting in the production of a cleaved form of circulating
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adipolin [57] (Figure 2). Diet-induced obese mice display a omentin-1 leads to enhancement of endothelial cell dif-
significant reduction of plasma levels of full-length and ferentiation and reduction of endothelial cell apoptosis
total (full and cleaved) adipolin compared to control mice, through an AMPK/eNOS-dependent mechanism [73]
leading to an increase in the ratio of cleaved to full-length (Figure 3). Systemic administration of omentin-1 to
isoform [58]. Furin expression is elevated in adipose tissue WT mice results in a significant increase in bloodflow
of obese mice. In addition, treatment of adipocytes with recovery and capillary density in ischemic limbs [73]. Of
TNF-a increases furin expression. These results suggest importance, the stimulatory effects of omentin-1 on
that obese states facilitate the cleavage of adipolin, pre- bloodflow recovery are dependent of its ability to activate
sumably through upregulation of furin in adipose tissue. It eNOS in ischemic limb. Thus, the beneficial actions of
has been shown that the full-length form of adipolin is omentin-1 on endothelial cell function are mediated, at
more effective in enhancing insulin-stimulated glucose least in part, though its ability to activate AMPK/eNOS
uptake in adipocytes than the cleaved form [57]. Collec- pathways.
tively, therapeutic strategies to increase expression of It has been shown that omentin-1 suppresses inflam-
adipolin, in particular the full-length isoform, at both matory responses in cultured endothelial cells via suppres-
the transcriptional and post-translational levels could be sion of JNK activation through the AMPK/eNOS signaling
useful for the treatment or prevention of obesity-related pathway [74] (Figure 3). In addition, treatment with omen-
metabolic disorders. tin-1 protein inhibits TNF-a-induced adhesion of THP-1
monocytes to human umbilical vein endothelial cells [75]
Omentin-1 (Figure 3). Omentin-1 also inhibits TNF-a-induced expres-
Omentin-1, also referred to as intelectin-1, was originally sion of intracellular adhesion molecule-1 and VCAM-1 in
identified as a soluble galactofuranose-binding lectin [61]. endothelial cells via suppression of the ERK/NF-kB path-
Human omentin-1 forms a disulfide-linked and N-glycosy- way (Figure 3). Moreover, omentin-1 inhibits TNF-a-in-
lated trimer [61]. It has been reported that human omen- duced adhesion of U937 monocytes to isolated rat VSMCs
tin-1 is abundantly expressed in visceral fat tissue [62]. [76] (Figure 3). Omentin-1 inhibits TNF-a-induced expres-
Omentin-1 is detectable in human blood, and circulating sion of VCAM-1 in VSMCs via suppression of p38 and JNK
omentin-1 levels are decreased in obese individuals [63]. pathways (Figure 3). Thus, omentin-1 functions as an
By contrast, omentin-1 concentrations are increased in adipokine that attenuates vascular inflammation. Taken
obese subjects after weight reduction [64]. Reduced levels together, omentin-1 may modulate obesity-related meta-
of omentin-1 are also observed in patients with impaired bolic and cardiovascular disorders via an anti-inflammatory
glucose tolerance and type 2 diabetes, and in overweight mechanism. Additional studies are necessary to clarify the
insulin-resistant women with polycystic ovary syndrome receptor-mediated signaling events that mediate omentin-
[65,66]. Furthermore, circulating omentin-1 levels nega- 1’s cardiovascular protection, and the in vivo role of omentin-
tively correlate with a multiplicity of metabolic risk factors 1 in the regulation of obese complications using mouse
such as increased waist circumstance, dyslipidemia, ele- genetic models.
vated blood pressure, and glucose intolerance [67]. In
agreement with these clinical observations, it has been Concluding remarks
shown that omentin-1 stimulates glucose uptake in re- It has been increasingly recognized that imbalance of
sponse to insulin in cultured adipocytes in vitro [62]. Thus, proinflammatory and anti-inflammatory adipokines con-
reduced levels of omentin-1 are associated with obesity- tributes to the development of obesity-linked disorders.
related metabolic dysfunction. Dysregulation of anti-inflammatory adipokines caused by
Recently, several clinical studies show an association fat accumulation participates in local or systemic inflam-
between omentin-1 concentrations and the clinical mani- matory responses, thereby leading to the initiation or
festations of carotid atherosclerosis and coronary artery progression of metabolic and cardiovascular disorders. In
disease (CAD). Omentin-1 levels are independently corre- this regard, resolution of the imbalance between proin-
lated with carotid intima media thickness (IMT) in appar- flammatory and anti-inflammatory adipokines, in particu-
ently healthy men [68]. In addition, serum omentin-1 lar the enhanced production of anti-inflammatory
levels are negatively correlated with arterial stiffness adipokines, could be valuable as a potential therapeutic
and carotid IMT in type 2 diabetic patients [69]. Low levels strategy for various obese complications. Furthermore,
of plasma omentin-1 are observed in patients with CAD therapeutic approaches to enhance receptor-mediated sig-
[70]. Omentin-1 levels are also inversely associated with naling pathways for anti-inflammatory adipokines may be
the presence and angiographic severity of CAD in patients beneficial in obesity-inducible inflammatory states. Al-
with metabolic syndrome and in postmenopausal women though much attention has been paid to identification of
[71]. These data suggest that omentin-1 acts as a useful new adipokines, most anti-inflammatory adipokines have
biomarker for obesity-associated metabolic and cardiovas- been discovered only in the past few years, and their
cular diseases. functional roles in disease processes have been poorly
Increasing evidence from experimental studies indi- clarified. Therefore, further elucidation of the functions,
cates that omentin-1 exerts favorable effects on the mechanisms, and regulation of anti-inflammatory adipo-
development of cardiovascular disease. It has been kines discussed here, or the identification of novel adipo-
reported that omentin-1 protein enhances vasodilation kines that modulate inflammatory responses, will lead to a
in isolated blood vessels through endothelium-derived better understanding of the pathogenesis of obese compli-
NO [72] (Figure 3). It was shown that treatment with cations.
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Acknowledgments 24 Summer, R. et al. (2008) Alveolar macrophage activation and an

This work was supported by a Grant-in-Aid for Scientific Research, a emphysema-like phenotype in adiponectin-deficient mice. Am. J.
Grant-in-Aid for Challenging Exploratory Research, and grants from the Physiol. Lung Cell. Mol. Physiol. 294, L1035–L1042
Takeda Science Foundation, the Uehara Memorial Foundation, the 25 Konter, J.M. et al. (2012) Adiponectin attenuates lipopolysaccharide-
Daiichi-Sankyo Foundation of Life Science, and the SENSHIN Medical induced acute lung injury through suppression of endothelial cell
Research Foundation to N.O. R.S. was supported by a Grant-in-Aid for activation. J. Immunol. 188, 854–863
Young Scientists B and by the Uehara Memorial Foundation. K.O. was 26 Shibata, R. et al. (2005) Adiponectin protects against myocardial
supported by a Grant-in-Aid for Scientific Research C and by The ischemia-reperfusion injury through AMPK- and COX-2-dependent
Cardiovascular Research Fund, Tokyo, Japan. mechanisms. Nat. Med. 11, 1096–1103
27 Holland, W.L. et al. (2011) Receptor-mediated activation of ceramidase
activity initiates the pleiotropic actions of adiponectin. Nat. Med. 17,
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