Adipose Tissue-Derived Omentin-1 Function

and Regulation
Takuya Watanabe,1* Kaho Watanabe-Kominato,1 Yui Takahashi,1 Miho Kojima,1 and Rena Watanabe1

ABSTRACT
Omentin-1, also known as intelectin-1, is a recently identified novel adipocytokine of 313 amino
acids, which is expressed in visceral (omental and epicardial) fat as well as mesothelial cells,
vascular cells, airway goblet cells, small intestine, colon, ovary, and plasma. The level of omentin-
1 expression in (pre)adipocytes is decreased by glucose/insulin and stimulated by fibroblast
growth factor-21 and dexamethasone. Several lines of experimental evidence have shown that
omentin-1 plays crucial roles in the maintenance of body metabolism and insulin sensitivity,
and has anti-inflammatory, anti-atherosclerotic, and cardiovascular protective effects via AMP-
activated protein kinase/Akt/nuclear factor-κB/mitogen-activated protein kinase (ERK, JNK, and
p38) signaling. Clinical studies have indicated the usage of circulating omentin-1 as a biomarker
of obesity, metabolic disorders including insulin resistance, diabetes, and metabolic syndrome,
and atherosclerotic cardiovascular diseases. It is also possible to use circulating omentin-1
as a biomarker of bone metabolism, inflammatory diseases, cancers, sleep apnea syndrome,
preeclampsia, and polycystic ovary syndrome. Decreased omentin-1 levels are generally associ-
ated with these diseases. However, omentin-1 increases to counteract the acute phase after onset
of these diseases. These findings indicate that omentin-1 may be a negative risk factor for these
diseases, and also act as an acute-phase reactant by its anti-inflammatory and atheroprotective
effects. Therapeutic strategies to restore omentin-1 levels may be valuable for the prevention or
treatment of these diseases. Weight loss, olive oil-rich diet, aerobic training, and treatment with
atorvastatin and antidiabetic drugs (metformin, pioglitazone, and exenatide) are effective means
of increasing circulating omentin-1 levels. This review provides insights into the potential use of
omentin-1 as a biomarker and therapeutic target for these diseases. © 2017 American Physio-
logical Society. Compr Physiol 7:765-781, 2017.

Didactic Synopsis Introduction

Major teaching points
r Omentin-1, also known as intelectin-1, is a recently iden-
tified novel adipocytokine that is mainly expressed in vis-
ceral fat.
r Omentin-1 is downregulated by glucose/insulin and upreg-
ulated by fibroblast growth factor-21 and dexamethasone.
r Omentin-1 exerts suppressive effects on insulin resistance,
atherosclerosis, and inflammation via AMP-activated pro-
tein kinase/Akt/nuclear factor-κB/mitogen-activated pro-
tein kinase (ERK, JNK, and p38) intracellular signaling
pathways.
r Circulating omentin-1 is used as a biomarker of obesity, dia-
betes, metabolic syndrome, atherosclerosis, ischemic heart
disease, inflammatory disease, and cancer.
r This review provides insights into the potential use of
omentin-1 as a biomarker and therapeutic target for these
diseases.
Mammalian adipose (body fat) is distributed variably and con-
sists of two types of fat, that is, white fat (subcutaneous and
visceral fat) and brown fat (36). Visceral adipose tissue (VAT)
is regarded as ectopic fat that is the cause of more adverse
metabolic and cardiovascular events, which leads to the new
term “adiposopathy” (13). The VAT contains adipocytes as
well as a variety of other cells, such as macrophages, mast
cells, fibroblasts, and stromal vascular cells (36). In addi-
tion to its roles in lipid metabolism and energy storage, the
VAT is also recognized as a key endocrine organ that secretes
approximately more than 600 bioactive cytokines, designated
as adipocytokines or adipokines (18). Adipocytokines act sys-
temically in an endocrine manner and locally in an autocrine
and paracrine manner (18, 36). Adipocytokines play crucial
* Correspondence to watanabe@toyaku.ac.jp
1 Laboratoryof Cardiovascular Medicine, Tokyo University of
Pharmacy and Life Sciences, Hachioji-City, Tokyo, Japan
Published online, July 2017 (comprehensivephysiology.com)
DOI: 10.1002/cphy.c160043
Copyright © American Physiological Society.

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Function and Regulation of Omentin-1
Figure 1 Favorable and unfavorable effects of novel adipocytokines on energy homeostasis, glucose metabolism, cardiovascular
system, inflammation, and oxidative stress. Adiponectin, omentin-1, vaspin, chemerin, resistin, and leptin are selected as novel adipocy-
tokines. (+) indicates favorable effect and (−) indicates unfavorable effect on energy homeostasis, glucose metabolism, cardiovascular
protection, anti-inflammation response, and antioxidative stress.
roles in regulating metabolic homeostasis, insulin sensitivity,
inflammatory responses, neuroendocrine activity, food and
water intake, bone metabolism, and cardiovascular function
(18, 36).
Obesity and metabolic syndrome, as characterized by
excess VAT within abdominal cavity and also around the car-
diovasculature, are associated with insulin resistance, type
2 diabetes, dyslipidemia, hypertension, and atherosclerosis.
These diseases are known to be mediated via increased
production of many adipocytokines, such as tumor necro-
sis factor-α (TNF-α), interleukin-6, angiotensinogen, plas-
minogen activator inhibitor-1, resistin, etc. (18, 36, 42, 59). In
contrast, VAT also produces a smaller number of adipocy-
tokines, including adiponectin, omentin, and vaspin, which
are beneficial in the setting of obesity-linked complications
and metabolic disorders (18, 36, 42, 59). Leptin is known to
have both beneficial and detrimental effects (59). Chemerin
has been recently shown to have inhibitory effects on vascular
inflammation, but its other effects are controversial depend-
ing on cell types (59). Figure 1 shows the favorable and
unfavorable effects of these novel adipocytokines on glucose
homeostasis, inflammation, oxidative stress (reactive oxygen
species [ROS] generation), and cardiovascular system. Cur-
rently, there is a great deal of research interest in omentin due
to having many favorable effects (43, 51, 59).
This review focuses on the structure and biosynthesis of
omentin, a recently identified adipocytokine, and its com-
prehensive roles in health and various diseases, and expands
on current and future trends in omentin-based therapy. All
abbreviations used in this review are listed in Table 1.
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Comprehensive Physiology
Structure and Biosynthesis of Omentin
A novel 34-kDa adipocytokine originally identified from a
human omental adipose tissue cDNA library (AY549722)
was designated as omentin (158). This protein ID is registered
as UniProt code Q8WWAO. A homolog with 83% amino
acid identity with omentin is referred to as omentin-2 (27).
Accordingly, original omentin is now known as omentin-1
(27), intelectin-1 (131), intestinal lactoferrin receptor (119),
endothelial lectin HL-1 (72), or galactofuranose-binding
lectin (156). It is expressed in mesothelial cells, vascular
smooth muscle cells (VSMCs) and endothelial cells (ECs),
particularly in VAT, epicardial fat, small intestine, colon,
thymus, ovary, and testis as well as in intestinal Paneth cells
and airway and intestinal goblet cells (31, 69, 107, 131). In
the intestine, intelectin-1 has been detected as both soluble
form and brush border membrane bound form (146). The
membrane bound form is regarded as intestinal lactoferrin
receptor (114).
As shown in Figure 2, the human omentin gene is located
on chromosome 1q21.3, and consists of eight exons and
seven introns (107, 131). As shown in Figure 3, full-length
omentin-1 consists of 313 amino acids, including an 18-amino
acid signal peptide, which is a highly hydrophobic region
in the amino-terminal region (132). An actual cleavage site
of human omentin-1 (intelectin-1) is located between Ser-18
and Thr-19 (132). From a different perspective, Gly-16/Trp-
17 and Thr-19/Asp-20 were reported as a putative cleavage
site (69, 107). In any report, mature omentin-1 (intelectin-1)
is regarded as a secretory protein. As shown in Figure 3,
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Comprehensive Physiology Function and Regulation of Omentin-1

Table 1 Abbreviation List

AMPK AMP-activated protein kinase HMDM Human monocyte-derived macrophage

BMD Bone mineral density HUVEC Human umbilical vein endothelial cell
BMI Body mass index ICAM-1 Intercellular adhesion molecule-1
CAD Coronary artery disease JNK c-Jun N-terminal kinase
CART Cocaine- and amphetamine-regulated transcript MPM Malignant pleural mesothelioma
CKD Chronic kidney disease NF-κB Nuclear factor-κB
COX-2 Cyclooxygenase-2 PCOS Polycystic ovary syndrome
CRH Corticotrophin releasing hormone PI3K Phosphoinositide 3-kinase
CRP C-reactive protein RANKL Receptor activator for NF-κB ligand
ECM Extracellular matrix ROS Reactive oxygen species
ELISA Enzyme-linked immunosorbent assay SAS Sleep apnea syndrome
ERK Extracellular signal-regulated kinase TNF-α Tumor necrosis factor-α
ESRD End-stage renal disease VAT Visceral adipose tissue
eNOS Endothelial nitric oxide synthase VCAM-1 Vascular adhesion molecule-1
HASMC Human aortic smooth muscle cell VSMC Vascular smooth muscle cell

human omentin-1 and mouse omentin-1 are >81.5% identical in chordates (115) and Xenopus embryonic epidermal lectin in
(132). However, mouse omentin-1 is expressed at high lev- frogs (88), are secreted to outside of body. These observations
els in intestine, but not VAT (159). As shown in Figure 4, suggest that the basic physiological role of omentin may be
full-length omentin-2 consists of 325 amino acids, which are an effector for external substances.
83.0% identical to omentin-1.
In fact, omentin-1 was demonstrated to be released from
cultured human VAT (120). Dexamethasone stimulates the Biology of Omentin
expression of omentin-1 in human VAT (97). Fibroblast
Human recombinant omentin-1 (full length, Trp-17–Arg-313,
growth factor-21 also stimulates the omentin-1 secretion
Thr-19–Arg-313, etc) is now being produced in HEK293
from human perivascular preadipocytes (10). In contrast, the
cells, CHO cells, and Escherichia coli. Polyclonal and mon-
expression and secretion of omentin-1 are decreased by glu-
oclonal antibodies to human and mouse omentin-1 are also
cose and insulin in human adipose tissue explants (122).
being synthesized. Concentrations of human omentin-1 in
It is noticeable that hyperinsulinemia strongly decreases its
human plasma, serum, and other body fluid are measured
expression level and secretion into conditioned media (122).
by enzyme-linked immunosorbent assay (ELISA). All the
Omentin-1 is the major circulating form of omentin and
reagents regarding omentin-1 as well as human recombi-
also abundant in human plasma (27), with levels in women
nant omentin-2, and polyclonal and monoclonal antibodies
being higher than those in men (80). Circulating omentin-1
to human and mouse omentin-2 are purchased from commer-
levels are known to be negatively correlated with free testos-
cial sources. As listed in Table 2, circulating blood levels
terone, androgen, leptin, TNF-α, and inteleukin-6 levels but
of omentin-1 in healthy subjects vary from approximately 5
be positively correlated with adiponectin levels in normal
to 800 ng/mL according to the manufacturer of the ELISA
and overweight subjects (43). A prolonged insulin-glucose
kit. Transgenic mice expressing the human omentin gene are
infusion decreases serum omentin-1 levels in healthy subjects
used in collaborative researches of Nagoya University with
(122). In vitro studies showed that omentin-1 has a half-life of
others (48, 58, 81, 82, 135). Omentin-knockout mice may be
30 h in mammalian reticulocytes (107). However, its half-life
available, but so far there is no publication using it.
in the plasma is unclear. Omentin-2 is expressed in VAS and
mainly released to the intestinal lumen, but is not detected in
plasma (27).
In addition to its hormonal (endocrine) roles, omentin-1
Receptor for Omentin
(intelectin-1) is largely secreted into the intestinal lumen and The specific receptors for omentin have not yet been iden-
the airway (exocrine), and nonmammalian homologs, such as tified. It is interesting to define the omentin-1 receptor on
the Xenopus cortical granule lectin family XCGL and XCGL2 adipocytes and other cells. Various physiological activities of

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Figure 2 Genomic structure of human omentin gene. (A) The genomic structure of the human omentin (intelectin) gene.
(B) The exon-intron junctions. Exons are indicated as square boxes and the open reading frame is indicated as black
regions. The sequences and numbers of exon junctions are shown earlier the square boxes. The consensus sequences
for splicing are underlined. The usage of this figure from the original paper (131) is permitted by the American Society
for Biochemistry and Molecular Biology.

omentin-1 may suggest that the signaling of omentin-1 is not
a pathway through a specific protein receptor. It is possible
that the receptor may be a nonprotein, such as carbohydrates
or glycolipids, on the cell surface. As omentin-1 (HL-1) is
homologous to the Xenopus oocyte cortical granule lectin
XL35, further studies are required to analyze the possible
carbohydrate binding specificity of omentin-1 to its receptor
(51). It is especially important to elucidate the putative recep-
tor, which provides an investigation of its agonist as a new
drug target.
Roles of Omentin
The roles of omentin-1 in physiological, pathophysiologi-
cal, and clinical features have been a subject of increasing
interest (23, 51). However, the biological roles of omentin-
1 are still not well known. As omentin-1 (intelectin-1) ini-
tially found in intestinal Paneth cells was associated with
galactofuranose within carbohydrate moieties of the bacterial
cell wall, this peptide has been implicated in the gut defen-
sive mechanisms against pathogenic bacteria, for example,

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Comprehensive Physiology Function and Regulation of Omentin-1

Figure 3 Comparison of amino acid sequences between human omentin-1 and mouse omentin-1. This figure illustrates
the alignment of amino acid sequences of human omentin-1 (GenBank AAS49907; intelectin-1, BAA96094) and mouse
omentin-1 (intelectin-1, BAA31992). The homologous amino acids are shown in outline characters on black backgrounds,
which are 81.5% identical (255/313 amino acids). The usage of this figure from the original paper (132) is permitted by
the Oxford University Press.

Escherichia coli (69). A recent study has shown that omentin-
1 has properties necessary to function in the immune system’s
surveillance complex (144). Omentin-1 targets Streptococcus
pneumoniae serotypes by selectively binding to surface gly-
cans through calcium ion-dependent coordination of a con-
served exocyclic, terminal 1,2-diol, suggesting that omentin-1
functions in microbial surveillance (144). On the other hand,
omentin-2 has no conserved ligand-binding site substitutions
unlike omentin-1. There are ligand-binding site residue vari-
ations between human omentin-2 and mouse omentin-2 with
no known biochemical and functional consequences (141).
In addition, omentin-1 (intelectin-1) expressed in intestinal
epithelia also acts as a receptor for an iron-binding pro-
tein, lactoferrin (114). Lactoferrin is taken by enterocytes via
receptor-mediated endocytosis (114).
Several lines of experimental and clinical evidence have
explored a wide range of topics, including omentin-1-
mediated cardiovascular protective effects (106, 125) and the
use of circulating omentin-1 levels as a bone metabolism
marker (84) and a biomarker of cancers (121), polycys-
tic ovary syndrome (PCOS) (40), obstructive sleep apnea
syndrome (SAS) (140), preeclampsia (77), inflammatory
disease (20), metabolic disorders including diabetes and
metabolic syndrome (52, 95), endothelial dysfunction (87),

Figure 4 Comparison of amino acid sequence between human omentin-1 and human omentin-2. This figure illustrates
the alignment of amino acid sequences of human omentin-1 (GenBank AAS49907; intelectin-1, BAA96094) and human
omentin-2 (intelectin-2, EAW52685). The homologous amino acids are shown in outline characters on black backgrounds,
which are 83.0% identical (264/318 amino acids). Alignment of amino acid sequences between human omentin-1 and
human omentin-2 is from Basic Local Alignment Search Tool.

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Table 2 Circulating Levels of Omentin-1 (ng/mL) in Health and Disease

Diseased Control P value References

Type 1 diabetes 119.3 ± 23.4 ↓ 206.8 ± 38.8 P < 0.001 (123)

Type 2 diabetes 313 (median) ↓ 426 (median) P = 0.008 (37)
Obesity 310.0 ± 11.0 ↓ 370.0 ± 12.0 P < 0.05 (27)
Metabolic syndrome 23.5 ± 5.9 ↓ 34.6 ± 4.2 P < 0.01 (78)
Atherosclerosis Carotid 518.6 ± 191.1 ↓ 815.3 ± 185.3 P < 0.001 (55)
Peripheral 206.0 ± 48.4 ↓ 345.0 ± 80.0 P = 0.001 (92)
Stable CAD Male 102.8 ± 69.0 ↓ 454.7 ± 128.6 P < 0.001 (112)
Female 247.5 ± 127.4 ↓ 506.0 ± 246.0 P < 0.001 (91)
Acute coronary syndrome 13.4 ± 2.7 ↑ 4.4 ± 1.5 P < 0.05 (143)
Heart failure 305 (35-473) ↓ 494 (35-630) P = 0.035 (89)
Atrial fibrillation 157 (134-187) ↓ 203 (168-245) P < 0.05 (128)
Kawasaki disease 7.8 ± 2.1 ↑ 6.0 ± 1.7 P = 0.0002 (33)
Chronic hepatitis C 29.5 ± 6.6 ↑ 11.1 ± 1.5 P < 0.05 (90)
Crohn’s disease 14.6 (11.4-18.1) ↓ 28.6 (24.7-33.2) P < 0.001 (160)
Ulcerative colitis 14.7 (11.5-18.2) ↓ 28.6 (24.7-33.2) P < 0.001 (160)
Colon carcinoma 618 (151-758) ↑ 376 (155-662) P < 0.001 (136)
Pancreatic adenocarcinoma 9.6 (3.6-219) ↑ 1.6 (0.8-5.0) P < 0.001 (57)
Renal cell carcinoma 3.6 ± 0.8 ↓ 9.9 ± 1.4 P < 0.001 (111)
CKD 251.4 ± 102.2 ↓ 342.6 ± 125.1 P < 0.01 (129)
Preeclampsia 174 (139-199) ↓ 230 (188-265) P < 0.001 (77)
PCOS 255.8 ± 78.2 ↓ 348.0 ± 112.6 P < 0.05 (122)
SAS 27.7 ± 7.6 ↓ 42.5 ± 5.2 P < 0.001 (138)
Hypothyroidism 405 (197-906) ↓ 483 (256-1207) P = 0.037 (21)
Anorexia nervosa 46.1 ± 3.8 ↑ 34.3 ± 2.6 P < 0.0001 (93)
Juvenile idiopathic arthritis 8.5 ± 3.0 ↑ 6.1 ± 1.9 P = 0.0001 (17)
Psoriasis 95.6 ± 44.4 ↓ 143.6 ± 49.0 P = 0.001 (165)
Systemic sclerosis 761 (628-1029) (↓) 850 (690-1040) P = 0.69 (85)

Data are expressed as mean ± standard error or deviation, and median (25-75th percentage or minimum-maximum). Arrows show changes in
omentin-1 levels compared with controls.
Abbreviations: CAD, coronary artery disease; CKD, chronic kidney disease; PCOS, polycystic ovary syndrome; SAS, sleep apnea syndrome.

and atherosclerosis (92, 161). Therefore, this review intro-
duces the comprehensive roles of omentin-1 in health and a
variety of diseases.
Diabetes, Obesity, Metabolic Syndrome,
and Fatty Liver
The chromosomal region of the human omentin gene has
previously been reported to be linked to type 2 diabetes in
several populations (27). Therefore, omentin-1 may be a can-
didate gene for type 2 diabetes susceptibility in humans.
In fact, Yang et al. (159) reported that omentin-1 enhances
insulin-stimulated glucose uptake via Akt activation in human
adipocytes. As listed in Table 2, several clinical studies have
shown that serum omentin-1 levels are significantly decreased
in patients with type 2 diabetes, obesity, diabesity (diabetes +
obesity), and metabolic syndrome (27, 52, 95, 166). Omentin-
1 is negatively correlated with intake of saturated fatty acids,
body mass index (BMI), insulin resistance, total cholesterol,
hemoglobin A1c, leptin, and systolic blood pressure, and
is positively correlated with adiponectin and high-density
lipoprotein cholesterol concentrations and very low-density
lipoprotein (LDL) particle size (27, 47, 78, 96, 113, 117, 163).
In children with type 1 diabetes, serum omentin-1 levels
are also decreased compared with healthy children (98, 123)
(Table 2). Further, serum omentin-1 levels decrease in accor-
dance with the presence of the three major complications,
such as retinopathy, nephropathy, and neuropathy in type 2
diabetic patients (53, 129, 139). Serum omentin-1 levels are

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also associated with cardiac autonomic neuropathy in type 1
diabetic and type 2 diabetic patients (26, 53). In addition, the
expression of omentin-1 in VAT is lower in obese patients with
non-alcoholic fatty liver disease (9). A recent study showed
that omentin-1 Val109Asp (326A/T) polymorphism might be
a candidate genetic factor for susceptibility to nonalcoholic
fatty liver disease (68).
Circulating omentin-1 levels increase after weight loss,
olive oil-rich diet, aerobic training, and treatment with antidi-
abetic drugs, such as metformin, pioglitazone, exenatide (a
glucagon-like peptide-1 analogue), and sitagliptin (a dipep-
tidyl peptidase-4 inhibitor) via improving insulin sensitivity
(32, 37, 54, 86, 124, 145, 147). In contrast, treatment with met-
formin combined with gliclazide, a sulfonylurea, decreases
omentin-1 levels in patients with type 2 diabetes (1). A recent
study indicated that atorvastatin increases serum omentin-1
levels in patients with coronary artery disease (CAD) (22).
Atherosclerosis and Peripheral
Vascular Diseases
Recent basic and clinical studies have shed light on the patho-
physiological roles of omentin-1 in vascular inflammation
and atherosclerosis. Atherosclerosis, the major cardiovascu-
lar problems, is a complex multicellular process in response to
vascular injury (76). Atherosclerosis is initiated by endothe-
lial inflammation characterized by upregulation of inter-
cellular adhesion molecule-1 (ICAM-1), vascular adhesion
molecule-1 (VCAM-1), and monocyte chemotactic protein-
1 (MCP-1), and monocyte adhesion/infiltration followed by
fatty streak formation with subendothelial accumulation of
lipid-laden monocyte-derived macrophages (44). Oxidized
LDL is known to stimulate macrophages to induce foam cell
formation. Simultaneously, VSMCs contribute to progression
of atherosclerotic plaque by their migration, proliferation, and
production of extracellular matrix (ECM) components, such
as collagen-1 and collagen-3 (143).
As shown in Figure 5, omentin-1 is abundantly
expressed in human monocytes, human monocyte-derived
macrophages (HMDMs), human umbilical vein endothelial
cells (HUVECs), and human aortic smooth muscle cells
(HASMCs) in vitro. The atheroprotective effects of omentin-1
are summarized in Figure 6. In vitro studies have shown that
omentin-1 suppresses TNF-α-induced expression of ICAM-1,
VCAM-1, and cyclooxygenase-2 (COX-2) in HUVECs and
adhesion of monocytes to HUVECs via ERK/nuclear factor-
κB (NF-κB), JNK/AMP-activated protein kinase (AMPK),
and endothelial nitric oxide synthase (eNOS) signaling path-
ways (155,171). Omentin-1 inhibits TNF-α-induced VCAM-
1 expression, platelet-derived growth factor-BB (PDGF-BB)
or angiotensin II-induced migration, PDGF-BB-induced pro-
liferation, and collagen-1 and collagen-3 expression via
p38, JNK, ERK, and NF-κB signaling pathways in VSMCs
(60,63,143). Omentin-1 also suppresses ROS production and
calcification in VSMCs (29, 60). Omentin-1 causes a shift to
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Function and Regulation of Omentin-1
Figure 5 Expression of human omentin-1 in human vascular cells.
Aliquots of protein extracts (50 μg) derived from human mono-
cytes, HMDMs, HUVECs, and HASMCs were separated by 10%
sodium dodecyl sulfate-polyacrylamide gel electrophoresis and then
immunoblotted with antibodies against human omentin-1 (upper). α-
Tubulin served as a loading control (beneath). Molecular size is
expressed in kilodaltons (kDa).
the anti-inflammatory M2 phenotype rather than the inflam-
matory M1 phenotype via peroxisome proliferator-activated
receptor-γ upregulation and NF-κB downregulation during
differentiation from human monocytes into macrophages
(143). Omentin-1 also suppresses oxidized LDL-induced
foam cell formation via downregulation of scavenger recep-
tors, such as CD36 and scavenger receptor class A, and acyl-
coenzyme A:cholesterol acyltransferase-1 in HMDMs (143).
In addition to atherogenesis, omentin-1 suppresses the migra-
tion and angiogenesis of HUVECs induced by human serum,
C-reactive protein (CRP), and vascular endothelial growth
factor (124).
In vivo, exposure to omentin-1 by either gain-of-function
genetic manipulation or by long-term infusion was shown to
attenuate the development of atherosclerotic lesions in both
the entire aortic surface and the sinus area in apolipoprotein
E-deficient mice (48, 143). The reduction of lesion forma-
tion was accompanied by an overall reduced inflammatory
phenotype with decreased mRNA expression of adhesion
molecules (ICAM-1, VCAM-1) and cytokines/chemokines
(TNF-α, interleukin-6, and MCP-1) as well as reduced mono-
cyte/macrophage infiltration and VSMC and collagen con-
tents in apolipoprotein E-deficient mice (48, 143). Chronic
omentin-1 infusion into apolipoprotein E-deficient mice sup-
presses the inflammatory M1 phenotype and inflammasomes,
such as CRP, COX-2, apoptosis-associated speck-like protein
containing a caspase recruitment domain, and NF-κB, and
ERK1/2 signaling in exudate peritoneal macrophages, and
lowers plasma total cholesterol levels (143).
Omentin-1 induces vasodilation in isolated rat blood ves-
sels by activating eNOS (154), and exerts suppressive effects
on systemic and pulmonary hypertension in rats (16, 61, 62).
Omentin-1 acts as a critical mediator of the protective
actions against myocardial hypertrophy in response to pres-
sure overload via stimulation of the AMPK signaling path-
way in mice (82). Omentin-1 stimulates ischemia-induced
771
Function and Regulation of Omentin-1 Comprehensive Physiology

Figure 6 Mechanisms underlying the atheroprotective effects of omentin-1. This figure illustrates the suppressive
effects of omentin-1 on atherogenesis in the arterial wall. Omentin-1 prevents atherosclerosis by suppressing the
inflammatory responses in endothelial cells (ECs), the adhesion of monocytes (Mo) to ECs, oxidized low-density
lipoprotein (LDL)-induced foam cell formation in Mo-derived macrophages (Mϕ), the migration and proliferation
of vascular smooth muscle cells (VSMCs), and the production of extracellular matrix (ECM), such as collagen-1
and collagen-3, by VSMCs. Abbreviations: ACAT-1, acyl-coenzyme A:cholesterol acyltransferase-1; ABCA1, ATP-
binding cassette transporter A1; DM, diabetes mellitus; HT, hypertension, ICAM-1, intercellular adhesion molecule-
1; M-CSF, macrophage colony-stimulating factor; NO, nitric oxide; VCAM-1, vascular adhesion molecule-1.

revascularization, and prevents myocardial ischemic injury
and arterial injury-induced neointimal formation via AMPK
and/or Akt-eNOS signaling pathways in mice (58, 81, 135).
Omentin-1 also suppresses doxorubicin-induced apoptosis
via inhibiting mitochondrial ROS generation in H9c2 rat car-
diomyoblasts (64).
A clinical study has shown that circulating omentin-1 lev-
els are independently associated with endothelial dysfunc-
tion even after matching for age and CRP in subjects with
impaired glucose tolerance (87). Several other studies have
shown that circulating omentin-1 levels are significantly lower
in patients with carotid atherosclerosis and peripheral arte-
rial disease compared with corresponding controls (55, 92)
(Table 2). These findings suggest that circulating omentin-1
levels could be a useful biomarker of vascular dysfunction
and atherosclerosis.
Cerebrovascular and Cardiovascular
Diseases
The findings described above indicate that omentin-1 can con-
tribute to the suppression of atherosclerotic plaque formation
by not only its direct effects on the vascular wall but also
its indirect effects on improvement of risk factors, such as
diabetes, obesity, hypertension, and dyslipidemia. Kadoglou
et al. (55) reported that low serum levels of omentin-1 are asso-
ciated with the severity and vulnerability of carotid plaques.
Circulating omentin-1 levels are inversely correlated with
matrix metalloproteinase-3, which mediates to alter plaque
vulnerability to rupture (103). A prospective study recently
showed that high plasma concentration of omentin-1 is asso-
ciated with increased future risk of stroke in healthy middle-
aged subjects with normal waist circumference, low levels of
triglyceride and high-sensitivity CRP, high adiponectin levels,
and no metabolic syndrome (83). As this study was performed
in metabolically healthy subjects, the results may be different
from those expected in subjects with obesity and metabolic
syndrome.
CAD is the most important morbidity and mortality
disease in the world. Omentin gene polymorphism was
analyzed in CAD patients. The prevalence of omentin-1
Val109Asp polymorphism did not differ significantly between
CAD patients and control subjects (162). However, Val/Val
(homozygous mutant) genotype was more frequently detected
by 2.5-fold in CAD patients compared with control subjects

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Figure 7 Expression of human omentin-1 in epicardial adipose tissue. These pictures (Alexa Fluor 488 confocal images) show fluorescent
immunohistochemistry staining of human omentin-1 (green) in epicardial adipose tissues in CAD and non-CAD patients.
(162). Next, the relationship between CAD and omentin-1
secretion from epicardial adipose fat is described. Adipocy-
tokines secreted from epicardial adipose tissues affect the
development of atherosclerotic lesions in coronary arteries
(50). The transverse secretion through epicardial fat vascular
wall is called as the vasocrine secretion (50). Omentin-1 is
abundantly expressed at pericoronary site in human epicardial
adipose tissue (34). There are conflicting results regarding the
expression of omentin-1 in epicardial adipose tissues in CAD
patients. Watanabe et al. (143) and Du et al. (28) reported that
the reduced expression of omentin-1, similar to adiponectin
(173), is associated with coronary atherosclerosis. Figure 7
shows the reduced epicardial fat omentin-1 expression in
a CAD patient compared with a non-CAD patient. In con-
trast, Harada et al. (45) reported the increased expression of
omentin-1 in epicardial adipose tissues in CAD patients.
The associations between circulating omentin-1 levels
and CAD are now discussed. Ucgun et al. (134) showed that
decreased serum levels of omentin-1 are associated with slow
coronary flow. As shown in Table 2, plasma omentin-1 levels
are reduced in patients with stable CAD except acute coro-
nary syndrome (91, 99, 112, 118). Serum omentin-1 levels are
decreased at the onset of acute coronary syndrome and then
increased after 6 months of follow-up (56). Watanabe et al.
(143) demonstrated increased levels of omentin-1 in plasma
and coronary atherosclerotic lesions in patients with acute
coronary syndrome (Table 2). These findings suggest that
omentin-1 may be an acute-phase reactant to counteract the
progression of atherosclerotic lesions. In addition, a recent
study has shown that high plasma omentin-1 levels are asso-
ciated with well-developed coronary collateral circulation
Volume 7, July 2017
Function and Regulation of Omentin-1
in CAD patients (172), which suggests the cardioprotective
effects of omentin-1.
Omentin-1 has recently been investigated as a possible
prognostic index for CAD and heart failure. Plasma omentin-
1 levels are decreased in patients with dilated cardiomyopa-
thy and heart failure (49, 89) (Table 2). Decreased omentin-1
levels are associated with a poor cardiac outcome in patients
with heart failure (89). In contrast, several studies have shown
that increased omentin-1 levels are associated with cardio-
vascular events, prognosis, and mortality (67, 104, 105). Fur-
ther large-scale longitudinal studies are needed to determine
whether low or high levels of omentin-1 reflect good prog-
nosis. Multivariable-adjusted analyses with gender, smoking,
obesity, insulin resistance, diabetes, and especially the period
of omentin-1 sampling after the onset of CAD or heart failure
are also warranted.
A recent study has shown the relationship between cir-
culating omentin-1 levels and arrhythmia (128). As shown
in Table 2, serum omentin-1 levels are significantly lower in
patients with atrial fibrillation than in healthy controls (128).
The reduced serum levels of omentin-1 are associated with
left atrial dilatation in patients with atrial fibrillation.
Role in Nervous System and Relation to
Neurological Diseases
Brunetti et al. (14) reported that bolus injection of omentin-
1 into the arcuate nucleus of the hypothalamus did not
change feeding without modifying mRNA expression of
hypothalamic feeding behavior-associated peptides, such as
773
Function and Regulation of Omentin-1
agouti-related peptide, neuropeptide Y, orexin-A, cocaine-
and amphetamine-regulated transcript (CART), corti-
cotrophin releasing hormone (CRH), and proopiome-
lanocortin. However, intraperitoneal injection of omentin-1
for a period of 2 weeks increased food intake with body
weight in rats (15). The orexigenic effects of omentin-1 may
be related, at least in part, to the decreased mRNA expression
of CART and CRH and the increased synthesis and release
of norepinephrine in the hypothalamus (15). These findings
may contribute to understanding the role of omentin-1 in the
nervous system, but never intend to indicate that omentin-1
induce obesity.
Omentin-1 ameliorates ischemic brain injury by promot-
ing EC function and revascularization, and inhibiting apop-
tosis in response to ischemia via the Akt-eNOS signaling
pathway (39). Omentin-1 also promotes the growth and sur-
vival of neural stem cells in vitro via the activation of the Akt
signaling pathway (169). These findings suggest the possi-
ble utility of omentin-1 in the treatment of vascular dementia
caused by ischemic stroke, and neurodegenerative diseases,
such as Alzheimer’s and Parkinson’s diseases.
Inflammatory and Autoimmune Diseases
Obesity-induced metabolic abnormalities are associated with
inflammatory status. Macrophages isolated from VAT are
responsible for proinflammatory cytokines, such as TNF-α
and interleukin-6, which are known to be negatively asso-
ciated with omentin-1 (43). The omental adipose tissue is
involved in the transmural and intra-abdominal inflamma-
tory process in Crohn’s disease (chronic inflammatory bowel
disease), and the levels of omentin-1 mRNA expression are
decreased in the omental adipose tissue of patients with
Crohn’s disease (107). The expression of toll-like receptor-4
is increased in patients with Crohn’s disease, possibly because
of a deficiency of toll-like receptor-4 signaling observed in this
disease. A treatment with a toll-like receptor-4 antagonist pre-
vents the development of colitis (127). These findings suggest
that omentin-1 may play a role in antagonizing the expression
of toll-like receptor-4 (51). Therefore, omentin-1 may play a
significant role as an anti-inflammatory agent in inflammatory
conditions. It is also thought that reduced levels of omentin-1
may cause inflammatory diseases. As shown in Table 2, cir-
culating levels of omentin-1 are also lower in patients with
inflammatory bowel diseases, such as Crohn’s disease and
ulcerative colitis (160), and painful temporomandibular dis-
orders (46). The gingival crevicular fluid of patients with
chronic periodontitis shows the reduced levels of omentin-1
(12), which are increased following periodontal therapy (6). In
patients with rheumatoid arthritis (chronic inflammatory joint
disorder), omentin-1 levels are decreased in synovial fluid
(110). Omentin-1 in synovial fluid may serve as a biomarker
for reflecting the degenerative process in osteoarthritis (151).
Omentin-1 is known as a prominent protein constituent
of pathologic mucus associated with eosinophilic airway
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Comprehensive Physiology
inflammation in patients with asthma (65). Kuperman et al.
(71) reported increased omentin-1 gene expression in airway
epithelial cells of patients with asthma. Omentin-1 is required
for interleukin-13-induced production of MCP-1 and MCP-3
in mouse lung epithelial cells, and promotes allergic airway
inflammation (38). The putative roles of omentin-1 include the
mucous response in allergy and bacteria infections. Omentin-
1 protects against lipopolysaccharide-induced acute respira-
tory distress syndrome by suppressing inflammation and pro-
moting the pulmonary endothelial barrier, at least partially,
via the Akt/eNOS signaling pathway (101).
We introduce the relationship of omentin-1 with autoim-
mune diseases and their complications. As shown in Table 2,
serum omentin-1 levels are decreased in patients with
hypothyroidism due to Hashimoto’s thyroiditis (21). In sys-
temic sclerosis, decreased serum levels of omentin-1 are
observed, and a loss of omentin-1-dependent protection
against vascular inflammation and remodeling may be related
to pathological vascular events (85). By contrast, the increase
of serum omentin-1 levels may serve as a biomarker for pul-
monary arterial hypertension in systemic sclerosis, which may
be attributed to the compensatory production of omentin-
1 against the increased vascular tone in pulmonary arteries
(85). As shown in Table 2, serum omentin-1 levels are also
increased in patients with Kawasaki disease, which is char-
acterized by systemic arteritis and coronary artery aneurysm
(33). In patients with systemic lupus erythematosus, plasma
omentin-1 levels are not markedly different from the normal
controls but are increased in the presence of nephritis (167).
Previous studies have shown the decreased levels of omentin-
1 in plasma and psoriatic lesions in psoriasis patients com-
pared with healthy controls (165) (Table 2). However, plasma
omentin-1 levels are increased in patients with psoriatic arthri-
tis compared with both psoriasis patients without arthritis and
healthy individuals (153).
As shown in Table 2, serum omentin-1 levels are increased
in patients with juvenile idiopathic arthritis, early acute pan-
creatitis, chronic pancreatitis, and chronic hepatitis C com-
pared with corresponding controls (17, 70, 90, 116). Portal
vein omentin-1 levels are increased in patients with liver cir-
rhosis (30). Although the precise reasons for these findings
are not known, it is speculated that omentin-1 may play a role
as a reactant protein to reduce inflammation. A recent study
has reported that elevated serum levels of omentin-1 might
be predictive for an impaired long-term survival in critically
ill patients with septic and non-septic diseases admitted to
intensive care unit (79).
Renal Diseases
Chronic inflammation, accelerated atherosclerosis, and
insulin resistance are the common pathogenic features of
chronic kidney disease (CKD). Tekce et al. (129) reported
the reduced serum levels of omentin-1 in CKD patients com-
pared with controls (Table 2). By contrast, Sengul et al. (109)
Volume 7, July 2017
Comprehensive Physiology
reported that serum omentin-1 levels are elevated in nondia-
betic CKD patients compared with healthy controls. Further,
serum omentin-1 levels are elevated in patients with end-stage
renal disease (ESRD) receiving hemodialysis compared with
controls (2). The high plasma levels of omentin-1 in CKD and
ESRD patients are attributed to the failure of degradation and
excretion of circulating omentin-1. Due to its high molecular
weight of 34 kDa, omentin-1 may not be significantly cleared
from the plasma during hemodialysis. In the presence of dia-
betes, serum omentin-1 levels are reduced in patients with
CKD and ESRD receiving hemodialysis (66, 129).
Cancers
Obese individuals are known to be at higher risk for the devel-
opment of gastrointestinal cancers and prostate cancer com-
pared with normal weight ones (43). The basic mechanism
of the relationship is still incompletely clarified. As a mech-
anism, a reduction of adiponectin levels is recognized as a
strong risk factor for early colorectal cancers (43). More-
over, PI3K/Akt signaling is believed to be involved in the
development of colorectal cancers (43). As there is a close
positive correlation between adiponectin and omentin-1 lev-
els, omentin-1 decline may contribute to the development of
colorectal cancers via the activation of PI3K/Akt signaling
pathway.
Omentin-1 functions as a tumor suppressor that affects the
growth, invasion, and metastasis of neuroblastoma through the
up-regulation of N-myc downstream-regulated gene-2 (73).
Omentin-1 inhibits proliferation and induces apoptosis in
human hepatocellular carcinoma cells, such as HepG2 and
HuH-7 cells, via the activation of JNK/p53/bcl-2/caspase-3
signaling pathways (168). Omentin-1 suppresses the progres-
sion of gastric cancer by inactivating the phosphoinositide
3-kinase (PI3K)/Akt/NF-κB signaling pathway (74). These
findings indicate a possibility of omentin-1 as a candidate
anticancer agent.
Omentin-1 transcript levels are significantly elevated in
gastric cancer tissues compared with normal gastric mucosa
(170). The expression of omentin-1 is higher in intestinal-type
carcinomas than in diffuse-type carcinomas (170). Omentin-1
expression in gastric cancer is positively correlated with tumor
differentiation and the expression of CDX2, a homeobox tran-
scription factor that serves as a tumor-suppressor gene, and
is inversely correlated with degrees of invasion, metastasis,
and clinical stage, without correlations with tumor location or
tumor size (170). Thus, the increased expression of omentin-1
in gastric cancer is closely associated with its clinicopatho-
logical features, and may be a useful prognostic indicator of
outcomes in patients with gastric cancer (170). In addition,
epithelioid-type malignant pleural mesothelioma (MPM), but
neither pleura-invading lung adenocarcinomas nor reactive
mesothelial cells near lung adenocarcinoma, shows stain-
ing with anti-omentin-1 antibodies (133). Pleural effusion of
MPM patients contains a higher level of omentin-1 than that
Volume 7, July 2017
Function and Regulation of Omentin-1
of lung cancer patients (133). Omentin-1 is a useful biomarker
of epithelioid-type MPM because of its high specificity and
simplicity of pathological assessments (142). These findings
suggest that immunohistochemical detection of omentin-1
may be very helpful for differential diagnosis of epithelioid-
type MPM and that high concentrations of omentin-1 in pleu-
ral effusion also can be used as a new reliable biomarker for
clinical diagnosis of MPM.
Circulating omentin-1 levels are elevated in patients with
liver, colon, colorectal, and prostate cancers (3,136,137,168)
(Table 2). As shown in Table 2, serum omentin-1 levels
increase with increasing tumor size in patients with pancreatic
adenocarcinoma (57). In contrast, the circulating omentin-1
levels were markedly decreased in patients with renal cell
carcinoma (111) (Table 2). The difference may be due to the
cancer location (organ and tissue) and clinical stage. There-
fore, omentin-1 levels are expected to have potential screening
and therapeutic implications for cancers.
Bone Metabolism and Diseases
Omentin-1 is a new type of Ca2+ -dependent soluble lectin
in humans. Omentin-1 stimulates human osteoblast prolifer-
ation via the PI3K/Akt signaling pathway (148). Omentin-
1 stimulates proliferation and suppresses both osteocal-
cin secretion and runt-related transcription factor-2 protein
expression in mouse osteoblasts. Omentin-1 also inhibits
matrix mineralization in mouse osteoblasts (149). Omentin-
1 reduces osteoclast formation by stimulating osteoprote-
gerin and inhibits the production of receptor activator for
NF-κB ligand (RANKL) in mouse osteoblasts (149, 150).
These findings indicate that omentin-1 ameliorates bone loss
induced by estrogen deficiency in vivo by downregulating the
RANKL/osteoprotegerin ratio (149, 150).
Serum omentin-1 levels showed no significant correla-
tion with bone mineral density (BMD) at different skeletal
sites in healthy adult Chinese men (20-80 years old) (75),
but showed a significant inverse correlation with BMD at
the lumbar spine in postmenopausal Iranian women (130).
Boron et al. (11) showed the association between omentin-
1 Val109Asp (326A/T) polymorphism and osteoporosis in
postmenopausal Polish women. These findings suggest that
omentin-1 may be a candidate biomarker for osteoporosis in
postmenopausal women.
Omentin-1 exerts a negative effect on bone remodeling in
girls with anorexia nervosa, a serious eating disorder char-
acterized by self-starvation and excessive weight loss. The
mechanism is attributed to the inhibitory effect of omentin-1
on both bone formation and resorption via the osteoprote-
gerin/RANKL system (35). Serum omentin-1 level is an inde-
pendent predictor of BMD in girls with anorexia nervosa, and
is negatively correlated with biochemical markers of bone
turnover, such as bone alkaline phosphatase and bone cross-
linked N-terminal telopeptides of collagen-1. These obser-
vations suggested that omentin-1 may have the suppressive
775
Function and Regulation of Omentin-1
effects on bone formation in girls with anorexia nervosa (41).
Elevated serum levels of omentin-1 are correlated with BMD
at the femoral neck and the serum levels of osteocalcin and
osteopontin in patients with multiple sclerosis (4).
Pregnancy and Gynopathy
Plasma omentin-1 levels are higher at 11 weeks of gestation
compared with the non-pregnant state (7). The mRNA expres-
sion of omentin-1 is reduced in the placenta and adipose tissue
obtained from women with preexisting obesity (7). Diabetes
in pregnancy is known to induce serious consequences for
both the mother and the growing fetus (body weight and glu-
cose metabolism). Serum levels of omentin-1 are lower in
gestational diabetic women than in normal glucose-tolerant
women (94). In addition, decreased serum levels of omentin-1
are associated with the presence and severity of preeclamp-
sia, a serious pregnancy complication that is characterized
by maternal hypertension, albuminuria, liver and kidney dys-
function, and fetal growth restriction (77) (Table 2). Maternal
circulating levels of omentin-1 are negatively correlated with
the fetal ponderal index (fetal weight [g]/fetal length [cm]3
× 100) (7). The aberrant omentin-1 expression in maternal
plasma, placenta, and adipose tissue may affect the induction
of metabolic disorders in the fetus and infant (51).
PCOS is characterized by irregular menses and hyperan-
drogenism, and is associated with insulin resistance and pan-
creatic β-cell dysfunction, impaired glucose tolerance, type 2
diabetes, dyslipidemia, and visceral obesity (122). As shown
in Table 2, plasma omentin-1 levels are lower in overweight
women with PCOS (122). As obesity is prevalent in PCOS,
it is not surprising that PCOS presents insulin resistance and
metabolic disorders (126). Postprandial hyperinsulinemia and
hyperglycemia contribute more to lower omentin-1 levels than
fasting values in the setting of PCOS. Other than fat mass,
increased androgen levels also contribute to the decreased
omentin-1 levels in women with PCOS (24). However, plasma
omentin-1 levels are decreased even in the nonobese PCOS
group. The decreased plasma levels of omentin-1 are asso-
ciated with insulin resistance in nonobese individuals with
PCOS independent of BMI status (157). In addition, Tan
et al. (124) reported that CRP is predictive for fluctuations in
serum omentin-1 levels after metformin treatment in PCOS
patients, which provides further evidence of the close rela-
tionship between omentin-1 and inflammation.
Cloix et al. (25) showed that omentin-1 is present in
human follicular cells, and the omentin-1 levels are simi-
lar in follicular fluid and plasma. In human granulosa-lutein
cells and human ovarian granulosa-like tumor cell line cells,
insulin-like growth factor-1 (IGF-1) increases both mRNA
and protein expression of omentin-1 via increased expression
of nicotinamide phosphoribosyltransferase (25). Omentin-1
improves IGF-1-induced progesterone and estradiol secretion
associated with the increased expressions of steroidogenic
acute regulatory protein and cytochrome P450 aromatase, and
IGF-1 receptor signaling (25).
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Comprehensive Physiology
Obesity- or Lean-Related Diseases
SAS is characterized by obesity and insulin resistance, and
is known as a risk factor for a variety of cerebrovascular and
cardiovascular diseases (5). The intermittent hypoxia by sleep
apnea is known to cause oxidative stress, via ROS generation,
and accelerate the development of vascular inflammation and
atherosclerosis in SAS patients (5). As shown in Table 2,
serum omentin-1 levels are lower in SAS patients (138). The
omentin-1 levels are increased after 3 months of the treatment
with continuous positive airway pressure (138).
Childhood obesity is a condition where excess body fat
(subcutaneous and visceral fat) negatively affects a child’s
health or well-being (8). Childhood obesity is known to
predispose to insulin resistance, type 2 diabetes, dyslipi-
demia, hypertension, and atherosclerosis, and also increase
the risk of stroke and cardiovascular diseases (152). Studies
regarding relationship between childhood obesity and circu-
lating omentin-1 levels showed three patterns of inconsistent
findings. First, Catli et al. (19) demonstrated the decreased
serum levels of omentin-1 in obese children compared with
normal-weight ones, and negative correlations between serum
omentin-1 levels and BMI and insulin resistance. Second,
Prats-Puig et al. (100) found that serum omentin-1 levels are
increased in obese patients with insulin resistance, high levels
of fasting serum triglyceride and blood pressures, family his-
tory of diabetes, and reduced levels of high-molecular weight
adiponectin. Last, Schipper et al. (108) did not find a sig-
nificant difference in plasma omentin-1 levels between obese
and lean children. In addition, Reyman et al. (102) reported no
significant difference in circulating omentin-1 levels among
vitamin-D-deficient obese, non-vitamin-D-deficient obese,
and healthy children. Anyway, Zehsaz et al. (164) recently
showed that 16-week exercise training significantly increases
serum omentin-1 levels in children with obesity. Further stud-
ies in large populations are needed to better-define the rela-
tionship between omentin-1 and childhood obesity.
Anorexia nervosa constitutes a chronic deficient or atro-
phy of adipose tissues, severe weight loss, and nutrition dis-
orders in the young (mainly girls). As shown in Table 2,
serum omentin-1 levels are significantly higher in girls with
restrictive anorexia nervosa than in healthy girls and those
with simple obesity (41,93). Serum omentin-1 levels are neg-
atively correlated with BMI (93). As the main symptom of
anorexia nervosa is emaciation, the lack of enlargement fat
cells leads to increased serum levels of omentin-1. In addition,
dieting and excessive physical efforts and low estradiol levels
may be involved in reduction of serum omentin-1 levels in
patients with anorexia nervosa.
These findings suggest that circulating omentin-1 levels
are reduced in conditions associated with insulin resistance,
such as obesity, PCOS, type 2 diabetes, gestational diabetes,
and obstructive SAS. While, an elevation in omentin-1 lev-
els may be regarded as a biomarker for leanness. Omentin-1
plays a potential role in energy homeostasis via AMPK phos-
phorylation.
Volume 7, July 2017
Comprehensive Physiology Function and Regulation of Omentin-1

Figure 8 Intracellular signaling pathways for multiple beneficial effects of omentin-1. This fig-
ure illustrates the secretion source, intracellular signals, and main beneficial effects of omentin-
1. Abbreviations: AMPK, AMP-activated protein kinase; eNOS, endothelial nitric oxide syn-
thase; ERK, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase; MAPK, mitogen-
activated protein kinase; NF-κB, nuclear factor-κB; PI3K, phosphoinositide 3-kinase.

Conclusions omentin-1-based medicines, for example, omentin-1 ana-

The novel adipocytokine omentin-1 secreted mainly from
VAT has effects on the maintenance of body metabolism, in
particular insulin sensitivity, and also pleiotropic effects, such
as anti-inflammatory and antiatherosclerotic effects, via the
intracellular Akt/AMPK/NF-κB and mitogen-activated pro-
tein kinase (ERK, JNK, and p38) signaling pathways (Fig. 8).
Many lines of evidence indicate that changes in omentin-1
levels in tissues and circulating blood are closely linked to
diabetes, obesity, atherosclerosis, inflammation, and related
diseases, such as metabolic syndrome, PCOS, SAS, cancer,
and cerebro-cardiovascular diseases. However, it remains
unclear which is the cause or the result between omentin-1
levels and these various diseases. It is most likely that decline
of omentin-1 may induce these diseases and omentin-1 may
tend to increase to counteract the acute phase after the onset.
These findings indicate that omentin-1 may be a negative
risk factor for these diseases, and also act as an acute-phase
reactant to exert the pleiotropic effects. Thus, appropriate
steps taken to maintain adequate levels of omentin-1 may
guarantee a long and healthy life. Weight loss, olive oil-rich
diet, aerobic training, and treatment with atorvastatin and
antidiabetic drugs, such as metformin, pioglitazone, and
exenatide, are effective for increasing endogenous omentin-1
levels via improving insulin sensitivity. Omentin-1 may open
up a new therapeutic window for combating obesity, insulin
resistance, inflammation, and related diseases, such as type
2 diabetes, atherosclerosis, CAD, cancers, etc. Therefore,
logues and omentin-1 receptor agonists, are expected as a
pharmaceutical strategy and an emerging new therapy against
these diseases. Further studies are required to identify the
specific receptor for omentin-1 to facilitate new drug devel-
opment. This review also provides insights into the potential
use of omentin-1 in plasma and tissues as a biomarker for the
diseases outlined earlier.
Acknowledgements
The authors would like to thank Dr. Taka-aki Matsuyama for
his technical assistance and Dolphin Corp. for their assistance
in editing this manuscript. This work was supported in part
by a Grant-in-Aid for Scientific Research (C) (26460659 to
T. Watanabe) from the Japan Society for the Promotion of
Science.
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