1. Introduction
Various adipokines, including adiponectin, adipsin, apelin, chemerin, fibroblast growth factor 21, interleukin-6 (IL-6), leptin, retinol-binding protein 4, osteonectin, omentin, plasminogen activator inhibitor-1, progranulin, resistin, tumor necrosis factor (TNF), vaspin, and vistafin are derived from the adipose tissue [
1,
2].
Adipokines participate in various physiological and pathological processes including insulin sensitivity, energy expenditure, glucose and lipid metabolism, inflammatory activity, neuroendocrine activity, immunity, cancer, homeostasis, angiogenesis, cardiovascular function, breeding and bone metabolism, and all functions of the endocrine-reproductive system axis [
2,
3,
4]. The majority of adipokines, such as TNF-α and IL-6, pose adverse effects and aggravate the severity of diseases [
5,
6]. On the contrary, a few of these, such as adiponectin and omentin, are “good” adipokines [
7,
8]. Omentin is an important molecule that connects organs with adipose tissue and exerts extensive protective effects [
9,
10]. Pulmonary diseases are devastating disorders with high morbidity and mortality, and understanding the cellular and molecular mechanisms of omentin function in these diseases is a key step towards improving research on pulmonary disease biology. Therefore, this review focuses on the latest advances in omentin biology and its effects on the development and progression of pulmonary diseases.
2. The Structure and Development of Omentin
Omentin is a novel hydrophilic adipokine of 313 amino acids (35 kDa), which contains a secretory signal sequence and a fibrinogen-related domain, and appears as a glycolized trimer of 120 kDa molecular weight in its negative form [
10,
11]. In 2005, omentin was officially depicted in an omental fat cDNA library with Uniprot code Q8WWAO and Genbank accession number AY549722 [
12]; it was initially identified in intestinal Paneth cells and endothelial cells with the name intelectin-1, intestinal lactoferrin receptor, galactofuranose binding lectin, and endothelial lectin [
13,
14]. However, specific receptors for omentin have not yet been identified. Omentin-1 and omentin-2 are two highly homologous isoforms with 83% amino acid identity, the genes encoding which are proximal to the 1q22–q23 chromosomal region associated with type-2 diabetes mellitus (T2DM) in many individuals [
12,
15]. Omentin-1 is the major circulating form with a concentration of 100 ng/mL to 1 μg/mL in human plasma, and has been more extensively studied than omentin-2 [
10]. Omentin-1 is a Ca
2+-dependent galactofuranose-binding lectin used for identifying bacterial components, and is important for defense against pathogenic bacteria [
12,
13]. In the following sections, we will refer to omentin-1 or intelectin-1 as omentin.
3. The Concentration of Omentin Fluctuates in Various Diseases
In recent years, considerable progress has been made in determining and characterizing the effects of omentin on different diseases. Based on a large number of epidemiological, clinical, and laboratory analyses, the changes in omentin levels in various diseases have been summarized in
Table 1.
Omentin levels are inversely related to obesity and positively to adiponectin levels [
16]. Several studies have shown that higher omentin levels were associated with leanness or acted as a positive factors against obesity [
16,
17,
18]. Reports also showed that pre-existing obese pregnant women had lower omentin levels in the placenta and adipose tissue than their normal weight counterparts [
19]. In addition, studies indicated that the serum levels of omentin were low in patients with impaired glucose regulation, T2DM [
20], gestational diabetes mellitus (GDM) [
21], T2DM with ischemic heart disease [
22,
23], and diabetic retinopathy [
24]. Recent reports showed that circulating omentin levels in women with polycystic ovary syndrome (PCOS) were significantly lower than that in normal women, independent of body mass [
25,
26]. Moreover, the results of a meta-analysis [
27] including 1264 subjects (733 patients with PCOS and 531 controls) showed a significant decrease in circulating omentin levels in patients with PCOS. Serum omentin levels apparently increased in PCOS individuals after administration of metformin. These prompted the speculation that omentin may play a significant role in the pathogenesis of PCOS [
28].
Several studies demonstrated a significant reduction in omentin levels in various cardiovascular diseases, including patients with carotid atherosclerosis [
29,
30,
31], coronary artery disease (CAD) [
32,
33], heart failure [
34], and dilated cardiomyopathy [
35]. Another study demonstrated that omentin increased in the epicardial adipose tissue (EAT) but decreased in plasma in patients with CAD [
32]. Harada explained this contradictory phenomenon by postulating that the high levels of omentin isolated from the EAT in myocardial ischemia may exert a cardioprotective effect [
32]. Surprisingly, recent studies showed that omentin levels were elevated in nonalcoholic fatty liver disease (NAFLD) [
36], an obesity-related disease, although obesity is associated with low levels of omentin. More studies are warranted to elucidate the mechanisms underlying these contradictory observations.
Omentin levels were reduced in certain autoimmune diseases, including psoriasis [
37,
38,
39], rheumatoid arthritis [
40,
41], Behcet’s disease [
42], Crohn’s disease [
43], ulcerative colitis [
44], chronic periodontitis [
45], and acute or chronic pancreatitis [
46]. Other studies demonstrated that omentin levels were highly elevated in individuals with psoriatic arthritis compared to individuals with psoriasis alone or healthy individuals [
47], although the precise mechanism underlying these observations is not obvious. In contrast, other research groups demonstrated that the presence of nephritis was associated with elevated plasma omentin levels in patients with systemic lupus erythematosus (SLE) [
48]. In addition, Peraire [
49] demonstrated that human immunodeficiency virus/highly active anti-retroviral therapy (HIV/HAART)-associated lipodystrophy syndrome (HALS) was related to decreased omentin levels in plasma, indicating that omentin may be an important contact between HIV/HAART and fat redistribution syndromes. Furthermore, the circulating levels of omentin were significantly lower in painful temporo-mandibular disorders (TMD), which may be mediated by inflammatory pathways [
50].
In addition, circulating omentin levels were also dramatically reduced in renal cell cancer [
51]; however, other cancers, such as malignant pleural mesothelioma (MPM) [
52], hepatic carcinoma [
53], prostate cancer [
54], colon and colorectal cancer [
55,
56], gastric cancer [
57], and pancreatic adenocarcinoma [
58] were associated with increased omentin levels. Omentin may have an anti-cancer effect property where omentin can influence two types of human hepatocellular carcinoma cells: HepG2 and HuH-7. Omentin significantly inhibited the proliferation and promoted apoptosis of HepG2 and HuH-7 cells via activating the Jun N-terminal kinase (JNK)-p53 signaling pathway [
53]. Moreover, omentin can accelerate the apoptosis of hepatocellular carcinoma cells (HCC) by increasing the bax/bacl-2 ratio and inducing capases-3 activation [
53]. Subsequently, studies were conducted to investigate the effect of omentin in the respiratory system. A study demonstrated that circulating omentin levels were also dramatically decreased in patients with acute respiratory distress syndrome (ARDS) [
59]. Omentin may play an important role in defense against pathogenic bacteria, and lower omentin levels in smokers may contribute to increased susceptibility to infection [
60]. However, the results obtained with patients exhibiting obstructive sleep apnea syndrome (OSAS) were controversial. Wang et al. observed that serum omentin levels were significantly lower in patients with OSAS [
61], while two other groups showed that these patients had considerably higher omentin levels [
62,
63]. The researchers also observed that omentin levels increased in airway epithelial cells of asthmatic individuals and speculated that omentin may be involved in the pathogenesis of asthma [
64,
65].
The serum levels of omentin were also significantly higher in other diseases, such as liver cirrhosis [
66] and anorexia nervosa [
67,
68], and in individuals undergoing hemodialysis with end stage renal disease [
69].
4. Protective Effects of Omentin in Various Pathophysiological Processes
Omentin is an important component that connects organs with adipose tissue and exerts extensive protective effects via various cell signaling pathways during physiological and pathological processes (
Figure 1). Yamawaki et al. indicated that omentin inhibited TNF-α-induced cyclooxygenase-2 (COX-2) expression via activation of adenosine 5′-monophosphate-activated protein kinase (AMPK), which further activated the endothelial nitric oxide synthase (eNOS)/NO pathway and blocked Jun N-terminal kinase (JNK) signaling, thereby playing an anti-inflammatory role in endothelial cells [
70]. Moreover, the activation of eNOS/NO induced vasodilation in isolated blood vessels [
71] and decreased agonist-induced increase in blood pressure [
72,
73]. Second, the omentin-induced AMPK phosphorylation can also reduce the RAS/ERK signaling cascade, accompanied by reduction of cardiac hypertrophy [
74] and smooth muscle cell (SMC) proliferation [
9,
75]. Third, studies demonstrated that omentin can promote the AMPK/AKT pathway directly by suppressing myocyte apoptosis in acute ischemic heart injury [
76] and decreasing the expression of proinflammatory mediators, including TNF-α, IL-6, and monocyte chemotactic protein-1 (MCP-1) in macrophages [
77].
Moreover, omentin protected against arterial calcification by inhibiting osteoblastic differentiation of calcifying vascular smooth muscle cells (CVSMCs) via the phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT) signaling pathway [
78]. This may be associated with increased production of osteoprotegerin (OPG) and decreased receptor activation for nuclear factor κB ligand (RANKL) in both CVSMCs and osteoblasts [
79]. In addition, omentin promoted human osteoblast (hOB) proliferation through the PI3K/AKT signaling pathway [
80]. Importantly, omentin suppressed adhesion of monocytes to TNF-α-activated endothelial cells by inhibiting ICAM-1 and VCAM-1 expression via PI3K-AKT signaling and by blocking the ERK/NF-κB pathway [
81].
Furthermore, omentin inhibited VCAM-1 expression in vascular smooth muscle cells (VSMCs) via phosphorylation of p38 and JNK at least in part through preventing NADPH oxidase (NOX)-derived superoxide production; it also restrained TNF-α-induced adhesion of U937 monocytes to isolated rat VSMCs [
82]. Finally, omentin also inhibited NOX/O2-/p38/heat shock protein 27 (HSP27) pathways to prevent platelet-derived growth factor (PDGF-BB)-induced smooth muscle cell (SMC) migration, which may be related to its protective role in neointimal hyperplasia [
83].
6. Discussion and Conclusions
Fluctuating omentin levels are widely associated with various diseases, including obesity, diabetes, cardiovascular disease, autoimmune disease, various malignant tumors, reproduction system diseases, nervous system diseases, and pulmonary diseases. Omentin can regulate inflammation status, vasomotor and endothelium function, proliferation, apoptosis, and differentiation of cell types via various molecular mechanisms.
Nonetheless, the mechanism via which omentin regulates various physiological and pathological functions is not completely elucidated. At present, the specific receptor for omentin is still unknown, which makes understanding the physiological function of omentin difficult.
Omentin may play significant roles in pulmonary diseases, such as MPM, asthma, OSAS, PAH, ARDS, COPD, and other lung disorders. Omentin in the pleural effusion may be a specific diagnostic marker for MPM, which is conducive for diagnosing MPM in the early stage, extending the median survival of patients with MPM. Omentin, which belongs to the category of “good” adipokine, exerts anti-inflammatory effects in various physiological and pathological processes. However, current studies have shown that omentin may participate in the pathogenesis of asthma. Omentin is essential for the expression of inflammatory factors in lung epithelial cells, which facilitate allergic airway inflammation, and it may be a component of airway mucus that contributes to pathologic mucus formation in asthma. Omentin levels were drastically reduced in patients with OSAS, which correlated with the severity of OSAS. Moreover, omentin can elicit anti-inflammatory and anti-migratory effects and inhibit vascular structural remodeling for PAH and RHF. Furthermore, omentin can protect pulmonary endothelial barrier function and decrease pulmonary microvascular permeability and inflammation in LPS-induced ARDS models. This indicated that omentin may act as an anti-inflammatory therapeutic drug for ARDS. Studies demonstrated that omentin levels decreased in the airway epithelium of healthy smokers, which is a major risk factor for infections and COPD. This suggests that omentin may contribute to defense against respiratory tract infections and COPD.
Extensive investigations are required to explore the effect of omentin in respiratory diseases. Whether omentin can be used for the diagnosis and assessment of intervention outcomes or development of new therapeutic targets requires further investigation. We expect this review to be helpful for a better understanding of the biological role of omentin in respiratory diseases.