Obesity, Inflammation, and Lung Injury (OILI): The Good

Wang, Cheryl

doi:https://doi.org/10.1155/2014/978463

Mediators of Inflammation

On this page

Abstract Introduction References Copyright Related Articles

Review Article | Open Access

Volume 2014 | Article ID 978463 | https://doi.org/10.1155/2014/978463

Obesity, Inflammation, and Lung Injury (OILI): The Good

Cheryl Wang^1,2

Academic Editor: Antonio Macciò

Received17 Feb 2014

Accepted19 Mar 2014

Published11 May 2014

Abstract

Obesity becomes pandemic, predisposing these individuals to great risk for lung injury. In this review, we focused on the anti-inflammatories and addressed the following aspects: adipocytokines and obesity, inflammation and other mechanisms, adipocytokines and lung injury in obesity bridged by inflammation, and potential therapeutic targets. To sum up, the majority of evidence supported that adiponectin, omentin, and secreted frizzled-related protein 5 (SFRP5) were reduced significantly in obesity, which is associated with increased inflammation, indicated by increase of TNFα and IL-6, through activation of toll-like receptor (TLR4) and nuclear factor light chain κB (NF-κB) signaling pathways. Administration of these adipocytokines promotes weight loss and reduces inflammation. Zinc-α2-glycoprotein (ZAG), vaspin, IL-10, interleukin-1 receptor antagonist (IL-1RA), transforming growth factor β (TGF-β1), and growth differentiation factor 15 (GDF15) are also regarded as anti-inflammatories. There were controversial reports. Furthermore, there is a huge lack of studies for obesity related lung injury. The effects of adiponectin on lung transplantation, asthma, chronic obstructive pulmonary diseases (COPD), and pneumonia were anti-inflammatory and protective in lung injury. Administration of IL-10 agonist reduces mortality of acute lung injury in rabbits with acute necrotizing pancreatitis, possibly through inhibiting proinflammation and strengthening host immunity. Very limited information is available for other adipocytokines.

1. Introduction

One-third of the adult Americans are obese and 2/3 are overweight [1, 2]. Obesity increases histrionically and is becoming pandemic worldwide in the past decades, predisposing these populations to great risk for gastric esophageal reflux disease (GERD) and subsequent aspiration pneumonia, asthma, obstructive sleep apnea syndrome (OSAS), and related comorbidities and mortality in lung injury, such as acute lung injury (ALI) and ARDS (acute/adult respiratory distress syndrome), even after being adjusted for other risk factors [3–6]. This remains true in a large array of studies in patients with ALI and critical conditions [7–9]. However, there were controversial reports as well.

Lung injury is a debilitating disease, with mortality close to that of breast cancer, costing our federal government at least 850 million dollars every year [10, 11]. This places a huge burden to our government as well as the suffering families. As the prevalence of obesity and its comorbidities increases skyrocketing, obesity related lung injury rises significantly in the past decades.

This may be mediated by depletion of the antioxidants, destroyed lung endothelium, reduced lung volume and chest wall compliance, and increased susceptibility of the lung to injury [12, 13]. Under obese state, there are changes with fat sites and sizes. Furthermore, obesity is a chronic systemic inflammatory process, with infiltration of macrophages and other cells. This inflammatory process is driven by the adipocytokines derived from adipocytes, macrophages, and other cells in adipose tissues, which cause an unbalance between the proinflammatory adipocytokines such as lepin, resistin, vasftin, and TNFα and the anti-inflammatory adipocytokines such as adiponectin, omentin, SFRP5, vaspin, ZAG, and interleukin-10 (IL-10) [14]. This process is accompanied by the polarization of macrophages, from “healthy” M2 to “unhealthy” M1 macrophages and the transformation of T helper (Th) cells from “beneficial” Treg and Th2 to “harmful” Th17 and Th1. These form an inflammatory soup, heavy with proinflammatory adipocytokines, which further activates Toll-like receptor 4 (TLR4), NF-κB, and other signaling pathways, initiating a cascade of inflammatory process [15].

Furthermore, these changes modulate host defense responses, namely, the innate and adaptive immunity [16], regulating the susceptibility of the lung for injury. When a variety of insults occur, such as ozone (O₃), gastric acid and bacterial and nonbacterial particles [6], the lung may become more susceptible for injury, depending on the overall balance between the offense and defense, the proinflammatory and anti-inflammatory adipocytokines.

Yet, limited articles have a comprehensive review of the overall balance of these adipocytokines and their relationship to the pathogenesis of lung injury. In our series of review articles, we will address these adipocytokines and their relationship with lung injury as the good, the bad, and the ugly: the anti-inflammatory (the good), the proinflammatory (the bad) and their impact on host defense response, and the immunity (the ugly). These contents will be included in three respective review articles, with the major objective to get a better view of the pathogenesis of lung injury in obesity, the molecular basis of other comorbidities in obesity, the research gaps in OILI, and the scientific and therapeutic targets in a more comprehensive and efficient fashion. And thus this important information will direct our research and scientific focus and further personalized medicine in this huge population in the near future.

In this review article, by reviewing the articles with animal models and preclinical trials as well as the clinical trials in human being related to OILI, we will focus on the anti-inflammatory adipocytokines (the good) and address from the following aspects: adipocytokines and obesity, inflammation and other mechanism involved, adipocytokines and lung injury in obesity bridged by inflammation, and some therapeutic potentials. The studies on obesity and inflammation will be addressed and summarized. Those related to lung injury will be discussed in detail. Some possible mechanisms involved are illustrated in Figure 1 and this review article will be summarized in Table 1.

Figure 1

Fit-fat-faint: the overall mechanism of obesity, inflammation, and lung injury. In fit individuals, small fat cells secret proinflammatory and anti-inflammatory adipocytokines. There are balances between these adipocytokines, macrophages M1 and M2, T helper cells Th1 and Th2, and Th17 and Treg. Under fat state, fat cells got larger and infiltrated by more macrophages and other cells, secreting more proinflammatory adipocytokines and causing an unbalance between proinflammation and anti-inflammation. These activate NF-κB and TLR4 signaling pathways and decrease host immunity, thus increasing susceptibility of the lung. When the 2nd hit occurs, such as aspirated acid under obesity or debilitated conditions, O₃ in the air, bacteria, and surgeries, it is easier for the susceptible lung to get injured (faint). The final outcome depends on the overall balance. ADP: adiponectin.

2. Obesity, Inflammation, and Lung Injury: The Good

A large array of adipokines, cytokines, chemokines, and other factors were derived from adipose tissues [17]. In this review article, we refer to them as adipocytokines. Besides adipocytes, macrophage is believed to be a major contributor for these factors. The majority of the evidence supported that adiponectin, omentin, and SFRP5 are anti-inflammatory, the good, and are decreased in obesity, which is associated with increased systemic inflammation, indicated by increased circulating TNFα, C reactive protein (CRP), IL-6, and other proinflammatory cytokines/chemokines [17, 18]. Administrations of these adipocytokines promote weight loss and reduce inflammation [19]. Other anti-inflammatory adipocytokines beneficial for weight loss are ZAG, vaspin, IL-10, IL-1RA, TGF-β1, and GDF15 [20]. Yet, there were controversial reports.

Regretfully, very limited information is available for their roles in the pathogenesis of lung injury. We will do our best to get valuable information from these limited studies and discuss some possibilities.

2.1. Adiponectin

Adiponectin was first identified in adipocytes and highly conserved cross species [21–23]. It is also found in cardiomyocytes and skeletal muscle [24–27]. Adiponectin accounts for 0.01% of total protein in circulation, with a normal range of 2–20 μg/mL, and is quickly cleared after secretion (half-life of 45 to 75 minutes) [28, 29]. Despite this fact, adiponectin concentration remains rather stable in plasma. A growing number of studies suggested that adiponectin is decreased in obesity and negatively correlated to visceral fat mass, inflammation, heart disease, injury, and many other diseases but positively to insulin sensitivity and promotes weight loss [30–33]. A positive correlation between adiponectin and fat mass at the lower extremities has been revealed but a negative one with that of the body trunk was typically seen in abdominal obesity. Furthermore, adiponectin drives fat deposit in small fat cells and subcutaneous adipose tissue but mobilizes visceral fat, supporting its beneficial effect in variety of organ injury, such as nonalcoholic fatty liver disease and fatty heart in obesity and T2DM. Administration of recombinant adiponectin or overexpression of adiponectin promotes weight loss increases insulin sensitivity and exerts anti-inflammatory effects [34]. There were controversial reports though [35–38].

Figure 2 shows the major mechanism involved. Adiponectin decreases oxidative stress, inflammation, angiogenesis [39], apoptosis, and increases mitochondrial biogenesis [40], locally (paracrine/autocrine) and systemically (endocrine). In obesity, the unhealthy adipose tissues and infiltrated macrophages (more M1 than M2) [41] reduce the production of adiponectin and favorite proinflammatory process [42, 43]. It was suggested that adiponectin reduces inflammation and alleviates disease states, possibly through its suppression of TNFα, IL-6, and CRP and upregulation of IL-10 and IL-1RA [44–46]. Additionally, adiponectin increases mitochondrial density and biogenesis, adipocyte flexibility, and the host adaptation to stress [47]. The major signaling pathways involved are AMPK and PPARα, PPARγ, MEK-Erk, PI3K-Akt, APPL1, T-cadherin, Ca2+ and SIRT1, and so forth [40, 48–52], which promote fatty acid oxidation and glucose uptake into skeletal muscle and inhibit gluconeogenesis in liver.

Figure 2

The major anti-inflammatory mechanism of adiponectin. Adiponectin polarizes macrophages from M1 to M2 and T helper cells from Th1 to Th2 and thus further increases immunity and has better anti-inflammatory effects. Furthermore, adiponectin activates AMPK and inhibits NF-κB signaling pathways and thus inhibits inflammation. Additionally, adiponectin inhibits oxidative stress and stimulates mitochondrial biogenesis. Under obese state, the production of adiponectin is lower which is correlated with worse proinflammation and possible lung injury.

Another important mechanism is the possible “polarizing effect” of adiponectin on macrophages and T helper cells. It was suggested that adiponectin may polarize macrophage from M1, proinflammatory state, to M2, anti-inflammatory state, as well as from “harmful” Th1/17 to “beneficial” Th2/Treg. This has been supported by both loss and gain of function studies [44, 53–58]. Moreover, adiponectin suppresses the proliferation of bone marrow-derived granulocyte and macrophage progenitors, inhibits phagocytic behavior of macrophages and proinflammatory cytokines secretion, and promotes anti-inflammatory cytokines of macrophages.

Adiponectin impacts host defense response and immunity, through inhibiting recruitment of leukocytes, increasing the remodeling of the lung, promoting phagocytosis of neutrophils and macrophages, modulating the productions of Th2 cytokines, and reducing/inhibiting B cell and natural killer (NK) cells in animal models [59]. Yet, little is known about the impact of adiponectin on host response in human beings, especially those related to lung injury. This is largely due to the difficulty in conducting large clinical and translational studies, as most of the patients are not in the conditions willing or able to be consented for these trials.

Adiponectin resembles the structures of complement factor C1q and surfactant proteins SpA and SpD of the lung, which function as pattern recognition molecules, and is possibly one major mechanism for adiponectin to limit the inflammation of the lung [60]. All three receptors of adiponectin, AdipoR1, AdipoR2, and T-cadherin, were detected in a variety of cells of the lung [61]. Furthermore, adiponectin can be transported from circulation to alveolar through T-cadherin on the endothelium. These support its potential roles in lung injury [62, 63]. Lung injury is a complicated pathogenesis process, including activation of immune system and inflammation, stimulation of endothelium, increased capillary permeability, neutrophil and macrophage infiltration, and leaking of albumin [64, 65]. The function of adiponectin in lung homeostasis is becoming a hot topic in the past few years, but it remains to be further determined and studied in more details. Recent data supported that obesity is a major risk factor for lung injury, and the adipose tissue derived adipokines and cytokines seem to play a very important role during this process [66–70]. This may be associated with activation and polarization of macrophages, stimulation of AMPK and COX2, and its effect on endothelium [71, 72]. Although there were controversial reports [73, 74], most of the evidence supported that reduced adiponectin level is associated with increased morbidity and mortality in critical care patients, lung transplantation, emphysema, asthma, chronic obstructive pulmonary disease (COPD), and acute lung injury of other causes [75–77], in animal models as well as in human beings. These were accompanied by macrophages activation, reduced clearance of apoptotic cells, and perivascular and lung inflammation [78, 79]. Moreover, administration of adiponectin improves outcome for asthma [80]. Additionally, in those contradicted reports mentioned above, adiponectin concentrations were tested during the critical illness, suggesting the possibility of the upregulation of adiponectin due to adaptation over time. This speculation was supported by the studies showing that increased adiponectin level and amelioration of the disease in mice with lupus when treated with PPARγ agonist [81], regardless of the already elevated adiponectin level in these mice. From this aspect, we could hypothesize that the changes of adiponectin may be more important than its actual concentration during critical illness. In another word, administration of adiponectin may still benefit these patients regardless their elevated adiponectin level. If this is associated with upregulated receptor or other mechanism, it remains unclear. This being said, it is not difficult to understand the controversial results in patients with COPD. In patients with COPD, due to the long-term hypoxia and human body adaptation, adiponectin concentrations may be high or low, depending on how long and how badly the patients were sick and how the human body is adapting. With similar theory, those different results in patients with critical illness (e.g., those from APACHE II) or bacterial pneumonia seem reasonable as well. After all, the human body is an elegant system with delicate regulations. One cytokine/protein up or down simply cannot tell the whole story. The one-fit-all medicine is far from enough. Apparently, studies investigating the relationship of the changes of adiponectin and clinical outcomes, how the human body adapts, and what the host responses are would possibly provide more valuable information for clinical applications and further personalized medicine, both as a biomarker for a variety of diseases, severity, and prognosis and as a therapeutic potential.

Interestingly, it was found that total adiponectin levels and its active form, high molecular weight (HMW) isoform, are lower in men than their peer women at children-bearing age, which seems be associated with the high testosterone level in men [82].

Overall, adiponectin promotes anti-inflammation through inhibiting proinflammatory response, polarizing macrophages (from M1 to M2), and T helper cells (from Th1/17 to Th2/Treg), inhibiting TLR4-mediated NF-κB activation, and protecting endothelium, suggesting that obesity may prime lung toward proinflammatory condition and more susceptible for injury due to hypoadiponectinemia, at least partially. Yet, the detailed mechanism remains to be further explored. Not much clinical data is available at this point.

Many drugs exert their effect via adiponectin and its receptors, decreased ceramide [46], and antiapoptotic sphingosine-1-phosphate (S1P), via its impact on insulin sensitivity and anti-inflammatory effects. This suggested that adiponectin could be a potential therapeutic target in obesity, metabolic syndrome, and its comorbidities, all of which are regarded as inflammatory processes. Yet, it remains unclear if adiponectin can be a potential therapeutic target for lung injury in human subjects. With the newly synthesized adiponectin receptor agonist, ADP355, and the defined adiponectin receptors in the lung, the role of adiponectin in the aforementioned inflammatory states, and its function as pattern recognition molecules, we expect that ADP355 would significantly benefit patients with obesity related lung injury. Apparently, more preclinical and clinical trials are warranted in the near future, for its function, mechanism, and potential therapeutic and preventive applications. Particularly, as adiponectin promotes weight loss and reduces inflammation and has receptors in the lung, studies targeting its role in OILI would be greatly beneficial for these populations. Both observational trials and therapeutic trials are largely needed.

2.2. Omentin

Omentin was initially found in intestinal cell (called intelectin) and then omental adipose tissue and human adipocytes (especially stromal vascular cells of visceral adipose tissue), but it is also expressed in lung, heart, placenta, and ovary [18, 83]. There are two forms, omentin 1 and omentin 2, which share 83% of amino acid sequences. Omentin 1 is rather more studied than omentin 2. In this article, we refer to omentin 1 as omentin. It was suggested that omentin level was lower in obese subjects, which is inversely associated with body mass index (BMI) and insulin resistance and positively with HDL and adiponectin [84]. Moreover, treatment for obesity with bariatric surgery or metformin increases serum level of omentin, which is associated with weight loss and improved insulin sensitivity, possibly through activating Akt signaling pathway. Studies showed the similarity of omentin and adiponectin [85–87], especially the effect on weight loss, insulin sensitivity, and type 2 diabetes (T2DM) [17, 88–92]. It was also reported that omentin level is low in Crohn’s disease, synovial fluid of patients with rheumatoid arthritis, polycystic ovary syndrome (PCOS), and other inflammatory diseases [90, 93, 94]. Paradoxically, one recent study showed that increased omentin level was associated with nonalcoholic fatty liver disease (NAFLD), the very common comorbidity in obesity and T2DM [95]. As obesity, T2DM and NAFLD were all regarded as inflammatory process; these contradicted results may indicate an adaptation response. As shown in some studies with adiponectin, treating patients with NAFLD may still increase omentin level as well as reducing inflammation. Further studies are warranted to elucidate this phenomenon, the possible mechanism, and the changes with intervention.

As shown in Figure 3, omentin activates AMPK and eNOS, blocks Akt pathways, inhibits CRP, TNFα, and NF-κB signaling pathways, reduces adhesion molecules, and thus has anti-inflammatory effect on smooth muscle cells and endothelium [96–99]. Administration with recombinant human omentin inhibits TNFα, decreases inflammation, and dilates vascular vessels, suggesting its potential therapeutic role in inflammation related conditions [100]. No study has assessed the possible impact of omentin on host defense response or immunity.

Figure 3

The anti-inflammatory mechanism of omentin. Omentin activates AMPK, which further blocks E-selection and reduces endothelial inflammation. AMPK also activates eNOS, which has vasodilation effect and blocks JNK signaling. JNK activates inflammation through TNFα mediated COX2 effect. Moreover, omentin inhibits NF-κB signaling pathway and thus inhibits inflammation. Under obese state, the production of omentin is lower which is associated with worse proinflammation and possible lung injury.

Three studies were conducted in patients with obstructive sleep apnea syndrome (OSAS) [101–103]. Two reported that omentin was elevated in patients with OSAS [103]. One was performed in Turkey and the other was in Germany. Both had rather small sample size. Another study was conducted in Chinese subjects and had a large sample size. It indicated that decreased serum omentin-1 levels could be regarded as an independent predictive marker for the presence and severity of OSAS. Omentin, the former called intelectin-1, is expressed in the lung. It was reported that intelectin-1 was secreted from malignant pleural mesothelioma and can be detected in pleural effusion, suggesting that it can be a biomarker for this malignancy. Furthermore, intelectin is needed for MCP-1 production in lung epithelium and causes airway inflammation in mice with asthma. If the receptor can be further determined, one may test if these effects are through paracrine/autocrine besides endocrine. As OSAS and asthma are highly associated with obesity, inflammation, and lung injury, this may suggest the association of omentin and lung injury. Additionally, given the fact that omentin blocks proinflammatory cytokines TNFα, and signaling pathway NF-κB, it may be protective in lung injury. Furthermore, considering the similarity of omentin and adiponectin, we hypothesize that omentin exerts anti-inflammatory effect in lung injury. However, the possible proinflammatory effect of omentin may not be ignored as well. With the availability of recombinant human omentin, it would be greatly helpful to know if there are receptors for omentin in the lung, if omentin is anti-inflammatory in lung injury, and if omentin exerts its effect through adiponectin or independently, all of which may direct the therapeutic development in OILI and other related diseases.

2.3. SFRP5

SFRP5 was first discovered in adipocytes couple of years ago and the data was published in science [104]. In this study, it was shown that SFRP5-deficient mice fed on high-fat diet aggravated fat accumulation, inflammation, and systemic oxidative stress. Administration of SFRP5 reduced inflammation and attenuated insulin resistance, through decoying WNT mediated JNK activation in macrophages and adipocytes, and thus has systemic effects. Overexpression of SFRP5 promotes adiponectin and decreases TNFα, IL-6, and MCP-1, suggesting its anti-inflammatory effect. A recent study in Chinese subjects showed that SFRP5 is low in patients with T2DM. Furthermore, calorie restriction in obese subjects promoted weight loss and increased insulin sensitivity, which is correlated with improved SFRP5 level [105]. There were controversial reports. One recent study showed that SFRP1 but not SFRP 2–5 was found to be decreased in obesity and this is associated with insulin resistance [106]. However, in this study, it did show that SFRP1 increased adiponectin and reduced IL-6 and MCP-1 levels, which is consistent with the previous studies. Other isoforms should be further tested. Perhaps, it is the ratio of SFRP5 to other isoforms that matters. Another contradicted study also showed increased SFRP5 expression in diet-induced obesity [107]. In this study, the authors argued that this might be due to the fact that SFRP5 inhibits WNT signaling pathway and thus suppresses adipocytes mitochondrial metabolism and promotes oxidative stress. Combed with the previous data, it is confirmed that SFRP5 exerts its effect via inhibiting WNT signaling. This brought up the possibility that the isoforms of SFRP may vary cross species and ethics groups. Furthermore, the WNT at different compartments has different effects, which may partially explain these controversial results. Apparently, more studies are warranted.

As shown in Figure 4, SFRP exerts its effects mainly through inhibiting WNT and JNK signaling pathways, which further inhibits the production of proinflammatory cytokines TNFα, IL-6, and MCP-1, and so forth. One recent study suggested that SFRPs might promote or suppress Wnt/β-catenin signaling, possibly depending on its receptors [108]. Additionally, SFRP5 regulates p53 and is a Hedgehog target to confine canonical WNT signaling. No information is available about its impact on host immunity and defense response.

Few studies were done in lung diseases. Limited information suggested that SFRP5 was low in pleura mesothelioma, and methylation of SFRP5 was associated with overall survival of lung cancer. Patients with unmethylated SFRP5 are more likely to benefit from EGFR-TKI therapy in non-small-cell lung cancer [109–111]. Based on its role in obesity and inflammation, we expect that SFRP5 exerts anti-inflammatory effect in obesity related lung injury. But it may depend on the compartments, the species, the ethnic groups, and other factors. With the availability of the recombinant SFRP5, more preclinical and clinical trials were needed to explore the effect of SFRP5 on OILI, as well as other comorbidities of obesity.

2.4. Vaspin

Vaspin is visceral adipose tissue-derived serpin (serpinA12) [112], and it is also rich in hypothalamus, skin, stomach, and subcutaneous adipose tissues [113]. Vaspin level is low in obesity, insulin resistance, and type 2 diabetes and increases with the attenuation of these conditions [114]. Furthermore, administration of vaspin suppresses leptin, TNFα, and resistin, reduces food intake, and improves glucose control and insulin sensitivity in obesity [115]. Yet, two recent studies with bariatric surgery in obese subjects revealed that vaspin decreased after surgery [116, 117], and the reduction was associated with leptin, HbA1c, and insulin sensitivity. These results were consistent with those treated with metformin [118]. This may suggest that there is a period of adaptation. Apparently, more detailed studies are needed to illustrate the time and impact of vaspin changes. Furthermore, vaspin was elevated in ulcerative colitis [119] and other inflammatory conditions, suggesting that it may exert proinflammatory effect as well. It was shown that vaspin is associated differently with metabolic syndrome in males and females, indicating its potential interaction or regulation by sex hormones [120]. This remains true in a variety of ethnic groups. Yet, these are observed phenomenon and the mechanism remains to be determined in detail.

Although the mechanism is largely unknown, it has been shown that vaspin inhibits vascular smooth muscle cells proliferation through inhibiting reactive oxidative species (ROS), MAPK, PI3K/Akt, and NF-κB signaling pathways [121]. One recent study suggested that the inhibition of vaspin on ROS may be through NADPH oxidase [122], which is part of mechanism for cardiovascular disease (CVD). A cell membrane glucose-regulated protein (GRP78) was identified and regarded as a liver-specific receptor for vaspin, suggesting its potential role in liver diseases. No information is available about its impact on host immunity and defense response.

One study showed that high body fat mass with low cardiorespiratory fitness may be associated with increased vaspin in Korean population [123], suggesting its possible role in lung. No receptor for vaspin was defined in lung yet. As vaspin inhibits ROS and NF-κB signaling pathways, activating AMPK and Akt pathways, along with its inverse relationship with respiratory fitness, we believe that vaspin may have a protective role in lung injury, through its anti-inflammatory effect. The important information would be to identify if there is a receptor for vaspin in the lung, if there is paracrine/autocrine effect of vaspin in lung, if the changes of vaspin is associated with less or worse lung injury in obesity, and if administration of vaspin attenuate lung injury. Additionally, it is worth the effort to determine if weight loss increases vaspin and if this is correlated with ameliorated lung injury.

2.5. Zinc-α2-glycoprotein (ZAG)

ZAG is expressed in adipose tissue, liver, breast, prostate, and so forth. It was identified as a lipid mobilizer in patients with cancer cachexia and obese mice, mediated by β3 adrenoreceptor through activating cyclic AMP (cAMP) pathway, increasing energy expenditure and lipolysis [124–127]. ZAG was expressed in visceral and subcutaneous adipose tissue and presented in stromal vascular cells and mature adipocytes [128]. So far, the majority of the evidence supported that ZAG level is lower in obesity and insulin resistance in mice with genetic defect or fed on high-fat diet as well as in human beings, and that there is an inverse relationship of ZAG with BMI and insulin resistance [129, 130]. Treatment for obesity and insulin resistance with liraglutide for 12 weeks increased ZAG level [131], indicating that ZAG may have a similar pattern as adiponectin. Additionally, overexpression of ZAG promoted weight loss and increased insulin sensitivity, through stimulating fatty acid oxidation. However, some studies [132, 133] revealed higher ZAG level in serum and white adipose tissue of obese/overweight individuals, as well as patients with chronic kidney disease, suggesting a possibility of “ZAG resistance,” like leptin resistance. Furthermore, it appeared that ZAG exerts its function as a lipid mobilizer in cancer cachexia more significantly.

ZAG was downregulated by TNFα and other proinflammatory cytokines in obesity, suggesting that its pattern is similar to that of adiponectin [128, 134]. Furthermore, studies in patients with CKD showed that ZAG is negatively correlated with TNFα and VCAM-1, suggesting its inverse relationship with systemic inflammation [135]. A negative association of reduced ZAG and increased CRP or MCP-1 was also reported in obesity, insulin resistance, and metabolic syndrome [136, 137]. Recent studies also demonstrated a positive correlation between ZAG and adiponectin and a negative one with leptin in human subjects [138]. It is possible that ZAG may act in paracrine/autocrine manner and facilitate adiponectin secretion from adipocytes.

Yet, very limited information is available for its relationship with lung injury. Based on the aforementioned, we think that ZAG may have anti-inflammatory effect on a variety of diseases, including lung injury. Considering its lipid mobilization in cancer, it may be valuable to find out what ZAG does in lung cancer, and if this is associated with the prognosis and clinical outcomes. But one may have to consider the possible “ZAG resistance.” Moreover, the fat mobilizing effect of ZAG was mediated by β3 adrenergic receptor, indicating its potential role in thermogenesis. Thus, it may be a therapeutic target in OILI. It would be greatly helpful if its receptor can be further identified. As the recombinant ZAG becomes available, both preclinical and clinical studies were needed to explore its function, mechanism, and potential therapeutic indications of ZAG.

2.6. IL-10

Interleukin-10 (IL-10) was initially identified as a product of Th2 cell and known as an anti-inflammatory cytokines inhibiting Th1 cell activity. It is derived from a variety of cells including monocytes, dendritic cells, lymphocytes, macrophages, and T cells. Although there were controversial reports, the majority of the evidence supported that IL-10 is negatively correlated to BMI, obesity, insulin resistance, and T2DM; furthermore, overexpression of IL-10 or administration of IL-10 reduces body weight, improves insulin sensitivity, and augments glucose control [139, 140].

Figure 5 indicates the major mechanisms of IL-10. IL-10 polarizes macrophages from classically activated M1 to alternatively activated M2 phenotype and Th1/17 to Th2/Treg, upregulates IL-1 receptor and TGF-β, inhibits phagocytosis and proinflammatory cytokines and chemokines, which further blocks TLR4, NF-κB, and other signaling pathways [15, 141, 142], and activates JAK/STAT signaling pathway. This results in decreased production of TNFα, IL-12, and other proinflammatory cytokines. Additionally, IL-10 is a switch factor for IgG1 and IgG3 and for IgA1 and IgA2, which has better protective effect for mucosa. Furthermore, therapy with mesenchymal stem cells (MSC) reprograms toward the polarization of macrophage M2 and increases IL-10 levels and thus has a protective role in sepsis, other infections, and acute lung injury [143].

Figure 5

The anti-inflammatory mechanism of IL-10. IL-10 activates JAK/STAT signaling pathway, which further activates SCOS3 and anti-inflammatory process. It also polarizes Th1/Th17 to Th2/Treg and M1 to M2, which have anti-inflammatory effect. Moreover, it promotes the switches of IgG1 to IgG3 and IgA1 to IgA2, which have better mucosal protective effect. IL-10 also inhibits phagocytosis. IL-10 is reduced in obesity and this may contribute to the proinflammatory state and possible lung injury.

Studies performed in lung transplantation showed that IL-10 decreases iNOS, IL-2, and TNFα, prevents ischemic-reperfusion injury, and inhibits acute rejection in animal models [144]. It was also proved that IL-10 protects lung from injury induced by LPS [145]. Early phase clinical trials suggested that IL-10 attenuates acute colitis [146], increases the tumor sensitivity of NK cells in rabbits with melanoma [147], promotes monocytes differentiating toward to tolerogenic DCs [148], and thus may have potential therapeutic value in autoimmune and transplantation related immune-compromised conditions. Interestingly, these studies suggested that only a small segment at C-terminal of IL-10 is responsible for its bioactivity. A synthetic IL-10 agonist, IT 9302, was administered to the rabbits with acute lung injury in acute necrotizing pancreatitis [149, 150]. It revealed that IT9302 reduced the mortality and the incidence of acute lung injury in rabbits with acute necrotizing pancreatitis, possibly by suppressing the productions of TNFα, IL-8, MCP-1, and adhesion molecule complex CD11b/CD18, as well as increasing serum IL-1β RA level. This is very encouraging, as most of the lung injury is related to inflammation and reduced immunity, such as OILI. In line with the aforementioned mechanism, along with the available agonists/analogues such as AM0010, SCH52000, RN1003, and IT9302, and its downstream signaling blockers such as CP-690 and CP-550, we hypothesized that IL-10 may have a protective role in lung injury, and more specifically, in acid aspiration induced lung injury in obesity. Related clinical trials are highly recommended to further define this, its bioactivity, safety, efficacy, and therapeutic indications.

2.7. Others: IL-1RA, TGF-β1, GDF-15, and So Forth

More adipocytokines showed anti-inflammatory effects on obesity and lung injury.

Interleukin-1 receptor antagonist (IL-1RA) was secreted naturally to encounter the effect of IL-1 and neutralize the proinflammatory effect of IL-1β, by competitively binding to IL-1 receptor I (IL-1RI). As it secrets at the time of IL-1 secretion, which is generally increased at the states of inflammation such as obesity, T2DM, and lung injury, it is understandable that IL-1RA is elevated in obese and diabetic subjects in Whitehall II cohorts [151] and a few other clinical trials. However, administration of recombinant IL-1RA (anakinra) lowers body weight and glucose level and decreases inflammation in patients with metabolic syndrome and T2DM [152, 153]. IL-1RA competitively binds to IL-1RI with IL-1 and thus decoys the inflammatory effects of IL-1. Deletion of IL-1RA leaves IL-1β unopposed and thus causes fetal inflammation systemically [154]. Under conditions with lung injury, IL-1 releases and triggers inflammation and IL-1RA releases to encounter this process. Administration of recombinant IL-1RA attenuates pulmonary fibrosis and pneumonia in animal models [155]. There are some ongoing/complete trials in subjects with rheumatoid arthritis, heart failure, pulmonary hypertension, diabetes, and other inflammatory conditions with recombinant IL-1RA anakinra. No ongoing/complete clinical trial in OILI was reported per the best of our knowledge.

TGF-β shows anti-inflammatory effect and has interaction with IL-10 [156, 157]. TGF-β is increased in obesity but overexpression of TGF-β inhibits adipogenesis [158]. Gene knockout of TGF-β confirmed its anti-inflammatory effect presented at the early stage and before the major attack of bacteria. Yet, these reports were controversial regarding its effect in obesity related lung injury. TGF-β1 has a very short half-life in circulation and this may contribute to these diverse results. TGF-β1 exerts its effect mainly through Smad signaling pathway. Some clinical trials with TGF-β1 antibodies such as GC1008, CAT-192, and LY2382770 are ongoing or complete in subjects with diabetes, diabetic kidney disease, and other inflammatory diseases. No ongoing/complete clinical trial in OILI was reported per the best of our knowledge.

GDF15, a member of TGF-β family, also known as macrophage inhibitory cytokine-1 (MIC-1), shares similarity with TGF-β [159, 160]. GDF15 increases in obesity but also suppresses food intake and reduces body weight in obese rodents [161]. GDF15 can be a biomarker for severity of lung diseases as well as inhibitor for cancer development [162]. No study was reported in OILI so far.

Although there are studies showing the anti-inflammatory effect of leptin, there are leptin receptors in lung, alveolar epithelium, and macrophages, and leptin plays very important roles in immunity and host defense response, especially for activation of cell mediated immunity, as leptin is regarded as a proinflammatory adipokine in obesity and lung injury, supported by the majority of the clinical trials and animal studies [59]. Thus, we include leptin in other papers and will not discuss much here.

3. Potential Therapeutic Targets

3.1. Adiponectin and Its Related Receptors

As addressed previously [19], due to the delayed discovery of the receptor for adiponectin, there is no clinical utilization of adiponectin. Yet, based on what we reviewed here, adiponectin showed a strong anti-inflammatory effect in obesity, through its activation of AMPK and stimulation of mitochondrial biogenesis, as well as its inhibition of NF-κB signaling pathways and oxidative stress; we believe that adiponectin and adiponectin receptor agonist as well as AMPK activator would greatly benefit patients from a variety of aspects, including lung injury in obesity. With the availability of adiponectin receptor agonist, ADP355 [163], we expect that more preclinical and clinical interventional trials in OILI will be conducted. Someday, patients with OILI and other inflammatory diseases will be greatly benefited, especially those with obesity.

One major obstacle is the route and form of the agents. For lung injury, inhalation and intravenous injection or infusion would be appropriate. Details for getting the active molecule into the system and the modification after administration need to work out. Alternates would be other agents promoting adiponectin production, such as PPARγ agonist, the market-available thiazolidinediones (TZDs), omega-3, and dietary modifications.

3.2. Omentin and Its Related Receptors

As the definitive receptor of omentin has not yet been identified in the lung, it is difficult to define the exact role of omentin in obesity related lung injury. More studies about its molecular and cellular mechanism are warranted for further advance. However, based on its inhibition to TNFα, IL-6, and other proinflammatory cytokines, its blocking on NF-κB and TLR4 signaling pathways, its potential role in OSAS, as well as its association with inflammatory states such as Crohn’s disease, rheumatoid arthritis, and PCOS, we believe that it favors anti-inflammation and may have therapeutic potential in obesity and its comorbidities including lung injury. Yet, most exploration of its therapeutic role is still in the preclinical stage, and there is no complete or ongoing clinical trial. With the availability of recombinant omentin, we believe that further studies from these aspects would provide valuable information in the near future.

3.3. SFRP5 and Its Related Receptor

Based on the effect of SFRP5 on weight loss, its signaling pathway, and the availability of the recombinant SFRP5, we expect more preclinical study and clinical trials in related area. As SFRP5 does reduce production of proinflammatory TNFα, IL-6, and MCP-1, we expect it to exert anti-inflammatory effect in obesity related lung injury.

3.4. IL-10 and Its Related Receptor

Based on the switch effects of IL-10 on macrophages, Th cells, IgG, IgA, and inhibition on proinflammation and Th1, IL-10 may have a great therapeutic potential in treating infections, inflammation, and related diseases including lung injury in obesity. As mentioned, synthetic interleukin-10 agonist such as IT9302 varnishes acute lung injury in rabbits with acute necrotizing pancreatitis [164] and promotes monocytes differentiation to tolerogenic DCs [165]. This suggested its therapeutic potential for autoimmune and transplantation-related disease, as well as its potential therapeutic benefit in OILI and other inflammatory diseases. Clinical trials with human synthetic interleukin-10 are still in the early phase, such as phase 1 trial with SCH 52000 in patients with Wegener’s granulomatosis, phase 2 trial with RN1003 for scar reduction, phase 2 trial with recombinant human interleukin-10 for psoriasis, and phase 2 trial with Tenovil TM in prevention of post-ERCP acute pancreatitis. No ongoing or complete clinical trial for this agonist in OILI was reported. More trials in wider area with larger population are encouraged.

4. Summary and Research Gaps

As shown in Table 1, we sum up this review article as follows.(1)The majority of evidence supported that adiponectin, omentin, and SFRP5 were reduced significantly in obesity, which is associated with increased inflammation and possible lung injury, indicated by increase of TNFα and IL-6, through activation of TLR4 and NF-κB signaling pathways.(2)Administration of these adipocytokines promotes weight loss and reduces inflammation.(3)IL-10, ZAG, vaspin, IL-1RA, TGF-β1, and GDF15 seem to be anti-inflammatory.(4)There were controversial reports, though.(5)Yet, there is a huge lack of studies for obesity related lung injury. Some groups investigated the effect of adiponectin on lung transplantation and subsequent changes for graft function, asthma, COPD, and pneumonia, supporting its anti-inflammatory effects and protective role. Synthetic IL-10 agonist reduces mortality of acute lung injury in rabbits with acute necrotizing pancreatitis, possibly through its inhibition of proinflammatory and promotion of anti-inflammatory adipocytokines, as well as its augmentation of host immunity. No study was performed in acid aspiration induced lung injury in obesity. More preclinical and clinical trials in wider area with larger population are warranted.(6)For other adipocytokines, there are very limited studies in obesity related lung injury.(7)In OILI, there is not much information available for clinical trials and translational research because most of the agonists were recently synthesized. Translational studies focusing on the mechanism should reveal valuable information for further investigation and therapeutic potentials. The early phase trials would need to focus on safety, efficacy, and bioavailability at this time point. In the near future, all kinds of related indications should be explored and determined.

Conflict of Interests

The author declares no conflict of interests.

References

K. A. Shaw, A. B. Caughey, and A. B. Edelman, “Obesity epidemic: how to make a difference in a busy OB/GYN practice,” Obstetrical & Gynecological Survey, vol. 67, no. 6, pp. 365–373, 2012.
View at: Publisher Site | Google Scholar
K. M. Flegal, M. D. Carroll, C. L. Ogden, and L. R. Curtin, “Prevalence and trends in obesity among US adults, 1999–2008,” Journal of the American Medical Association, vol. 303, no. 3, pp. 235–241, 2010.
View at: Publisher Site | Google Scholar
M. N. Gong, E. K. Bajwa, B. T. Thompson, and D. C. Christiani, “Body mass index is associated with the development of acute respiratory distress syndrome,” Thorax, vol. 65, no. 1, pp. 44–50, 2010.
View at: Publisher Site | Google Scholar
D. J. Lederer, S. M. Kawut, N. Wickersham et al., “Obesity and primary graft dysfunction after lung transplantation: the lung transplant outcomes group obesity study,” American Journal of Respiratory and Critical Care Medicine, vol. 184, no. 9, pp. 1055–1061, 2011.
View at: Publisher Site | Google Scholar
O. Gajic, O. Dabbagh, P. K. Park et al., “Early identification of patients at risk of acute lung injury: evaluation of lung injury prediction score in a multicenter cohort study,” American Journal of Respiratory and Critical Care Medicine, vol. 183, no. 4, pp. 462–470, 2011.
View at: Publisher Site | Google Scholar
P. Mancuso, “Obesity and lung inflammation,” Journal of Applied Physiology, vol. 108, no. 3, pp. 722–728, 2010.
View at: Publisher Site | Google Scholar
C. E. Hack, L. A. Aarden, and L. G. Thijs, “Role of cytokines in sepsis,” Advances in Immunology, vol. 66, pp. 101–195, 1997.
View at: Google Scholar
L. G. Thijs and C. E. Hack, “Time course of cytokine levels in sepsis,” Intensive Care Medicine, vol. 21, supplement 2, pp. S258–S263, 1995.
View at: Publisher Site | Google Scholar
M. Bhatia and S. Moochhala, “Role of inflammatory mediators in the pathophysiology of acute respiratory distress syndrome,” Journal of Pathology, vol. 202, no. 2, pp. 145–156, 2004.
View at: Publisher Site | Google Scholar
G. D. Rubenfeld, E. Caldwell, E. Peabody et al., “Incidence and outcomes of acute lung injury,” New England Journal of Medicine, vol. 353, no. 16, pp. 1685–1693, 2005.
View at: Publisher Site | Google Scholar
L. K. Reiss, U. Uhlig, and S. Uhlig, “Models and mechanisms of acute lung injury caused by direct insults,” European Journal of Cell Biology, vol. 91, no. 6-7, pp. 590–601, 2012.
View at: Publisher Site | Google Scholar
S. Q. Simpson and L. C. Casey, “Role of tumor necrosis factor in sepsis and acute lung injury,” Critical Care Clinics, vol. 5, no. 1, pp. 27–47, 1989.
View at: Google Scholar
C. L. Klein, T. S. Hoke, W. Fang, C. J. Altmann, I. S. Douglas, and S. Faubel, “Interleukin-6 mediates lung injury following ischemic acute kidney injury or bilateral nephrectomy,” Kidney International, vol. 74, no. 7, pp. 901–909, 2008.
View at: Publisher Site | Google Scholar
V. D. O. Leal and D. Mafra, “Adipokines in obesity,” Clinica Chimica Acta, vol. 419, pp. 87–94, 2013.
View at: Publisher Site | Google Scholar
J. M. Olefsky and C. K. Glass, “Macrophages, inflammation, and insulin resistance,” Annual Review of Physiology, vol. 72, pp. 219–246, 2009.
View at: Publisher Site | Google Scholar
R. M. Strieter, J. A. Belperio, and M. P. Keane, “Host innate defenses in the lung: the role of cytokines,” Current Opinion in Infectious Diseases, vol. 16, no. 3, pp. 193–198, 2003.
View at: Google Scholar
C. Herder, M. Carstensen, and D. M. Ouwens, “Anti-inflammatory cytokines and risk of type 2 diabetes,” Diabetes, Obesity and Metabolism, vol. 15, supplement 3, pp. 39–50, 2013.
View at: Google Scholar
B. K. Tan, R. Adya, and H. S. Randeva, “Omentin: a novel link between inflammation, diabesity, and cardiovascular disease,” Trends in Cardiovascular Medicine, vol. 20, no. 5, pp. 143–148, 2010.
View at: Publisher Site | Google Scholar
S. Kralisch, J. Klein, M. Bluher, R. Paschke, M. Stumvoll, and M. Fasshauer, “Therapeutic perspectives of adipocytokines,” Expert Opinion on Pharmacotherapy, vol. 6, no. 6, pp. 863–872, 2005.
View at: Publisher Site | Google Scholar
P. C. Calder, N. Ahluwalia, F. Brouns et al., “Dietary factors and low-grade inflammation in relation to overweight and obesity,” British Journal of Nutrition, vol. 106, supplement 3, pp. S5–S78, 2011.
View at: Google Scholar
A. H. Berg, T. P. Combs, and P. E. Scherer, “ACRP30/adiponectin: an adipokine regulating glucose and lipid metabolism,” Trends in Endocrinology and Metabolism, vol. 13, no. 2, pp. 84–89, 2002.
View at: Publisher Site | Google Scholar
P. E. Scherer, S. Williams, M. Fogliano, G. Baldini, and H. F. Lodish, “A novel serum protein similar to C1q, produced exclusively in adipocytes,” Journal of Biological Chemistry, vol. 270, no. 45, pp. 26746–26749, 1995.
View at: Publisher Site | Google Scholar
L. Shapiro and P. E. Scherer, “The crystal structure of a complement-1q family protein suggests an evolutionary link to tumor necrosis factor,” Current Biology, vol. 8, no. 6, pp. 335–338, 1998.
View at: Google Scholar
R. Piñeiro, M. J. Iglesias, R. Gallego et al., “Adiponectin is synthesized and secreted by human and murine cardiomyocytes,” FEBS Letters, vol. 579, no. 23, pp. 5163–5169, 2005.
View at: Publisher Site | Google Scholar
Y. Wang, W. B. Lau, E. Gao et al., “Cardiomyocyte-derived adiponectin is biologically active in protecting against myocardial ischemia-reperfusion injury,” American Journal of Physiology-Endocrinology and Metabolism, vol. 298, no. 3, pp. E663–E670, 2010.
View at: Publisher Site | Google Scholar
A. M. Delaigle, M. Senou, Y. Guiot, M.-C. Many, and S. M. Brichard, “Induction of adiponectin in skeletal muscle of type 2 diabetic mice: in vivo and in vitro studies,” Diabetologia, vol. 49, no. 6, pp. 1311–1323, 2006.
View at: Publisher Site | Google Scholar
A. M. Van Berendoncks, A. Garnier, P. Beckers et al., “Functional adiponectin resistance at the level of the skeletal muscle in mild to moderate chronic heart failure,” Circulation: Heart Failure, vol. 3, no. 2, pp. 185–194, 2010.
View at: Publisher Site | Google Scholar
A. T. Turer and P. E. Scherer , “Adiponectin: mechanistic insights and clinical implications,” Diabetologia, vol. 55, no. 9, pp. 2319–2326, 2012.
View at: Publisher Site | Google Scholar
H. Tilg and A. R. Moschen, “Role of adiponectin and PBEF/visfatin as regulators of inflammation: involvement in obesity-associated diseases,” Clinical Science, vol. 114, no. 3-4, pp. 275–288, 2008.
View at: Publisher Site | Google Scholar
A. T. Turer, A. Khera, C. R. Ayers et al., “Adipose tissue mass and location affect circulating adiponectin levels,” Diabetologia, vol. 54, no. 10, pp. 2515–2524, 2011.
View at: Publisher Site | Google Scholar
J. R. Kizer, “A tangled threesome: adiponectin, insulin sensitivity, and adiposity: can mendelian randomization sort out causality?” Diabetes, vol. 62, no. 4, pp. 1007–1009, 2013.
View at: Publisher Site | Google Scholar
J. Hoffstedt, E. Arvidsson, E. Sjölin, K. Wåhlén, and P. Arner, “Adipose tissue adiponectin production and adiponectin serum concentration in human obesity and insulin resistance,” Journal of Clinical Endocrinology and Metabolism, vol. 89, no. 3, pp. 1391–1396, 2004.
View at: Publisher Site | Google Scholar
M. B. Schulze, I. Shai, E. B. Rimm, T. Li, N. Rifai, and F. B. Hu, “Adiponectin and future coronary heart disease events among men with type 2 diabetes,” Diabetes, vol. 54, no. 2, pp. 534–539, 2005.
View at: Publisher Site | Google Scholar
I. Padmalayam and M. Suto, “Role of adiponectin in the metabolic syndrome: current perspectives on its modulation as a treatment strategy,” Current Pharmaceutical Design, vol. 19, no. 32, pp. 5755–5763, 2013.
View at: Publisher Site | Google Scholar
D. M. Maahs, L. G. Ogden, J. K. Snell-Bergeon et al., “Determinants of serum adiponectin in persons with and without type 1 diabetes,” American Journal of Epidemiology, vol. 166, no. 6, pp. 731–740, 2007.
View at: Publisher Site | Google Scholar
H. Leth, K. K. Andersen, J. Frystyk et al., “Elevated levels of high-molecular-weight adiponectin in type 1 diabetes,” Journal of Clinical Endocrinology and Metabolism, vol. 93, no. 8, pp. 3186–3191, 2008.
View at: Publisher Site | Google Scholar
R. K. Semple, N. H. Halberg, K. Burling et al., “Paradoxical elevation of high-molecular weight adiponectin in acquired extreme insulin resistance due to insulin receptor antibodies,” Diabetes, vol. 56, no. 6, pp. 1712–1717, 2007.
View at: Publisher Site | Google Scholar
N. Sattar, G. Wannamethee, N. Sarwar et al., “Adiponectin and coronary heart disease: a prospective study and meta-analysis,” Circulation, vol. 114, no. 7, pp. 623–629, 2006.
View at: Publisher Site | Google Scholar
S. Landskroner-Eiger, B. Qian, E. S. Muise et al., “Proangiogenic contribution of adiponectin toward mammary tumor growth in vivo,” Clinical Cancer Research, vol. 15, no. 10, pp. 3265–3276, 2009.
View at: Publisher Site | Google Scholar
M. Iwabu, T. Yamauchi, M. Okada-Iwabu et al., “Adiponectin and AdipoR1 regulate PGC-1α and mitochondria by Ca 2+ and AMPK/SIRT1,” Nature, vol. 464, no. 7293, pp. 1313–1319, 2010.
View at: Publisher Site | Google Scholar
N. Klöting, M. Fasshauer, A. Dietrich et al., “Insulin-sensitive obesity,” American Journal of Physiology-Endocrinology and Metabolism, vol. 299, no. 3, pp. E506–E515, 2010.
View at: Publisher Site | Google Scholar
K. Sun, C. M. Kusminski, and P. E. Scherer, “Adipose tissue remodeling and obesity,” Journal of Clinical Investigation, vol. 121, no. 6, pp. 2094–2101, 2011.
View at: Publisher Site | Google Scholar
S. Wang, L. M. Sparks, H. Xie, F. L. Greenway, L. De Jonge, and S. R. Smith, “Subtyping obesity with microarrays: implications for the diagnosis and treatment of obesity,” International Journal of Obesity, vol. 33, no. 4, pp. 481–489, 2009.
View at: Publisher Site | Google Scholar
D. Dietze-Schroeder, H. Sell, M. Uhlig, M. Koenen, and J. Eckel, “Autocrine action of adiponectin on human fat cells prevents the release of insulin resistance-inducing factors,” Diabetes, vol. 54, no. 7, pp. 2003–2011, 2005.
View at: Publisher Site | Google Scholar
M. Awazawa, K. Ueki, K. Inabe et al., “Adiponectin enhances insulin sensitivity by increasing hepatic IRS-2 expression via a macrophage-derived IL-6-dependent pathway,” Cell Metabolism, vol. 13, no. 4, pp. 401–412, 2011.
View at: Publisher Site | Google Scholar
W. L. Holland, R. A. Miller, Z. V. Wang et al., “Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin,” Nature Medicine, vol. 17, no. 1, pp. 55–63, 2011.
View at: Publisher Site | Google Scholar
I. W. Asterholm and P. E. Scherer, “Enhanced metabolic flexibility associated with elevated adiponectin levels,” American Journal of Pathology, vol. 176, no. 3, pp. 1364–1376, 2010.
View at: Publisher Site | Google Scholar
X. Xin, L. Zhou, C. M. Reyes, F. Liu, and L. Q. Dong, “APPL1 mediates adiponectin-stimulated p38 MAPK activation by scaffolding the TAK1-MKK3-p38 MAPK pathway,” American Journal of Physiology-Endocrinology and Metabolism, vol. 300, no. 1, pp. E103–E110, 2011.
View at: Publisher Site | Google Scholar
C. Hug, J. Wang, N. S. Ahmad, J. S. Bogan, T. Tsao, and H. F. Lodish, “T-cadherin is a receptor for hexameric and high-molecular-weight forms of Acrp30/adiponectin,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 28, pp. 10308–10313, 2004.
View at: Publisher Site | Google Scholar
J. R. Rao, D. J. Keating, C. Chen, and H. C. Parkington, “Adiponectin increases insulin content and cell proliferation in MIN6 cells via PPARγ-dependent and PPARγ-independent mechanisms,” Diabetes, Obesity and Metabolism, vol. 14, no. 11, pp. 983–989, 2012.
View at: Publisher Site | Google Scholar
N. Wijesekara, M. Krishnamurthy, A. Bhattacharjee, A. Suhail, G. Sweeney, and M. B. Wheeler, “Adiponectin-induced ERK and Akt phosphorylation protects against pancreatic beta cell apoptosis and increases insulin gene expression and secretion,” Journal of Biological Chemistry, vol. 285, no. 44, pp. 33623–33631, 2010.
View at: Publisher Site | Google Scholar
M. Awazawa, K. Ueki, K. Inabe et al., “Adiponectin suppresses hepatic SREBP1c expression in an AdipoR1/LKB1/AMPK dependent pathway,” Biochemical and Biophysical Research Communications, vol. 382, no. 1, pp. 51–56, 2009.
View at: Publisher Site | Google Scholar
K. Ohashi, J. L. Parker, N. Ouchi et al., “Adiponectin promotes macrophage polarization toward an anti-inflammatory phenotype,” Journal of Biological Chemistry, vol. 285, no. 9, pp. 6153–6160, 2010.
View at: Publisher Site | Google Scholar
N. Luo, X. Wang, B. H. Chung et al., “Effects of macrophage-specific adiponectin expression on lipid metabolism in vivo,” American Journal of Physiology-Endocrinology and Metabolism, vol. 301, no. 1, pp. E180–E186, 2011.
View at: Publisher Site | Google Scholar
S. Engeli, M. Feldpausch, K. Gorzelniak et al., “Association between adiponectin and mediators of inflammation in obese women,” Diabetes, vol. 52, no. 4, pp. 942–947, 2003.
View at: Publisher Site | Google Scholar
J. Krakoff, T. Funahashi, C. D. A. Stehouwer et al., “Inflammatory markers, adiponectin, and risk of type 2 diabetes in the Pima Indian,” Diabetes Care, vol. 26, no. 6, pp. 1745–1751, 2003.
View at: Publisher Site | Google Scholar
N. Ouchi, S. Kihara, T. Funahashi et al., “Reciprocal association of C-reactive protein with adiponectin in blood stream and adipose tissue,” Circulation, vol. 107, no. 5, pp. 671–674, 2003.
View at: Publisher Site | Google Scholar
G. S. Hotamisligil, N. S. Shargill, and B. M. Spiegelman, “Adipose expression of tumor necrosis factor-α: direct role in obesity-linked insulin resistance,” Science, vol. 259, no. 5091, pp. 87–91, 1993.
View at: Google Scholar
P. Mancuso, “Obesity and lung inflammation,” Journal of Applied Physiology, vol. 108, no. 3, pp. 722–728, 2010.
View at: Publisher Site | Google Scholar
H. Nakatsuji, H. Kobayashi, K. Kishida et al., “Binding of adiponectin and C1q in human serum, and clinical significance of the measurement of C1q-adiponectin / total adiponectin ratio,” Metabolism, vol. 62, no. 1, pp. 109–120, 2013.
View at: Publisher Site | Google Scholar
T. Yamauchi, J. Kamon, Y. Ito et al., “Cloning of adiponectin receptors that mediate antidiabetic metabolic effects,” Nature, vol. 423, no. 762, p. 769, 2004.
View at: Publisher Site | Google Scholar
S. M. Sliman, R. B. Patel, J. P. Cruff et al., “Adiponectin protects against hyperoxic lung injury and vascular leak,” Cell Biochemistry and Biophysics, vol. 67, no. 2, pp. 399–414, 2013.
View at: Publisher Site | Google Scholar
J. M. Konter, J. L. Parker, E. Baez et al., “Adiponectin attenuates lipopolysaccharide-induced acute lung injury through suppression of endothelial cell activation,” Journal of Immunology, vol. 188, no. 2, pp. 854–863, 2012.
View at: Publisher Site | Google Scholar
S. E. Orfanos, I. Mavrommati, I. Korovesi, and C. Roussos, “Pulmonary endothelium in acute lung injury: from basic science to the critically ill,” Intensive Care Medicine, vol. 30, no. 9, pp. 1702–1714, 2004.
View at: Publisher Site | Google Scholar
K. Tsushima, L. S. King, N. R. Aggarwal, A. De Gorordo, F. R. D'Alessio, and K. Kubo, “Acute lung injury review,” Internal Medicine, vol. 48, no. 9, pp. 621–630, 2009.
View at: Publisher Site | Google Scholar
R. D. Stapleton, A. E. Dixon, P. E. Parsons, L. B. Ware, and B. T. Suratt, “The association between BMI and plasma cytokine levels in patients with acute lung injury,” Chest, vol. 138, no. 3, pp. 568–577, 2010.
View at: Publisher Site | Google Scholar
M. N. Gong, E. K. Bajwa, B. T. Thompson, and D. C. Christiani, “Body mass index is associated with the development of acute respiratory distress syndrome,” Thorax, vol. 65, no. 1, pp. 44–50, 2010.
View at: Publisher Site | Google Scholar
S. Towfigh, M. V. Peralta, M. J. Martin et al., “Acute respiratory distress syndrome in nontrauma surgical patients: a 6-year study,” Journal of Trauma-Injury, Infection and Critical Care, vol. 67, no. 6, pp. 1239–1243, 2009.
View at: Publisher Site | Google Scholar
A. Anzueto, F. Frutos-Vivar, A. Esteban et al., “Influence of body mass index on outcome of the mechanically ventilated patients,” Thorax, vol. 66, no. 1, pp. 66–73, 2011.
View at: Publisher Site | Google Scholar
O. Gajic, O. Dabbagh, P. K. Park et al., “Early identification of patients at risk of acute lung injury: evaluation of lung injury prediction score in a multicenter cohort study,” American Journal of Respiratory and Critical Care Medicine, vol. 183, no. 4, pp. 462–470, 2011.
View at: Publisher Site | Google Scholar
R. Shibata, K. Sato, D. R. Pimentel et al., “Adiponectin protects against myocardial ischemia-reperfusion injury through AMPK- and COX-2-dependent mechanisms,” Nature Medicine, vol. 11, no. 10, pp. 1096–1103, 2005.
View at: Publisher Site | Google Scholar
R. Summer, F. F. Little, N. Ouchi et al., “Alveolar macrophage activation and an emphysema-like phenotype in adiponectin-deficient mice,” American Journal of Physiology-Lung Cellular and Molecular Physiology, vol. 294, no. 6, pp. L1035–L1042, 2008.
View at: Publisher Site | Google Scholar
H. Rokni Yazdi, S. Lari, D. Attaran, H. Ayatollahi, and A. Mohsenizadeh, “The serum levels of adiponectin and leptin in mustard lung patients,” Human & Experimental Toxicology, 2013.
View at: Google Scholar
A. J. Walkey, T. W. Rice, J. Konter et al., “Plasma adiponectin and mortality in critically ill subjects with acute respiratory failure,” Critical Care Medicine, vol. 38, no. 12, pp. 2329–2334, 2010.
View at: Publisher Site | Google Scholar
A. J. Walkey, T. W. Rice, J. Konter et al., “Plasma adiponectin and mortality in critically ill subjects with acute respiratory failure,” Critical Care Medicine, vol. 38, no. 12, pp. 2329–2334, 2010.
View at: Publisher Site | Google Scholar
P. Garcia and A. Sood, “Adiponectin in pulmonary disease and critically ill patients,” Current Medicinal Chemistry, vol. 19, no. 32, pp. 5493–5500, 2012.
View at: Publisher Site | Google Scholar
S. Leivo-Korpela, L. Lehtimäki, K. Vuolteenaho et al., “Adiponectin is associated with dynamic hyperinflation and a favourable response to inhaled glucocorticoids in patients with COPD,” Respiratory Medicine, vol. 108, no. 1, pp. 122–128, 2014.
View at: Google Scholar
K. Ohashi, J. L. Parker, N. Ouchi et al., “Adiponectin promotes macrophage polarization toward an anti-inflammatory phenotype,” Journal of Biological Chemistry, vol. 285, no. 9, pp. 6153–6160, 2010.
View at: Publisher Site | Google Scholar
R. Summer, F. F. Little, N. Ouchi et al., “Alveolar macrophage activation and an emphysema-like phenotype in adiponectin-deficient mice,” American Journal of Physiology-Lung Cellular and Molecular Physiology, vol. 294, no. 6, pp. L1035–L1042, 2008.
View at: Publisher Site | Google Scholar
S. A. Shore, R. D. Terry, L. Flynt, A. Xu, and C. Hug, “Adiponectin attenuates allergen-induced airway inflammation and hyperresponsiveness in mice,” Journal of Allergy and Clinical Immunology, vol. 118, no. 2, pp. 389–395, 2006.
View at: Publisher Site | Google Scholar
T. Aprahamian, R. G. Bonegio, C. Richez et al., “The peroxisome proliferator-activated receptor γ agonist rosiglitazone ameliorates murine lupus by induction of adiponectin,” Journal of Immunology, vol. 182, no. 1, pp. 340–346, 2009.
View at: Google Scholar
H. Nishizawa, L. Shimomura, K. Kishida et al., “Androgens decrease plasma adiponectin, an insulin-sensitizing adipocyte-derived protein,” Diabetes, vol. 51, no. 9, pp. 2734–2741, 2002.
View at: Google Scholar
R. Z. Yang, M. Lee, H. Hu et al., “Identification of omentin as a novel depot-specific adipokine in human adipose tissue: possible role in modulating insulin action,” American Journal of Physiology-Endocrinology and Metabolism, vol. 290, no. 6, pp. E1253–E1261, 2006.
View at: Publisher Site | Google Scholar
G. Catli, A. Anik, A. Abaci, T. Kume, and E. Bober, “Low omentin-1 levels are related with clinical and metabolic parameters in obese children,” Experimental and Clinical Endocrinology & Diabetes, vol. 121, no. 10, pp. 595–600, 2013.
View at: Publisher Site | Google Scholar
C. M. De Souza Batista, R. Yang, M. Lee et al., “Omentin plasma levels and gene expression are decreased in obesity,” Diabetes, vol. 56, no. 6, pp. 1655–1661, 2007.
View at: Publisher Site | Google Scholar
P. Yan, D. Liu, M. Long, Y. Ren, J. Pang, and R. Li, “Changes of serum omentin levels and relationship between omentin and adiponectin concentrations in type 2 diabetes mellitus,” Experimental and Clinical Endocrinology and Diabetes, vol. 119, no. 4, pp. 257–263, 2011.
View at: Publisher Site | Google Scholar
A. Saremi, M. Asghari, and A. Ghorbani, “Effects of aerobic training on serum omentin-1 and cardiometabolic risk factors in overweight and obese men,” Journal of Sports Sciences, vol. 28, no. 9, pp. 993–998, 2010.
View at: Publisher Site | Google Scholar
H. Y. Pan, L. Guo, and Q. Li, “Changes of serum omentin-1 levels in normal subjects and in patients with impaired glucose regulation and with newly diagnosed and untreated type 2 diabetes,” Diabetes Research and Clinical Practice, vol. 88, no. 1, pp. 29–33, 2010.
View at: Publisher Site | Google Scholar
J. M. Moreno-Navarrete, V. Cataln, F. Ortega et al., “Circulating omentin concentration increases after weight loss,” Nutrition and Metabolism, vol. 7, p. 27, 2010.
View at: Publisher Site | Google Scholar
B. K. Tan, R. Adya, S. Farhatullah, J. Chen, H. Lehnert, and H. S. Randeva, “Metformin treatment may increase omentin-1 levels in women with polycystic ovary syndrome,” Diabetes, vol. 59, no. 12, pp. 3023–3031, 2010.
View at: Publisher Site | Google Scholar
A. Esteghamati, S. Noshad, S. Rabizadeh, M. Ghavami, A. Zandieh, and M. Nakhjavani, “Comparative effects of metformin and pioglitazone on omentin and leptin concentrations in patients with newly diagnosed diabetes: a randomized clinical trial,” Regulatory Peptides, vol. 182, pp. 1–6, 2013.
View at: Publisher Site | Google Scholar
A. Siejkaa, J. Jankiewicz-Wikaa, K. Kolomeckib et al., “Long-term impact of vertical banded gastroplasty (VBG) on plasma concentration of leptin, soluble leptin receptor, ghrelin, omentin-1, obestatin, and retinol binding protein 4 (RBP4) in patients with severe obesity,” Cytokine, vol. 64, no. 2, pp. 490–493, 2013.
View at: Google Scholar
A. Schäffler, M. Neumeier, H. Herfarth, A. Fürst, J. Schölmerich, and C. Büchler, “Genomic structure of human omentin, a new adipocytokine expressed in omental adipose tissue,” Biochimica et Biophysica Acta-Gene Structure and Expression, vol. 1732, no. 1–3, pp. 96–102, 2005.
View at: Publisher Site | Google Scholar
L. Šenolt, M. Polanská, M. Filková et al., “Vaspin and omentin: new adipokines differentially regulated at the site of inflammation in rheumatoid arthritis,” Annals of the Rheumatic Diseases, vol. 69, no. 7, pp. 1410–1411, 2010.
View at: Publisher Site | Google Scholar
C. M. de Souza Batista, R. Yang, M. Lee et al., “Omentin plasma levels and gene expression are decreased in obesity,” Diabetes, vol. 56, no. 6, pp. 1655–1661, 2007.
View at: Publisher Site | Google Scholar
H. Yamawaki, J. Kuramoto, S. Kameshima, T. Usui, M. Okada, and Y. Hara, “Omentin, a novel adipocytokine inhibits TNF-induced vascular inflammation in human endothelial cells,” Biochemical and Biophysical Research Communications, vol. 408, no. 2, pp. 339–343, 2011.
View at: Publisher Site | Google Scholar
K. Kazama, T. Usui, M. Okada, Y. Hara, and H. Yamawaki, “Omentin plays an anti-inflammatory role through inhibition of TNF-α-induced superoxide production in vascular smooth muscle cells,” European Journal of Pharmacology, vol. 686, no. 1–3, pp. 116–123, 2012.
View at: Publisher Site | Google Scholar
X. Zhong, X. Li, F. Liu, H. Tan, and D. Shang, “Omentin inhibits TNF-α-induced expression of adhesion molecules in endothelial cells via ERK/NF-κB pathway,” Biochemical and Biophysical Research Communications, vol. 425, no. 2, pp. 401–406, 2012.
View at: Publisher Site | Google Scholar
K. Kazama, T. Usui, M. Okada, Y. Hara, and H. Yamawaki, “Omentin plays an anti-inflammatory role through inhibition of TNF-α-induced superoxide production in vascular smooth muscle cells,” European Journal of Pharmacology, vol. 686, no. 1–3, pp. 116–123, 2012.
View at: Publisher Site | Google Scholar
H. Yamawaki, “Vascular effects of novel adipocytokines: focus on vascular contractility and inflammatory responses,” Biological and Pharmaceutical Bulletin, vol. 34, no. 3, pp. 307–310, 2011.
View at: Publisher Site | Google Scholar
S. Zirlik, K. Hildner, A. Targosz et al., “Melatonin and omentin: influence factors in the obstructive sleep apnoea syndrome?” Journal of Physiology and Pharmacology, vol. 64, no. 3, pp. 353–360, 2013.
View at: Google Scholar
Q. Wang, X. Feng, C. Zhou, P. Li, and J. Kang, “Decreased levels of serum omentin-1 in patients with obstructive sleep apnoea syndrome,” Annals of Clinical Biochemistry, vol. 50, part 3, pp. 230–235, 2013.
View at: Google Scholar
O. K. Kurt, M. Tosun, A. Alcelik, B. Yilmaz, and F. Talay, “Serum omentin levels in patients with obstructive sleep apnea,” Sleep Breath, 2013.
View at: Google Scholar
N. Ouchi, A. Higuchi, K. Ohashi et al., “Sfrp5 is an anti-inflammatory adipokine that modulates metabolic dysfunction in obesity,” Science, vol. 329, no. 5990, pp. 454–457, 2010.
View at: Publisher Site | Google Scholar
D. M. Schulte, N. Müller, K. Neumann et al., “Pro-inflammatory wnt5a and anti-inflammatory sfrp5 are differentially regulated by nutritional factors in obese human subjects,” PLoS ONE, vol. 7, no. 2, Article ID e32437, 2012.
View at: Publisher Site | Google Scholar
A. Ehrlund, N. Mejhert, S. Lorente-Cebrián et al., “Characterization of the Wnt inhibitors secreted frizzled-related proteins (SFRPs) in human adipose tissue,” Journal of Clinical Endocrinology & Metabolism, vol. 98, no. 3, pp. E503–E508, 2013.
View at: Publisher Site | Google Scholar
H. Mori, T. C. Prestwich, M. A. Reid et al., “Secreted frizzled-related protein 5 suppresses adipocyte mitochondrial metabolism through WNT inhibition,” Journal of Clinical Investigation, vol. 122, no. 7, pp. 2405–2416, 2012.
View at: Google Scholar
C. P. Xavier, M. Melikova, Y. Chuman, A. Uren, B. Baljinnyam, and J. S. Rubin, “Secreted Frizzled-related protein potentiation versus inhibition of Wnt3a/β-catenin signaling,” Cellular Signalling, vol. 26, no. 1, pp. 94–101, 2014.
View at: Publisher Site | Google Scholar
J. Zhu, Y. Wang, J. Duan et al., “DNA Methylation status of Wnt antagonist SFRP5 can predict the response to the EGFR-tyrosine kinase inhibitor therapy in non-small cell lung cancer,” Journal of Experimental & Clinical Cancer Research, vol. 31, p. 80, 2012.
View at: Publisher Site | Google Scholar
M. Castro, L. Grau, P. Puerta et al., “Multiplexed methylation profiles of tumor suppressor genes and clinical outcome in lung cancer,” Journal of Translational Medicine, vol. 8, p. 86, 2010.
View at: Publisher Site | Google Scholar
A. Y. Lee, B. He, L. You et al., “Expression of the secreted frizzled-related protein gene family is downregulated in human mesothelioma,” Oncogene, vol. 23, no. 39, pp. 6672–6676, 2004.
View at: Publisher Site | Google Scholar
K. Hida, J. Wada, J. Eguchi et al., “Visceral adipose tissue-derived serine protease inhibitor: a unique insulin-sensitizing adipocytokine in obesity,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 30, pp. 10610–10615, 2005.
View at: Publisher Site | Google Scholar
N. Klöting, P. Kovacs, M. Kern et al., “Central vaspin administration acutely reduces food intake and has sustained blood glucose-lowering effects,” Diabetologia, vol. 54, no. 7, pp. 1819–1823, 2011.
View at: Publisher Site | Google Scholar
B. S. Youn, N. Klöting, J. Kratzsch et al., “Serum vaspin concentrations in human obesity and type 2 diabetes,” Diabetes, vol. 57, no. 2, pp. 372–377, 2008.
View at: Publisher Site | Google Scholar
S. Schultz and A. G. Beck-Sickinger, “Chemerin and vaspin: possible targets to treat obesity?” ChemMedChem, vol. 8, no. 4, pp. 549–559, 2013.
View at: Publisher Site | Google Scholar
A. Handisurya, M. Riedl, G. Vila et al., “Serum vaspin concentrations in relation to insulin sensitivity following RYGB-induced weight loss,” Obesity Surgery, vol. 20, no. 2, pp. 198–203, 2010.
View at: Publisher Site | Google Scholar
H. Sell, A. Divoux, C. Poitou et al., “Chemerin correlates with markers for fatty liver in morbidly obese patients and strongly decreases after weight loss induced by bariatric surgery,” Journal of Clinical Endocrinology and Metabolism, vol. 95, no. 6, pp. 2892–2896, 2010.
View at: Publisher Site | Google Scholar
B. K. Tan, D. Heutling, J. Chen et al., “Metformin decreases the adipokine vaspin in overweight women with polycystic ovary syndrome concomitant with improvement in insulin sensitivity and a decrease in insulin resistance,” Diabetes, vol. 57, no. 6, pp. 1501–1507, 2008.
View at: Publisher Site | Google Scholar
T. Morisaki, F. Takeshima, H. Fukuda et al., “High serum vaspin concentrations in patients with ulcerative colitis,” Digestive Diseases and Sciences, vol. 59, no. 2, pp. 315–521, 2013.
View at: Publisher Site | Google Scholar
J. M. Kim, T. N. Kim, and J. C. Won, “Association between serum vaspin level and metabolic syndrome in healthy korean subjects,” Metabolic Syndrome and Related Disorders, vol. 11, no. 6, pp. 385–391, 2013.
View at: Publisher Site | Google Scholar
H. Li, W. Peng, J. Zhuang et al., “Vaspin attenuates high glucose-induced vascular smooth muscle cells proliferation and chemokinesis by inhibiting the MAPK, PI3K/Akt, and NF-κB signaling pathways,” Atherosclerosis, vol. 228, no. 1, pp. 61–68, 2013.
View at: Publisher Site | Google Scholar
P. Zahradka, “Inhibition of NADPH oxidase by vaspin may prevent progression of atherosclerosis,” Acta Physiologica, vol. 209, no. 3, pp. 195–198, 2013.
View at: Google Scholar
J. K. Cho, T. Han, and H. S. Kang, “Combined effects of body mass index and cardio/respiratory fitness on serum vaspin concentrations in Korean young men,” European Journal of Applied Physiology, vol. 108, no. 2, pp. 347–353, 2010.
View at: Publisher Site | Google Scholar
C. Bing, Y. Bao, J. Jenkins et al., “Zinc-α2-glycoprotein, a lipid mobilizing factor, is expressed in adipocytes and is up-regulated in mice with cancer cachexia,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 8, pp. 2500–2505, 2004.
View at: Publisher Site | Google Scholar
S. T. Russell and M. J. Tisdale, “Studies on the anti-obesity activity of zinc-α 2-glycoprotein in the rat,” International Journal of Obesity, vol. 35, no. 5, pp. 658–665, 2011.
View at: Publisher Site | Google Scholar
S. T. Russell and M. J. Tisdale, “Role of β-adrenergic receptors in the anti-obesity and anti-diabetic effects of zinc-α2-glycoprotien (ZAG),” Biochimica et Biophysica Acta-Molecular and Cell Biology of Lipids, vol. 1821, no. 4, pp. 590–599, 2012.
View at: Publisher Site | Google Scholar
C. Bing, “Lipid mobilization in cachexia: mechanisms and mediators,” Current Opinion in Supportive and Palliative Care, vol. 5, no. 4, pp. 356–360, 2011.
View at: Publisher Site | Google Scholar
C. Bing, T. Mracek, D. Gao, and P. Trayhurn, “Zinc-α2-glycoprotein: an adipokine modulator of body fat mass,” International Journal of Obesity, vol. 34, no. 11, pp. 1559–1565, 2010.
View at: Publisher Site | Google Scholar
S. T. Russell and M. J. Tisdale, “Studies on the antiobesity effect of zinc-α 2-glycoprotein in the ob/ob mouse,” International Journal of Obesity, vol. 35, no. 3, pp. 345–354, 2011.
View at: Publisher Site | Google Scholar
D. M. Selva, A. Lecube, C. Hernández, J. A. Baena, J. M. Fort, and R. Simó, “Lower zinc-α2-glycoprotein production by adipose tissue and liver in obese patients unrelated to insulin resistance,” Journal of Clinical Endocrinology and Metabolism, vol. 94, no. 11, pp. 4499–4507, 2009.
View at: Publisher Site | Google Scholar
M. Yang, R. Liu, S. Li et al., “Zinc-α2-glycoprotein is associated with insulin resistance in humans and is regulated by hyperglycemia, hyperinsulinemia, or liraglutide administration: cross-sectional and interventional studies in normal subjects, insulin-resistant subjects, and subjects with newly diagnosed diabetes,” Diabetes Care, vol. 36, no. 5, pp. 1074–1082, 2013.
View at: Publisher Site | Google Scholar
D. C. Yeung, K. S. Lam, Y. Wang, A. W. Tso, and A. Xu, “Serum zinc-α2-glycoprotein correlates with adiposity, triglycerides, and the key components of the metabolic syndrome in Chinese subjects,” Journal of Clinical Endocrinology and Metabolism, vol. 94, no. 7, pp. 2531–2536, 2009.
View at: Publisher Site | Google Scholar
C. C. Pelletier, L. Koppe, M. L. Croze et al., “White adipose tissue overproduces the lipid-mobilizing factor zinc α2-glycoprotein in chronic kidney disease,” Kidney International, vol. 83, no. 5, pp. 878–886, 2013.
View at: Publisher Site | Google Scholar
D. Gao, P. Trayhurn, and C. Bing, “Macrophage-secreted factors inhibit ZAG expression and secretion by human adipocytes,” Molecular and Cellular Endocrinology, vol. 325, no. 1-2, pp. 135–142, 2010.
View at: Publisher Site | Google Scholar
V. O. Leal, J. C. Lobo, M. B. Stockler-Pinto et al., “Is zinc-α2-glycoprotein a cardiovascular protective factor for patients undergoing hemodialysis?” Clinica Chimica Acta, vol. 413, no. 5-6, pp. 616–619, 2012.
View at: Publisher Site | Google Scholar
T. Mracek, Q. Ding, T. Tzanavari et al., “The adipokine zinc-α2-glycoprotein (ZAG) is downregulated with fat mass expansion in obesity,” Clinical Endocrinology, vol. 72, no. 3, pp. 334–341, 2010.
View at: Publisher Site | Google Scholar
V. Ceperuelo-Mallafré, S. Näf, X. Escoté et al., “Circulating and adipose tissue gene expression of zinc-α2- glycoprotein in obesity: its relationship with adipokine and lipolytic gene markers in subcutaneous and visceral fat,” Journal of Clinical Endocrinology and Metabolism, vol. 94, no. 12, pp. 5062–5069, 2009.
View at: Publisher Site | Google Scholar
M. P. Marrades, J. A. Martínez, and M. J. Moreno-Aliaga, “ZAG, a lipid mobilizing adipokine, is downregulated in human obesity,” Journal of Physiology and Biochemistry, vol. 64, no. 1, pp. 61–66, 2008.
View at: Google Scholar
E. Hong, J. K. Hwi, Y. Cho et al., “Interleukin-10 prevents diet-induced insulin resistance by attenuating macrophage and cytokine response in skeletal muscle,” Diabetes, vol. 58, no. 11, pp. 2525–2535, 2009.
View at: Publisher Site | Google Scholar
E. van Exel, J. Gussekloo, A. J. de Craen, M. Frölich, A. B. D. Wiel, and R. G. J. Westendorp, “Low production capacity of interleukin-10 associates with the metabolic syndrome and type 2 diabetes: the Leiden 85-plus study,” Diabetes, vol. 51, no. 4, pp. 1088–1092, 2002.
View at: Google Scholar
C. Herder, M. Carstensen, and D. M. Ouwens, “Anti-inflammatory cytokines and risk of type 2 diabetes,” Diabetes, Obesity and Metabolism, vol. 15, supplement 3, pp. 39–50, 2013.
View at: Google Scholar
J. Banchereau, V. Pascual , and A. O'Garra, “From IL-2 to IL-37: the expanding spectrum of anti-inflammatory cytokines,” Nature Immunology, vol. 13, no. 10, pp. 925–931, 2012.
View at: Publisher Site | Google Scholar
M. L. Bustos, L. Huleihela, E. M. Meyer et al., “Activation of human mesenchymal stem cells impacts their therapeutic abilities in lung injury by increasing interleukin (IL)-10 and IL-1RN levels,” Stem Cells Translational Medicine, vol. 2, no. 11, pp. 884–895, 2013.
View at: Publisher Site | Google Scholar
H. Itano, W. Zhang, J. H. Ritter, T. J. McCarthy, T. Mohanakumar, and G. A. Patterson, “Adenovirus-mediated gene transfer of human interleukin 10 ameliorates reperfusion injury of rat lung isografts,” Journal of Thoracic and Cardiovascular Surgery, vol. 120, no. 5, pp. 947–956, 2000.
View at: Google Scholar
T. J. Standiford, R. M. Strieter, N. W. Lukacs, and S. L. Kunkel, “Neutralization of IL-10 increases lethality in endotoxemia: cooperative effects of macrophage inflammatory protein-2 and tumor necrosis factor,” Journal of Immunology, vol. 155, no. 4, pp. 2222–2229, 1995.
View at: Google Scholar
T. A. Grool, H. van Dullemen, J. Meenan et al., “Anti-inflammatory effect of interleukin-10 in rabbit immune complexinduced colitis,” Scandinavian Journal of Gastroenterology, vol. 33, no. 7, pp. 754–758, 1998.
View at: Publisher Site | Google Scholar
M. Kurte, M. López, A. Aguirre et al., “A synthetic peptide homologous to functional domain of human IL-10 down-regulates expression of MHC class I and transporter associated with antigen processing 1/2 in human melanoma cells,” Journal of Immunology, vol. 173, no. 3, pp. 1731–1737, 2004.
View at: Google Scholar
M. N. López, B. Pesce, M. Kurte et al., “A synthetic peptide homologous to IL-10 functional domain induces monocyte differentiation to TGF-β+ tolerogenic dendritic cells,” Immunobiology, vol. 216, no. 10, pp. 1117–1126, 2011.
View at: Publisher Site | Google Scholar
M. O. Osman, N. O. Jacobsen, J. U. Kristensen et al., “It 9302, a synthetic interleukin-10 agonist diminishes acute lung injury in rabbits with acute necrotizing pancreatitis,” Surgery, vol. 124, no. 3, pp. 584–592, 1998.
View at: Publisher Site | Google Scholar
M. O. Osman, B. Gesser, J. T. Mortensen, K. Matsushima, S. L. Jensen, and C. G. Larsen, “Profiles of pro-inflammatory cytokines in the serum of rabbits after experimentally induced acute pancreatitis,” Cytokine, vol. 17, no. 1, pp. 53–59, 2002.
View at: Publisher Site | Google Scholar
M. Carstensen, C. Herder, M. Kivimäki et al., “Accelerated increase in serum interleukin-1 receptor antagonist starts 6 years before diagnosis of type 2 diabetes: whitehall II prospective cohort study,” Diabetes, vol. 59, no. 5, pp. 1222–1227, 2010.
View at: Publisher Site | Google Scholar
C. M. Larsen, M. Faulenbach, A. Vaag et al., “Interleukin-1-receptor antagonist in type 2 diabetes mellitus,” New England Journal of Medicine, vol. 356, no. 15, pp. 1517–1526, 2007.
View at: Publisher Site | Google Scholar
E. J. P. van Asseldonk, R. Stienstra, T. B. Koenen, L. A. B. Joosten, M. G. Netea, and C. J. Tack, “Treatment with Anakinra improves disposition index but not insulin sensitivity in nondiabetic subjects with the metabolic syndrome: a randomized, double-blind, placebo-controlled study,” Journal of Clinical Endocrinology and Metabolism, vol. 96, no. 7, pp. 2119–2126, 2011.
View at: Publisher Site | Google Scholar
I. Aksentijevich, S. L. Masters, P. J. Ferguson et al., “An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist,” New England Journal of Medicine, vol. 360, no. 23, pp. 2426–2437, 2009.
View at: Publisher Site | Google Scholar
S. Herold, T. Tabar, H. Janßen et al., “Exudate macrophages attenuate lung injury by the release of IL-1 receptor antagonist in gram-negative pneumonia,” American Journal of Respiratory and Critical Care Medicine, vol. 183, no. 10, pp. 1380–1390, 2011.
View at: Publisher Site | Google Scholar
J. Banchereau, V. Pascual, and A. O'Garra, “From IL-2 to IL-37: the expanding spectrum of anti-inflammatory cytokines,” Nature Immunology, vol. 13, no. 10, pp. 925–931, 2012.
View at: Google Scholar
M. O. Li and R. A. Flavell, “Contextual regulation of inflammation: a duet by transforming growth factor-β and interleukin-10,” Immunity, vol. 28, no. 4, pp. 468–476, 2008.
View at: Publisher Site | Google Scholar
N. Zamani and C. W. Brown, “Emerging roles for the transforming growth factor-β superfamily in regulating adiposity and energy expenditure,” Endocrine Reviews, vol. 32, no. 3, pp. 387–403, 2011.
View at: Publisher Site | Google Scholar
T. Kempf, A. Guba-Quint, J. Torgerson et al., “Growth differentiation factor 15 predicts future insulin resistance and impaired glucose control in obese nondiabetic individuals: results from the XENDOS trial,” European Journal of Endocrinology, vol. 167, no. 5, pp. 671–678, 2012.
View at: Publisher Site | Google Scholar
G. Vila, M. Riedl, C. Anderwald et al., “The relationship between insulin resistance and the cardiovascular biomarker growth differentiation factor-15 in obese patients,” Clinical Chemistry, vol. 57, no. 2, pp. 309–316, 2011.
View at: Publisher Site | Google Scholar
L. Macia, V. Tsai, A. D. Nguyen et al., “Macrophage inhibitory cytokine 1 (MIC-1/GDF15) decreases food intake, body weight and improves glucose tolerance in mice on normal & obesogenic diets,” PLoS ONE, vol. 7, no. 4, Article ID e34868, 2012.
View at: Publisher Site | Google Scholar
K. Yanaba, Y. Asano, Y. Tada, M. Sugaya, T. Kadono, and S. Sato, “Clinical significance of serum growth differentiation factor-15 levels in systemic sclerosis: association with disease severity,” Modern Rheumatology, vol. 22, no. 5, pp. 668–675, 2012. 22(5): p. 668-675.
View at: Publisher Site | Google Scholar
L. Otvos Jr., E. Haspinger, F. LaRussa et al., “Design and development of a peptide-based adiponectin receptor agonist for cancer treatment,” BMC Biotechnology, vol. 11, p. 90, 2011.
View at: Publisher Site | Google Scholar
M. O. Osman, N. O. Jacobsen, J. U. Kristensen et al., “It 9302, a synthetic interleukin-10 agonist diminishes acute lung injury in rabbits with acute necrotizing pancreatitis,” Surgery, vol. 124, no. 3, pp. 584–592, 1998.
View at: Publisher Site | Google Scholar
M. N. López, B. Pesce, M. Kurte et al., “A synthetic peptide homologous to IL-10 functional domain induces monocyte differentiation to TGF-β+ tolerogenic dendritic cells,” Immunobiology, vol. 216, no. 10, pp. 1117–1126, 2011.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2014 Cheryl Wang. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

4293

Downloads

2289

Citations