BioMed Research International

Volume 2014 (2014), Article ID 658913, 14 pages

http://dx.doi.org/10.1155/2014/658913

Review Article

New Insight into Adiponectin Role in Obesity and Obesity-Related Diseases

Ersilia Nigro,¹ Olga Scudiero,1,2 Maria Ludovica Monaco,¹ Alessia Palmieri,¹ Gennaro Mazzarella,³ Ciro Costagliola,⁴ Andrea Bianco,⁵ and Aurora Daniele1,6

¹CEINGE-Biotecnologie Avanzate Scarl, Via Salvatore 486, 80145 Napoli, Italy

²Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Via De Amicis 95, 80131 Napoli, Italy

³Dipartimento di Scienze Cardio-Toraciche e Respiratorie, Seconda Università degli Studi di Napoli, Via Bianchi 1, 80131 Napoli, Italy

⁴Cattedra di Malattie dell’Apparato Visivo, Dipartimento di Medicina e Scienze della Salute, Università del Molise, Via De Sanctis 1, 86100 Campobasso, Italy

⁵Cattedra di Malattie dell’Apparato Respiratorio, Dipartimento di Medicina e Scienze della Salute, Università del Molise, Via De Sanctis 1, 86100 Campobasso, Italy

⁶Dipartimento di Scienze e Tecnologie Ambientali Biologiche Farmaceutiche, Seconda Università degli Studi di Napoli, Via Vivaldi 42, 81100 Caserta, Italy

Received 2 April 2014; Accepted 12 June 2014; Published 7 July 2014

Academic Editor: Beverly Muhlhausler

Copyright © 2014 Ersilia Nigro et al. 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.

Abstract.

Obesity is a major health problem strongly increasing the risk for various severe related complications such as metabolic syndrome, cardiovascular diseases, respiratory disorders, diabetic retinopathy, and cancer. Adipose tissue is an endocrine organ that produces biologically active molecules defined “adipocytokines,” protein hormones with pleiotropic functions involved in the regulation of energy metabolism as well as in appetite, insulin sensitivity, inflammation, atherosclerosis, cell proliferation, and so forth. In obesity, fat accumulation causes dysregulation of adipokine production that strongly contributes to the onset of obesity-related diseases. Several advances have been made in the treatment and prevention of obesity but current medical therapies are often unsuccessful even in compliant patients. Among the adipokines, adiponectin shows protective activity in various processes such as energy metabolism, inflammation, and cell proliferation. In this review, we will focus on the current knowledge regarding the protective properties of adiponectin and its receptors, AdipoRs (“adiponectin system”), on metabolic complications in obesity and obesity-related diseases. Adiponectin, exhibiting antihyperglycemic, antiatherogenic, and anti-inflammatory properties, could have important clinical benefits in terms of development of therapies for the prevention and/or for the treatment of obesity and obesity-related diseases.

1. Introduction

Obesity is due to excessive fat accumulation that may impair health resulting from social behaviour and environmental and genetic factors [1, 2]. During the last 20 years, obesity has rapidly become a global pandemic health problem: catastrophic data come from America and from Europe where ~35% and ~20% of the population, respectively, are obese [3–5]. Globally, the World Health Organization (WHO) has predicted that, in 2015, ~2,3 billion of adults will be overweight; 700 million will be obese, while ~200 million of school aged children will be obese/overweight (http://www.IASO.org/). The major risk factors for developing obesity are environmental and genetic. In 1962, J. Neel theorized the “thrifty gene hypothesis” to partially explain the rise in obesity-related diseases in the world [6]. According to this, various genes promoting the efficient utilization and storage of fuel would have been favored by natural selection to allow the survival of the human race during famines while today, in times of food abundance, they predispose to obesity and type 2 diabetes mellitus (T2DM) [6]. Genetic alterations predispose to obesity by increasing the risk of disease development by 40–70% [1, 7]. So far, more than 200 candidates’ genes in mice and more than 100 in humans have been implicated in body weight regulation [7, 8]. In particular, the genes responsible for the monogenic form of obesity are leptin, leptin receptor, melanocortin receptor 4, proopiomelanocortin, prohormone convertase 1, and Agouti related protein [9–12]. In addition, the genes having high scores of association with obesity are fat mass and obesity associated, catenin β-like 1, v-maf musculoaponeurotic fibrosarcoma oncogene 7 homolog, transmembrane protein 18, phosphodiesterase related, Niemann-Pick disease type C1, prolactin, and obesity candidate gene G protein β3 [12–14]. Genome-wide association studies identified a number of loci correlated to adult and childhood obesity [15–17]. Moreover, recently, large deletions and duplications that represent copy number variation (CNV) have been linked to the early onset obesity in children [13]. The complexity of the “obesity problem” has become clearer since adipose tissues have been recognized as an endocrine organ that produces biologically active substances defined as “adipokines,” protein hormones with pleiotropic functions in the regulation of energy metabolism as well as in appetite, insulin sensitivity, inflammation, atherosclerosis, and proliferation [18, 19]. Amongst the others, the most biological relevant adipokines are leptin, plasminogen activator inhibitor (PAI-1), tumor necrosis factor (TNF-α), interleukin 6 (IL-6), resistin, and adiponectin [19, 20]. The latter plays a pivotal role in various processes such as energy metabolism, inflammation, and cell proliferation. In this review, we will focus on insulin sensitizing, antiatherogenic, and anti-inflammatory properties of adiponectin and its AdipoRs. We will describe the latest knowledge on the role of adiponectin and its AdipoRs in obesity and obesity-related diseases.

2. Adiponectin

2.1. Biology

Adiponectin, also known as adipocyte complement-related protein of 30 kDa (Acrp30), was identified by different groups [21–24]. Adiponectin is an adipokine abundantly produced and secreted by adipose tissues and widely recognized for its antidiabetic, anti-inflammatory, antiatherogenic, and cardioprotective effects [25–27]. Adiponectin is a protein hormone of 244 amino acids that circulates in high concentrations (5–30 μg/mL) accounting for 0.01% of total serum proteins. Adiponectin expression and serum levels are decreased in obese patients, pigs, and rodents [28, 29]. Sexual dimorphism has been observed in adiponectin expression, with males showing lower levels than females [28]. Adiponectin is synthesized as a monomer of 28–30 kDa that is assembled in homooligomers of various molecular weights: low molecular weight (LMW) trimeric form, medium molecular weight hexameric (MMW), and high molecular weight (HMW) [24, 30]. The monomeric peptide sequence is composed of four regions: an amino-terminal peptide, a short hypervariable region, a collagen-like domain containing 22 Gly-X-Pro or Gly-X-Y repeats, and a carboxy-terminal globular domain C1q like [24]. In serum, the adiponectin monomeric form is present as a full-length form (fAdiponectin) or as a globular form of the protein (gAdiponectin) [31, 32]. gAdiponectin is generated through proteolytic cleavage product of fAdiponectin and contains the globular head without the collagen-like domain enabling the formation of trimers but not HMW oligomers [33, 34]. Recently, it has been observed that the monomeric form stimulates AMPK activation in muscle and increases fatty acid oxidation and peripheral glucose uptake [35]. Furthermore, an increase of the gAdiponectin has been correlated to the improvement of whole-body energy metabolism and of adipose tissue functions [29, 36]. Adiponectin undergoes extensive and complex posttranslational processing critical to the formation and secretion of adiponectin multimers; in humans, the most important modification is a hydroxylation and glycosylation of four conserved lysine residues (lys65, lys68, lys77, and lys101) and/or the hydroxylation of proline residues within the collagenous domain; assembly of human adiponectin oligomers depends on the disulfide bond formation mainly mediated by cysteine 39 [37]. Furthermore, different adiponectin complexes do not interconvert after secretion [38]. Adiponectin homooligomers assembly of different molecular weights is an important process strongly correlated to the biological functions of this adipokine. It is well known that HMW oligomers are the major relevant forms in insulin sensitivity activities of adiponectin and that low amounts of HMW oligomers represent an independent risk factor for metabolic pathologies such as obesity-related diseases [39]. For these reasons, HMW/total adiponectin ratio seem to be more useful than total adiponectin for the assessment of the risk of several diseases including obesity, insulin resistance (IR),T2DM, metabolic syndrome (MetS), and cardiovascular diseases (CVDs) [29, 40–42].

Adiponectin is encoded by APM1 gene (adipose most abundant gene transcript1) composed of three exons spanning 16 kb. APM1 is localized on the long arm of chromosome 3 in the 3q27 region reported as closely associated with various quantitative trait loci (QTL) for the MetS and T2DM [43]. Some rare mutations and specific single-nucleotide polymorphisms (SNPs) have been identified in APM1 gene; the formers are significantly related to T2DM and hypoadiponectinemia while the studies for the SNPs reported controversial results [43–49].

2.2. Adiponectin Receptors

Adiponectin acts through two major functionally distinct and ubiquitously expressed receptors, AdipoR1 and AdipoR2; the former is the most abundant form in skeletal muscle, whereas the latter is the most abundant form in the liver [24]. In addition, AdipoR1 has a very strong affinity for gAdiponectin whereas AdipoR2 has a very strong affinity for fAdiponectin [24]. AdipoR1 and AdipoR2 are seven transmembrane G-protein coupled receptors (GPCRs) but, as members of the PAQR (progestin and AdipoQ receptor) family, the N-terminus end is found in the cytoplasmic region of the cell whereas the C-terminus end is found externally [24]. After adiponectin activation, AdipoR1 and AdipoR2 assemble in both homo- and heterodimeric complexes [24]. Both receptors have a physiological relevance in metabolic processes. Successively in 2004, T-cadherin, a member of the cadherin superfamily, was identified as a potent receptor for hexamers as well as HMW adiponectin oligomers [50]. In conclusion the adiponectin pathway depends on the molecular form of adiponectin, on the relative abundance of its receptors, and on the target tissue [51].

2.3. Adiponectin Actions in Energy Metabolism

Adiponectin exhibits key metabolic functions on skeletal muscle and liver [26]. In muscle, the insulin sensitivity functions of adiponectin are mediated via AMP kinase (AMPK) and peroxisome proliferator-activated receptor α (PPARα) [24, 52]. In liver, adiponectin activates glucose transport and inhibits gluconeogenesis via AMPK, whereas adiponectin activates fatty acid oxidation and decreases inflammation through the PPARα pathway [53]. Interestingly, activation of AMPK seems to be mediated mainly by AdipoR1, whereas activation of PPAR-α seems to be mediated by AdipoR2 [52]. In addition, adiponectin, in liver, enhances insulin sensitivity promoting phosphorylation of the insulin receptor and of the adaptor protein insulin receptor substrate 1 (IRS-1) [52]. In pancreas, adiponectin acts on cell proliferation stimulating insulin secretion [54]. In adipose tissues, adiponectin increases basal glucose uptake and enhances insulin-stimulated glucose uptake through AMPK activation [53]. In addition, in vitro studies demonstrated that adiponectin regulates fat lipid metabolism inhibiting lipolysis [55, 56]. However, a significantly increase of lipolysis is observed in both adiponectin gene knockout mice and primary adipocytes from these mice [55].

2.4. Adiponectin Actions in Inflammation

Adiponectin exhibits protective activity in several inflammatory diseases including atherosclerosis, CVDs, and IR [40, 57, 58]. Moreover, in vitro studies showed that adiponectin attenuates inflammation in endothelial, muscle, epithelial cells, and macrophages mainly by AMPK and cyclic AMP-protein kinase A (cAMP-PKA) activation [59, 60]. Molecular mechanisms of adiponectin may be direct actions on inflammatory cells suppressing reactive oxygen species and stimulating the expression of the anti-inflammatory IL-10 cytokine, suppression of the NF-κB inflammatory signaling pathway, and downregulation of inflammatory responses involving TNF-α [58, 60–63].

2.5. Adiponectin Effects on Cell Proliferation

Recently, in vitro studies have demonstrated adiponectin involvement in various cancer cell types including breast, endometrial, colon, stomach, prostate, and leukemia [64, 65]; Adiponectin, in fact, inhibits cell growth and induces apoptosis in dose-dependent manner both in vitro and in vivo through different molecular pathways (for review, see [66, 67]). Through AMPK stimulation, adiponectin counteracts carcinogenesis by p21 and p53 that in turn regulate growth arrest and apoptosis in colon cancer cells [68, 69]. Moreover, tumor suppressor effects of adiponectin are mediated via AKT and ERK signaling pathways in lung and pancreatic cell lines [55, 60, 67]. However, a potential proliferative and antiapoptotic role of adiponectin has also been suggested by separate investigations [70, 71]. Epidemiologic studies have highlighted associations between decreased adiponectin levels with cancer development with some exceptions. In fact, in patients affected by breast and endometrial cancer, adiponectin levels are decreased; inversely, in patients affected by lung, prostate, gastric, liver, pancreatic and hematological, colon, and renal cancers adiponectin levels are increased.

3. Adiponectin and Obesity

Obesity is a major health problem increasing risk for MetS, CVDs, respiratory disorders, diabetic retinopathy, and cancer. In obese patients, visceral body fat may affect health conditions, through an abnormal production of adipokines. Adiponectin plays a pivotal role in energy metabolism; concentration of both total adiponectin and HMW decreases in obesity and increases after weight loss [28, 29, 72, 73]. In addition, total and HMW adiponectin oligomers are inversely correlated to BMI, glucose, insulin and triglyceride levels, degree of IR, and, importantly, visceral fat accumulation [29]. Numerous studies demonstrated a strong correlation between HMW and several metabolic abnormalities, while the role of MMW and to a lesser extent of LMW oligomers has been poorly investigated [3, 41, 74]. The manner by which adipose tissue expands (increases in size, hypertrophy, and/or in number of cells, hyperplasia) could regulate synthesis and secretion of adiponectin. Drolet et al. demonstrated an inverse relationship between mean adipocytes diameter and adiponectin secretion [75]. AdipoR1 and AdipoR2 expression is significantly decreased in T2DM and obesity state [75]. In obesity and T2DM, alterations in the expression of adiponectin and its AdipoRs reduce adiponectin sensitivity leading to IR which in turn aggravates hyperinsulinemia. After weight loss, adiponectin levels rise together with a specific increase of the most biologically active oligomers HMW. Interestingly, a recent work found that, in severe obesity (BMI ≥ 40 Kg/m²), following weight loss (about 10% weight), not only total and HMW adiponectin, but also the monomeric form levels increase [29]. This finding could suggest a functional recovery of adipose tissue after weight loss in severely obese patients.

Genetic alterations were correlated to adiponectin expression in metabolic diseases [76]; for example, p.G48R, P.Y111H, p.R112C, and p.G90S mutations are strongly associated with low levels of total adiponectin and HMW oligomers in patients affected by T2DM and obesity [43, 45, 46, 77]. Furthermore, 12 SNPs in adiponectin gene (APM1) were identified; some of these SNPs and haplotypes are correlated to hypoadiponectinemia, IR, and increased risk of T2DM [43]. In German and North America subjects, SNP +45 is associated with diabetes and IR; in French subjects, c.11377 and c.11391 SNPs are significantly associated with low levels of adiponectin and T2DM; in Italy, c.11377 SNP resulted to be correlated to adiponectin levels in severe obese patients [43, 47, 78]. Recently, haplotype analysis in 631 non-Hispanic white and 553 African-American subjects identified a strong link between noncontiguous ACDC haplotypes and adiponectin levels [79].

4. Adiponectin and Obesity-Related Diseases

The expansion of adipose tissues results in oxidative stress and inflammatory responses. Moreover, through a cross talk between adipocytes and the immune system, a significant infiltration in adipose tissue of immune and inflammatory cells is generated increasing local and successively systemic levels of various inflammatory cytokines. The dysregulation of cytokines and adipokines production strongly contributes to the onset of several obesity complications as MetS, CVDs, respiratory disorders, diabetic retinopathy, and cancer [80–82]. We will focus on the role of adiponectin.

4.1. Metabolic Syndrome

Metabolic syndrome (MetS), an emerging public health problem, is multiplex metabolic risk factors associated with a 5-fold risk of T2DM and a 2-fold risk of CVDs. Recently, chronic low-grade inflammation has been implicated among the major factors in the development of the MetS [83]. The inflammatory state in MetS is represented by elevated concentrations of a variety of inflammatory regulators such as C-reactive protein, TNF-α, resistin, IL-6, IL-8, visfatin, and adiponectin. The latter is inversely related to both adiposity and proinflammatory cytokines [84]. In addition, it was demonstrated that low HMW adiponectin levels are independently associated with the development of MetS [39]. Furthermore, lower adiponectin levels are found in adult patients, as well as in children with MetS [39]. Conversely, Kim et al. demonstrated that higher adiponectin levels are protective for incident metabolic syndrome in men and women and predict new-onset metabolic syndrome [85]. Recently, it has been demonstrated that, in patients with MetS compared to control subjects, skeletal muscle mRNA expression of AMPKα is lower, whereas the expression of AdipoR1 is upregulated [24]. On the other hand, in vivo studies on genetic overexpression studies or administration of recombinant adiponectin revealed positive metabolic effects [24]. In macrophages, adiponectin supplementation suppresses the production and secretion of proinflammatory cytokines TNF-α and IL-6, decreasing the synthesis of monocyte adhesion molecules in endothelial cells [58]. In parallel, adiponectin enhances the production of anti-inflammatory cytokines in epithelial cells and macrophages [60, 86].

4.2. Hypertension

The relationship between obesity and hypertension is well established and attributed to many factors among which are sympathetic nervous system activation, endothelial dysfunction (caused by increase in free fatty acids, oxidative stress), and an aberrant adipokine production [87]. In fact, lower adiponectin levels are detected in adults with hypertension [85]. Accordingly, total adiponectin levels have been found to be lower in obesity-associated hypertensives than in lean hypertensives or lean normotensives [88]. Iwashima et al. analyzed endothelial function in hypertensive patients, finding a positive correlation between serum adiponectin level and vasodilator response to reactive hyperemia [89]. They also found that, in adiponectin-KO mice, endothelial function is significantly reduced by inhibition of endothelial adhesion molecules as well as macrophage-to-foam cell transformation [89]. Several studies evidenced that adults with hypertension have lower adiponectin levels than normotensive adults and that the increase in adiponectin levels has been associated with reduced risk of hypertension. Adiponectin is a biologically relevant modulator of vascular remodeling linking obesity and vascular disease. Adiponectin protectively regulates blood pressure via brain- and endothelium-mediated mechanisms [89, 90]. In fact, in vitro studies have shown that adiponectin inhibits the expression and the biological effects of TNFα, of adhesion molecules, and the macrophage-to-foam cell transformation [91]. The antiatherogenic properties of adiponectin are mainly due to NO production in endothelial cells, using phosphatidylinositol 3-kinase-dependent pathways, as well as AMPK pathway [89, 90]. The NO production, in physiologic condition, relaxes vessels and exerts anti-inflammation and antithrombotic effects on the vascular wall [92]. In addition, adiponectin decreases smooth muscle cell proliferation and TNFα expression in macrophages [91].

4.3. Chronic Kidney Diseases

Chronic kidney diseases (CKD) and various functional/structural lesions of the kidney (glomerulomegaly, glomerulosclerosis, diabetic nephropathy, carcinoma of the kidney, and nephrolithiasis) are correlated to obesity. The factors that are linked to the development of obesity include, among the others, energy intake and hyperinsulinemia; furthermore, adipokines as leptin and proinflammatory cytokines, as well as adiponectin, may contribute to renal injury [93]. Endothelial dysfunction has been described as the main pathogenic mechanism responsible for CKD while weight loss and restoration of adipokine levels represent crucial factors to ameliorate the progression of renal diseases [94]. In patients with nephrotic syndrome, adiponectin has been found strongly increased, and a direct association with proteinuria has been found [95, 96]. Moreover, a prognostic implication of adiponectin has been hypothesized since hyperadiponectinemia has been associated with mortality in patients with CKD. However, the mechanism by which adiponectin increases in renal failure has not been clarified and the clinical significance of plasma adiponectin level in patients with moderate renal dysfunction is controversial: in vitro studies indicated that adiponectin binds to cystatin C, an inhibitor of the cathepsin family, which abrogates, in a dose-dependent manner, the suppressive effects of adiponectin on adhesion molecules induced by TNF-α-induced [97]. Moreover, in adiponectin knockout mice, Sharma et al. evidenced high levels of microalbuminuria, oxidative stress, and podocyte damage that are reduced after exogenous adiponectin administration [98].

4.4. Atherosclerosis

Multiple mechanisms link obesity with CVDs [82, 99]. Many adipokines mediate the cross talk between adipose tissues, heart, and vasculature in the “adipo-cardiovascular axis”; the altered release of adipokines promotes a prothrombotic state contributing to CVDs and atherosclerosis [19, 100]. Several studies indicate that adiponectin has a beneficial role in CVDs and atherosclerosis. Low serum adiponectin levels are predictors of atherosclerosis and myocardial infarction. In addition, there is a robust association between hypoadiponectinemia and coronary heart disease: clinical trials have confirmed that low levels of adiponectin are associated with higher incidence of cardiovascular events and worse outcome [82]. Interestingly, several studies suggested that the HMW adiponectin is a more accurate independent risk factor for CVDs than total adiponectin level [57, 83]. Serum adiponectin levels have been found to be inversely correlated to a marker of carotid atherosclerosis (intima thickness). However, Sattar et al. reported no significant relationship between serum adiponectin levels and risk of coronary heart disease and another study showed high adiponectin levels as predictor of adverse outcome in patients with acute coronary syndrome [101]. These contradictory results might arise from confounding factors and different oligomers of adiponectin tested. Mice lacking adiponectin have severe neointimal injured arteries, and adiponectin restores neointimal proliferation; moreover, in cultured smooth muscle cells, adiponectin attenuated DNA synthesis induced by growth factors, heparin-binding epidermal growth factor- (EGF-) like growth factor (HB-EGF), basic fibroblast growth factor, and EGF and cell proliferation and migration induced by HB-EGF. In cultured endothelial cells, adiponectin attenuated HB-EGF expression stimulated by tumor necrosis factor alpha [102]. In vitro studies have proved that adiponectin strongly inhibits the production of inflammatory cytokines and adhesion molecules in endothelial cells; in addition adiponectin reduces the transformation of macrophage to foam cells, inhibits TNFα production, and stimulates the production of the anti-inflammatory IL-10 cytokine [103].

4.5. Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is one of the major causes of morbidity and mortality worldwide; systemic inflammation and extrapulmonary comorbidities contribute to the overall disease severity [104–109]. Obesity in COPD is associated with increased symptoms of dyspnoea, poorer health-related quality of life, increased levels of fatigue, and exercise performance limitations [110, 111]. Low BMI is an independent risk factor for mortality in subjects with COPD, and this association is strongest in subjects with severe disease. In humans, adiponectin serum levels are elevated in COPD patients. It is known that levels of total adiponectin are low in smokers without COPD, while high levels are observed in COPD patients [41, 112, 113]. Different studies showed that total serum levels of adiponectin represent a significant diagnostic and prognostic marker of COPD. The oligomerization pattern of adiponectin is altered in COPD; in particular the higher levels of adiponectin are associated with a specific increase of HMW [41, 114]. Protective anti-inflammatory role of HMW oligomers has been demonstrated both in vivo and in vitro studies. We have shown that in A549 cells exposed to TNFα and/or IL1β, adiponectin reduces in dose- and time-dependent manner cytotoxic effects of TNFα and IL1β improving cell viability and decreasing apoptosis [60]. In addition, adiponectin inhibits NF-κB nuclear transactivation and induces the expression of the anti-inflammatory IL10 cytokine via ERK1/2 and AKT through the specific mediation of AdipoR1. Finally, the mouse model lacking adiponectin spontaneously develops a COPD-like phenotype with extrapulmonary effects, including systemic inflammation, body weight loss, and osteoporosis. A protective role of adiponectin on mice lung through inhibition of alveolar macrophage function and vascular homeostasis regulation has been found by Summer et al. [115].

4.6. Obstructive Sleep Apnoea Syndrome

Obstructive sleep apnoea syndrome (OSAS) is a highly prevalent condition characterized by repeated disruptions of breathing during sleep [116]. Obesity is a major risk factor for OSA [116]. Systemic inflammation and oxidative stress are thought to play key roles in the activation of a variety of pathological mechanisms that are involved in OSA, including increased cardiovascular sympathetic tone, impaired regulation of coagulation, impaired glucose metabolism, and endothelial dysfunction. Adiponectin levels are significantly lower in patients with OSAS being related to its severity and arterial oxygen saturation. Hargens et al. confirmed that adiponectin levels are lower in the OSAS patients compared to controls [117]. However, two recent works indicate that adiponectin levels are not affected in OSAS. The lack of clarity regarding the role of adiponectin in OSAS is certainly due to the potential coexistence of confounding factors, such as visceral obesity or IR. It is argued that the decrease of adiponectin in OSAS is due to the intermittent hypoxia which causes a decrease in the secretion of total and HMW adiponectin by adipocytes [118, 119].

4.7. Diabetic Retinopathy

Obesity is a risk factor for diabetic microvascular complications. In fact, the glucose levels in T2DM are responsible for the increased risk of both microvascular (retinopathy, nephropathy, and neuropathy) and macrovascular complications (ischaemic heart disease, stroke, and peripheral vascular disease) [120]. Diabetic retinopathy, the most frequent diabetic microvascular complication, affects 30–50% of all diabetic patients [120]. Circulating levels of adiponectin decrease both in obesity and in T2DM. Moreover, T2DM patients, suffering from diabetic retinopathy (proliferative as well as nonproliferative), show lower levels of adiponectin than matched patients without retinopathy [121]. Additionally, hypoadiponectinemia is positively correlated with the severity of retinopathy in T2DM [122]. Recently, Costagliola et al. analyzed the levels of vascular endothelial growth factor (VEGF) and adiponectin in the aqueous humor of patients with diabetic proliferative retinopathy (PDR) and found that they were significantly higher than those recorded in control subjects [123, 124]. A possible explanation of this finding may be attributed to the increased blood retinal barrier permeability documented in PDR patients [125]. Another possible explanation could be the local reparative response to endothelial dysfunction; in fact, adiponectin induces endothelial nitric oxide production in vitro [126]. Moreover, intravitreal bevacizumab, an angiogenesis inhibitor, significantly reduced the levels of VEGF and adiponectin [123]. The treatment with anti-VEGF agents as bevacizumab significantly reduced macular edema and it is possible that bevacizumab also modulates mediators involved in the pathogenesis of macular edema as adiponectin. This finding could be due to the effect of VEGF inhibition on adipocytes differentiation. In fact, in vivo the inhibition of VEGF receptor affects adipocytes differentiation, with a consequent decrease of adipokines secretion. Thus, it is not surprising that the bevacizumab treatment, through a VEGF inhibition, could be responsible for the reduction of adiponectin levels [127].

4.8. Cancer

Obesity is a risk factor for many cancers [128]. The cross talk between macrophages, adipocytes, and epithelial cells via obesity-associated hormones may enhance cancer risk and/or progression.

Reports from the International Agency for Research into Cancer and the World Cancer Research Fund (WCRF) show that strong evidence exists for an association of obesity with endometrial, esophageal adenocarcinoma, colorectal, postmenopausal breast, prostate, and renal cancers whereas the less common malignancies are leukemia, non-Hodgkin’s lymphoma, multiple myeloma, malignant melanoma, and thyroid tumors [85, 128, 129]. Several obesity-related host factors can influence breast tumor initiation, progression, and/or response to therapy including insulin, insulin-like growth factor-1, leptin, adiponectin, steroid hormones, cytokines, vascular regulators, and inflammation-related molecules [130]. In several human studies, adiponectin has been found to be associated with a number of cancer types: decreased in breast and endometrial cancer but increased in nonsmall cell lung cancer, prostate, gastric, liver, pancreatic, and hematological cancers, colon cancer, and renal cell carcinoma [131–134]. In vitro studies suggested that in certain cancers, such as colorectal, breast, and liver cancers, adiponectin promotes tumor growth, while in others it suppresses it [64]. Moreover, the intracellular pathway underling adiponectin actions has been investigated. It is well established that adiponectin is able to activate several intracellular pathways including AMPK, MAPK, and PI3K/AKT. AMPK interferes with cellular growth signaling through mTOR, thus inhibiting the promotion of carcinogenesis. On the other hand, adiponectin activates AMPK in several cell lines promoting growth arrest and apoptosis via increased p53 and p21 expression. Furthermore, growth factors activate PI3K which results in the phosphorylation of AKT that promotes cellular growth and proliferation. Adiponectin treatment of breast and colorectal cancer cell lines decreases the phosphorylation of PI3K and AKT while the phosphorylation is increased in lung and pancreas cell lines, leading in both cases to a suppression of tumor growth [55, 60, 68]. The superfamily of MAPKs involves c-Jun N-terminal kinases (JNK) and p38 and extracellular signal-regulated kinases (ERK1/2). ERK1/2 is mitogenic, stimulating cell growth. Adiponectin treatment on hepatocellular carcinoma cell line resulted in increased JNK activation while on a lung cell line in ERK1/2 activation and subsequent apoptosis and suppression of cell growth. On the contrary, endometrial and breast cancer cell lines showed that adiponectin inhibited ERK1/2 signaling, resulting in decreased cellular viability [41]. Increased or decreased expression of AdipoRs has been reported in several cell lines and in vivo cancer tissues [41, 135–137]. In addition, AdipoRs expression has been implicated as a prognostic marker for some cancer types since a differential expression was found according to disease stage [135]. Further studies on the role of adiponectin in cancer may facilitate the development of new therapeutic targets.

5. Obesity Treatments

Advances have been made towards the care and prevention of obesity but medical treatments are often unsuccessful even in compliant patients. Today, available treatments include combination of diet, physical exercise, and pharmaceutical regimens where monoagent therapy is not as effective as combination ones. Bariatric surgery is considered the most efficient treatment in severely obese patients (BMI ≥ 40 kg/m²) [138, 139]. Adiponectin, showing antihyperglycemic, antiatherogenic, and anti-inflammatory properties, could have important clinical benefits such us enabling the development of therapies for the prevention and/or for treatment of obesity and its obesity-related diseases.

Various therapeutic approaches are targeted to increase adiponectin expression or its activity with different strategies: (1) caloric restriction and physical exercise, (2) administration of inducers, (3) administration of recombinant adiponectin, and (4) peptide mimetic approaches. Many of these interventions have demonstrated therapeutic benefits in animal models of metabolic diseases (Table 1).

Table 1: Summary of Adiponectin as therapeutic target.

Compound
Category
Main results
Pubblications

Caloric restriction
Increase of adiponectin serum levels.

Decrease of the ratio of TNF to adiponectin.
Salas-Salvadó et al., 2006 [140], Weiss et al., 2006 [141]

Long-term physical exercise
Small to moderate increase in adiponectin levels.

Short-term activity is not determinant.
Simpson and Singh, 2008 [142], Rokling-Andersen et al., 2007 [143]

Caloric restriction + physical exercise
Increase of adiponectin serum levels.

Increase of mRNA of AdipoRs in muscle and adipose tissues, mRNA levels of Adiponectin in adipose tissues and in serum.
Rokling-Andersen et al., 2007 [143], Christiansen et al., 2010 [144]

Curcumin, capsaicin, and 6 gingerol
Adiponectin inducer
Promotion of adiponectin endogenous production.
Yamazaki et al., 2008 [145]

Synthetic and natural products
Adiponectin inducer
Anthocyanin enanches adiponectin secretion. Xanthohumol increases adiponectin levels and attenuates diabetes in mice. Rimonabant significantly elevates adiponectin and reduces waist circumference. Telmisartan increases plasma adiponectin levels. Benzafibrate increases adiponectin levels in adipocytes and in serum of mice. sulfatide increases adiponectin production in adipocytes. Catechins enhance the expression and secretion of adiponectin in dose and time dependent manner in adipocytes.
Tsuda et al., 2004 [146], Nozawa, 2005 [147], Moriuchi et al., 2007 [148], Hiuge et al., 2007 [149], Bruun et al., 2007 [150]

Metformin
Adiponectin inducer
Increase of adiponectin serum levels and reduction of BMI and insulin resistance.
Adamia et al., 2007 [151]

Statins
Adiponectin inducer
Increase of adiponectin levels.
Sahebkar, 2013 [152]

Thiazolidinedione (TZD)
Adiponectin inducer
Increase of AdipoRs receptors in adipocytes and macrophages.

Increase of adiponectin secretion from adipocytes and of both serum adiponectin concentration and ratio of HMW/total adiponectin.
Tsuchida et al., 2005 [153]; Phillips et al., 2008 [154]; M. Liu and F. Liu, 2009 [155]

fAdiponectin
Recombinant adiponectin
Correction of amino acids metabolism altered by high-fat diet.

Protection against injury in pig with myocardial ischemia-reperfusion through suppression of inflammation, apoptosis, and oxidative stress.
Liu et al., 2013 [156], Kondo et al., 2010 [157]

gAdiponectin
Recombinant adiponectin
Decrease of plasma free fatty acids levels in mice. Induction of weight reduction in mice on high/fat/sucrose diet.

Amelioration of atherosclerosis.
Fruebis et al., 2001 [31], Yamauchi et al., 2003 [158]

gAdiponectin fused to Fc fragment
Recombinant adiponectin
Improve of the fasting glucose levels and of the tolerance to glucose in mice.
Ge et al., 2010 [33]

ADP 355
AdipoRs agonist
Suppression of tumor growth in cancer cell lines and mice.
Otvos et al., 2011 [159]

Natural compounds library (9 compounds validated)
AdipoRs agonists
agonist demonstrated by in vitro tests.
Sun et al., 2013 [160]

AdipoRon
AdipoRs agonist
Amelioration of diabetes in genetically obese rodents and prolongation of the shortness life span of rodents on high-fat diet.
Okada-Iwabu et al., 2013 [161]

(1) Caloric Restriction and Physical Exercise. Caloric restriction increases adiponectin gene expression in humans and animals. In fact, reduction of ~10 to 20% weight in obese subjects significantly increased the expression of adiponectin in WAT and in serum [140]. A statistically relevant increase in adiponectin levels has also been found in response to specific diet regimens: low-fat diet, daily supplementation of fish or omega 3, and fiber supplementation [162–166]. However, adiponectin levels, in most studies, are not modified by regular exercise without diet restriction [167, 168]. Current evidence indicates a possible synergistic effect of physical activity and calorie-restricted diet on adiponectin and its oligomers modulation [143]. However, exercise without significant weight loss does not appear to improve adiponectin levels [142, 143]. In conclusion, dietary management can be an effective therapeutic mean of increasing adiponectin levels. Similar to humans, caloric restriction increases adiponectin gene expression and circulating levels in animal models [169].

(2) Administration of Inducers. Drugs like rosiglitazone and pioglitazone, belonging to the thiazolidinedione (TZD) class of PPARγ agonists, have been clinically and experimentally proven to be potent inducers of adiponectin expression [153–155]; accordingly, many of the metabolic effects of rosiglitazone or pioglitazone are absent and/or decreased in adiponectin knockout mice. Recently, statins have been reported to increase circulating adiponectin levels [152]. Metformin (MET) improves peripheral insulin sensitivity and increases insulin mediated skeletal muscle glucose uptake. However, there are studies showing that MET has no effect on intracellular levels and secretion of adiponectin. Further studies will be needed to address these controversies [151]. Several new synthetic drugs such as telmisartan, bezafibrate, rimonabant, and natural products such as anthocyanin, xanthohumol, catechins, and sulfatide have been reported to enhance adiponectin production [146–150]. Recently, curcumin, the components of ginger and red pepper, [6] gingerol, and capsaicin have been identified as stimulators of adiponectin production in mouse and human adipocytes and lowered blood glucose and triglyceride levels in mice [145].

(3) Administration of Recombinant Adiponectin. Recombinant adiponectin supplementation has been tested in different animal studies. Liu et al. analyzed adiponectin administration in adiponectin knockout mice after high-fat diet feeding and found amelioration in metabolic profile (glucose handling, insulin signaling, triglycerides levels, and mitochondrial structure and function) [156]. Moreover, Kondo et al. demonstrated in mice and in pig models that adiponectin protects against ischemia/reperfusion injury through its ability to suppress inflammation, apoptosis, and oxidative stress [157]. However, lack of an easy, cost efficient production of the recombinant full-length adiponectin and its brief circulating half-life represents limits to its therapeutic use. Therefore, many researchers have focused on the production of adiponectin variant containing only the C-terminal globular domain [31, 158]. Ge et al. generated an alternative globular adiponectin consisting of three monomers fused to an Fc fragment; the combined effects of single-chain and Fc fusion improved the serum half-life from less than 2 h to close to 2 weeks [33].

(4) Peptide Mimetic Approaches. The difficulty of converting adiponectin into a viable drug has been demonstrated; therefore, these days, AdipoRs activation is showing one of the most promising novel therapeutic approaches for treating obesity-related disorders. Otvos et al. found the first-in-class adiponectin receptor agonist, ADP 355 [159]. Sun et al. recently identified, through a high throughput screening against a natural compounds library, nine AdipoRs agonists [160]. Four of them, matairesinol, arctiin, (-)-arctigenin, and gramine, show high affinity for AdipoR1. Four of these compounds, parthenolide, taxifoliol, deoxyschizandrin, and syringing, show high affinity for AdipoR2 [160]. Recently, Okada-Iwabu et al. identified a small AdipoRs agonist, AdipoRon that, in vitro, binds to both AdipoR1 and AdipoR2 with high affinity [161]. AdipoRon improves, in different mice models, IR and glucose tolerance showing very similar effects to adiponectin.

6. Conclusions

Obesity is a pandemic condition that leads to health impairment by increasing the risk of developing diseases such as T2DM, MetS, CVDs, respiratory disorders, and several types of cancer. The molecular mechanism underlying the development and establishment of obesity needs to be better understood. At present, it is well recognized that fat accumulation in obesity results in an altered expression of several hormones, growth factors, and adipokines. Adiponectin may act as a protective and safe endocrine/paracrine/autocrine factor to prevent the establishment and/or progression of lethal conditions related to obesity. Currently, obesity therapeutic regimes include diet therapy, exercise, and behavior modifications but are often associated with poor treatment outcome and therefore new molecular therapeutic targets need to be investigated. In this context, expression enhancement of adiponectin and its AdipoRs may represent a useful therapeutic approach against obesity and obesity-related diseases. Further research is needed to better understand the pathophysiological role of adiponectin in obesity and obesity-related disorders and to clarify the potential clinical application in humans.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

Acknowledgments

This study was supported by the Regione Campania (DGRC n. 1901 del 22/12/2009), the MIUR (Grant number: PS35-126/IND), the IRCCS-SDN Foundation, and the Ministero della Salute. We thank Susan Campbell for editing the text and Vittorio Lucignano.

References

S. M. Wright and L. J. Aronne, “Causes of obesity,” Abdominal Imaging, vol. 37, no. 5, pp. 730–732, 2012.

J. M. Friedman, “Obesity in the new millennium,” Nature, vol. 404, no. 6778, pp. 632–634, 2000.

K. R. Fitzgerald, “Review of article: prevalence of obesity and trends in the distribution of body mass index among US adults, 1999-2010 by Katherine M. Flegal, PhD; Margaret D. Carroll, MSPH; Brian K. Kit, MD; Cynthia L. Ogden, PhD (JAMA 2012;307:491-7),” Journal of Vascular Nursing, vol. 31, no. 3, pp. 131–132, 2013.

T. H. I. Fakhouri, C. L. Ogden, M. D. Carroll, B. K. Kit, and K. M. Flegal, “Prevalence of obesity among older adults in the United States, 2007–2010.,” National Center for Health Statistics Data Brief, no. 106, pp. 1–8, 2012.

A. Berghöfer, T. Pischon, T. Reinhold, C. M. Apovian, A. M. Sharma, and S. N. Willich, “Obesity prevalence from a European perspective: a systematic review,” BMC Public Health, vol. 8, article 200, 2008.

C. N. Hales and D. J. P. Barker, “The thrifty phenotype hypothesis,” British Medical Bulletin, vol. 60, pp. 5–20, 2001.

N. Srivastava, R. Lakhan, and B. Mittal, “Pathophysiology and genetics of obesity,” Indian Journal of Experimental Biology, vol. 45, no. 11, pp. 929–936, 2007.

Q. Xia and S. F. A. Grant, “The genetics of human obesity,” Annals of the New York Academy of Sciences, vol. 1281, no. 1, pp. 178–190, 2013.

A. Alfieri, F. Pasanisi, S. Salzano et al., “Functional analysis of melanocortin-4-receptor mutants identified in severely obese subjects living in Southern Italy,” Gene, vol. 457, no. 1-2, pp. 35–41, 2010.

N. Kakar, J. Ahmad, C. Kubisch, and G. Borck, “Exon skipping and severe childhood-onset obesity caused by a leptin receptor mutation,” American Journal of Medical Genetics A, vol. 161, no. 10, pp. 2672–2674, 2013.

I. S. Farooqi, S. Drop, A. Clements et al., “Heterozygosity for a POMC-null mutation and increased obesity risk in humans,” Diabetes, vol. 55, no. 9, pp. 2549–2553, 2006.

G. Argyropoulos, T. Rankinen, D. R. Neufeld et al., “A polymorphism in the human agouti-related protein is associated with late-onset obesity,” The Journal of Clinical Endocrinology and Metabolism, vol. 87, no. 9, pp. 4198–4202, 2002.

I. S. Goldlust, K. E. Hermetz, L. M. Catalano, et al., “Mouse model implicates GNB3 duplication in a childhood obesity syndrome,” Proceedings of the National Academy of Sciences, vol. 110, no. 37, pp. 14990–14994, 2013.

C. J. Willer, E. K. Speliotes, and R. J. Loos, “Six new loci associated with body mass index highlight a neuronal influence on body weight regulation,” Nature Genetics, vol. 41, no. 1, pp. 25–34, 2009.

J. Cao, N. Puri, K. Sodhi, L. Bellner, N. G. Abraham, and A. Kappas, “Apo A1 mimetic rescues the diabetic phenotype of HO-2 knockout mice via an increase in HO-1 adiponectin and LKBI signaling pathway,” International Journal of Hypertension, vol. 2012, Article ID 628147, 8 pages, 2012.

E. K. Speliotes, C. J. Willer, and S. I. Berndt, “Association analyses of 249, 796 individuals reveal eighteen new loci associated with body mass index,” Nature Genetics, vol. 42, no. 11, pp. 937–948, 2010.

G. Thorleifsson, G. B. Walters, D. F. Gudbjartsson et al., “Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity,” Nature Genetics, vol. 41, no. 1, pp. 18–24, 2009.

V. Mohamed-Ali, J. H. Pinkney, and S. W. Coppack, “Adipose tissue as an endocrine and paracrine organ,” International Journal of Obesity, vol. 22, no. 12, pp. 1145–1158, 1998.

G. Rega-Kaun, C. Kaun, and J. Wojta, “More than a simple storage organ: adipose tissue as a source of adipokines involved in cardiovascular disease,” Thrombosis and Haemostasis, vol. 110, no. 4, pp. 641–50, 2013.

H. Kwon and J. E. Pessin, “Adipokines mediate inflammation and insulin resistance,” Frontiers in Endocrinology, vol. 4, article 71, 2013.

P. E. Scherer, S. Williams, M. Fogliano, G. Baldini, and H. F. Lodish, “A novel serum protein similar to C1q, produced exclusively in adipocytes,” The Journal of Biological Chemistry, vol. 270, no. 45, pp. 26746–26749, 1995.

K. Maeda, K. Okubo, I. Shimomura, T. Funahashi, Y. Matsuzawa, and K. Matsubara, “cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (adipose most abundant gene transcript 1),” Biochemical and Biophysical Research Communications, vol. 221, no. 2, pp. 286–289, 1996.

Y. Nakano, T. Tobe, N. Choi-Miura, T. Mazda, and M. Tomita, “Isolation and characterization of GBP28, a novel gelatin-binding protein purified from human plasma,” Journal of Biochemistry, vol. 120, no. 4, pp. 803–812, 1996.

T. Kadowaki and T. Yamauchi, “Adiponectin and adiponectin receptors,” Endocrine Reviews, vol. 26, no. 3, pp. 439–451, 2005.

P. A. Kern, G. B. di Gregorio, T. Lu, N. Rassouli, and G. Ranganathan, “Adiponectin expression from human adipose tissue: relation to obesity, insulin resistance, and tumor necrosis factor-α expression,” Diabetes, vol. 52, no. 7, pp. 1779–1785, 2003.

B. Lee and J. Shao, “Adiponectin and energy homeostasis,” Reviews in Endocrine and Metabolic Disorders, vol. 15, no. 2, pp. 149–156, 2014.

K. Ohashi, N. Ouchi, and Y. Matsuzawa, “Anti-inflammatory and anti-atherogenic properties of adiponectin,” Biochimie, vol. 94, no. 10, pp. 2137–2142, 2012.

A. Daniele, R. Cammarata, M. Masullo et al., “Analysis of adiponectin gene and comparison of its expression in two different pig breeds,” Obesity, vol. 16, no. 8, pp. 1869–1874, 2008.

A. de Rosa, M. Ludovica Monaco, M. Capasso et al., “Adiponectin oligomers as potential indicators of adipose tissue improvement in obese subjects,” European Journal of Endocrinology, vol. 169, no. 1, pp. 37–43, 2013.

T. Schraw, Z. V. Wang, N. Halberg, M. Hawkins, and P. E. Scherer, “Plasma adiponectin complexes have distinct biochemical characteristics,” Endocrinology, vol. 149, no. 5, pp. 2270–2282, 2008.

J. Fruebis, T. S. Tsao, S. Javorschi et al., “Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 4, pp. 2005–2010, 2001.

K. Kishida, H. Nagaretani, H. Kondo et al., “Disturbed secretion of mutant adiponectin associated with the metabolic syndrome,” Biochemical and Biophysical Research Communications, vol. 306, no. 1, pp. 286–292, 2003.

H. Ge, Y. Xiong, B. Lemon et al., “Generation of novel long-acting globular adiponectin molecules,” Journal of Molecular Biology, vol. 399, no. 1, pp. 113–119, 2010.

H. Waki, T. Yamauchi, J. Kamon et al., “Generation of globular fragment of adiponectin by leukocyte elastase secreted by monocytic cell line THP-1,” Endocrinology, vol. 146, no. 2, pp. 790–796, 2005.

G. Almer, M. Saba-Lepek, S. Haj-Yahya, et al., “Globular domain of adiponectin: promising target molecule for detection of atherosclerotic lesions,” Biologics, vol. 5, pp. 95–105, 2011.

J. P. Wen, C. E. Liu, Y. T. Hu, G. Chen, and L. X. Lin, “Globular adiponectin regulates energy homeostasis through AMP-activated protein kinase-acetyl-CoA carboxylase (AMPK/ACC) pathway in the hypothalamus,” Molecular and Cellular Biochemistry, vol. 344, no. 1-2, pp. 109–115, 2010.

U. B. Pajvani, X. Du, T. P. Combs et al., “Structure-function studies of the adipocyte-secreted hormone Acrp30/adiponectin: Implications for metabolic regulation and bioactivity,” The Journal of Biological Chemistry, vol. 278, no. 11, pp. 9073–9085, 2003.

F. Simpson and J. P. Whitehead, “Adiponectin—it’s all about the modifications,” The International Journal of Biochemistry & Cell Biology, vol. 42, no. 6, pp. 785–788, 2010.

E. K. Calton, V. S. Miller, and M. J. Soares, “Factors determining the risk of the metabolic syndrome: is there a central role for adiponectin?” The European Journal of Clinical Nutrition, vol. 67, no. 5, pp. 485–491, 2013.

A. Daniele, A. de Rosa, M. de Cristofaro et al., “Decreased concentration of adiponectin together with a selective reduction of its high molecular weight oligomers is involved in metabolic complications of myotonic dystrophy type 1,” European Journal of Endocrinology, vol. 165, no. 6, pp. 969–975, 2011.

A. Daniele, A. De Rosa, E. Nigro et al., “Adiponectin oligomerization state and adiponectin receptors airway expression in chronic obstructive pulmonary disease,” The International Journal of Biochemistry and Cell Biology, vol. 44, no. 3, pp. 563–569, 2012.

M. Liu and F. Liu, “Up- and down-regulation of adiponectin expression and multimerization: mechanisms and therapeutic implication,” Biochimie, vol. 94, no. 10, pp. 2126–2130, 2012.

F. Vasseur, N. Helbecque, C. Dina et al., “Single-nucleotide polymorphism haplotypes in the both proximal promoter and exon 3 of the APM1 gene modulate adipocyte-secreted adiponectin hormone levels and contribute to the genetic risk for type 2 diabetes in French Caucasians,” Human Molecular Genetics, vol. 11, no. 21, pp. 2607–2614, 2002.

K. Hara, P. Boutin, Y. Mori et al., “Genetic variation in the gene encoding adiponectin is associated with an increased risk of type 2 diabetes in the Japanese population,” Diabetes, vol. 51, no. 2, pp. 536–540, 2002.

H. Waki, T. Yamauchi, J. Kamon et al., “Impaired multimerization of human adiponectin mutants associated with diabetes. Molecular structure and multimer formation of adiponectin,” The Journal of Biological Chemistry, vol. 278, no. 41, pp. 40352–40363, 2003.

H. Kondo, I. Shimomura, Y. Matsukawa et al., “Association of adiponectin mutation with type 2 diabetes: a candidate gene for the insulin resistance syndrome,” Diabetes, vol. 51, no. 7, pp. 2325–2328, 2002.

A. Daniele, R. Cammarata, F. Pasanisi et al., “Molecular analysis of the adiponectin gene in severely obese patients from Southern Italy,” Annals of Nutrition and Metabolism, vol. 53, no. 3-4, pp. 155–161, 2009.

R. Bracale, G. Labruna, C. Finelli et al., “The absence of polymorphisms in ADRB3, UCP1, PPAR, and ADIPOQ genes protects morbid obese patients toward insulin resistance,” Journal of Endocrinological Investigation, vol. 35, no. 1, pp. 2–4, 2012.

V. J. Bermúdez, E. Rojas, A. Toledo et al., “Single-nucleotide polymorphisms in adiponectin, AdipoR1, and AdipoR2 genes: Insulin resistance and type 2 diabetes mellitus candidate genes,” American Journal of Therapeutics, vol. 20, no. 4, pp. 414–421, 2013.

C. Hug, J. Wang, N. S. Ahmad, J. S. Bogan, T. S. 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.

T. Yamauchi, Y. Nio, T. Maki et al., “Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions,” Nature Medicine, vol. 13, no. 3, pp. 332–339, 2007.

R. Ye and P. E. Scherer, “Adiponectin, driver or passenger on the road to insulin sensitivity?” Molecular Metabolism, vol. 2, no. 3, pp. 133–141, 2013.

X. Wu, H. Motoshima, K. Mahadev, T. J. Stalker, R. Scalia, and B. J. Goldstein, “Involvement of AMP-activated protein kinase in glucose uptake stimulated by the globular domain of adiponectin in primary rat adipocytes,” Diabetes, vol. 52, no. 6, pp. 1355–1363, 2003.

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.

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,” The Journal of Biological Chemistry, vol. 285, no. 44, pp. 33623–33631, 2010.

Z. Wedellová, J. Dietrich, M. Šiklová-Vítková et al., “Adiponectin inhibits spontaneous and catecholamine-induced lipolysis in human adipocytes of non-obese subjects through AMPK-dependent mechanisms,” Physiological Research, vol. 60, no. 1, pp. 139–148, 2011.

M. T. Villarreal-Molina and B. Antuna-Puente, “Adiponectin: anti-inflammatory and cardioprotective effects,” Biochimie, vol. 94, no. 10, pp. 2143–2149, 2012.

N. Ouchi and K. Walsh, “Adiponectin as an anti-inflammatory factor,” Clinica Chimica Acta, vol. 380, no. 1-2, pp. 24–30, 2007.

A. Subedi and P. H. Park, “Autocrine and paracrine modulation of microRNA-155 expression by globular adiponectin in RAW 264.7 macrophages: involvement of MAPK/NF-κB pathway,” Cytokine, vol. 64, no. 3, pp. 638–641, 2013.

E. Nigro, O. Scudiero, D. Sarnataro et al., “Adiponectin affects lung epithelial A549 cell viability counteracting TNFa and IL-1ß toxicity through AdipoR1,” International Journal of Biochemistry and Cell Biology, vol. 45, no. 6, pp. 1145–1153, 2013.

N. Ouchi, M. Ohishi, S. Kihara et al., “Association of hypoadiponectinemia with impaired vasoreactivity,” Hypertension, vol. 42, no. 3, pp. 231–234, 2003.

R. Shibata, N. Ouchi, S. Kihara, K. Sato, T. Funahashi, and K. Walsh, “Adiponectin stimulates angiogenesis in response to tissue ischemia through stimulation of AMP-activated protein kinase signaling,” Journal of Biological Chemistry, vol. 279, no. 27, pp. 28670–28674, 2004.

H. Kobayashi, N. Ouchi, S. Kihara et al., “Selective suppression of endothelial cell apoptosis by the high molecular weight form of adiponectin.,” Circulation research, vol. 94, no. 4, pp. e27–31, 2004.

M. Dalamaga, K. N. Diakopoulos, and C. S. Mantzoros, “The role of adiponectin in cancer: a review of current evidence,” Endocrine Reviews, vol. 33, no. 4, pp. 547–594, 2012.

S. Obeid and L. Hebbard, “Role of adiponectin and its receptors in cancer,” Cancer Biology and Medicine, vol. 9, no. 4, pp. 213–220, 2012.

K. Lang and J. Ratke, “Leptin and Adiponectin: new players in the field of tumor cell and leukocyte migration,” Cell Communication and Signaling, vol. 7, article 27, 2009.

M. P. Scheid and G. Sweeney, “The role of adiponectin signaling in metabolic syndrome and cancer,” Reviews in Endocrine and Metabolic Disorders, vol. 15, no. 2, pp. 157–167, 2013.

A. Y. Kim, Y. S. Lee, K. H. Kim et al., “Adiponectin represses colon cancer cell proliferation via AdipoR1- and -R2-mediated AMPK activation,” Molecular Endocrinology, vol. 24, no. 7, pp. 1441–1452, 2010.

M. R. Nalabolu, K. Palasamudram, and K. Jamil, “Adiponectin and leptin molecular actions and clinical significance in breast cancer,” International Journal of Hematology-Oncology and Stem Cell Research, vol. 8, no. 1, pp. 31–40, 2014.

O. O. Ogunwobi and I. L. P. Beales, “Adiponectin stimulates proliferation and cytokine secretion in colonic epithelial cells,” Regulatory Peptides, vol. 134, no. 2-3, pp. 105–113, 2006.

M. H. Lee, R. L. Klein, H. M. El-Shewy, D. K. Luttrell, and L. M. Luttrell, “The adiponectin receptors AdipoR1 and AdipoR2 activate ERK1/2 through a Src/Ras-dependent pathway and stimulate cell growth,” Biochemistry, vol. 47, no. 44, pp. 11682–11692, 2008.

S. Kaser, T. Tatarczyk, A. Stadlmayr et al., “Effect of obesity and insulin sensitivity on adiponectin isoform distribution,” European Journal of Clinical Investigation, vol. 38, no. 11, pp. 827–834, 2008.

L. K. Meyer, T. P. Ciaraldi, R. R. Henry, A. C. Wittgrove, and S. A. Phillips, “Adipose tissue depot and cell size dependency of adiponectin synthesis and secretion in human obesity,” Adipocyte, vol. 2, no. 4, pp. 217–226, 2013.

M. P. Hamilton, M. O. Gore, C. R. Ayers, X. Wu, D. K. McGuire, and P. E. Scherer, “Adiponectin and cardiovascular risk profile in patients with type 2 diabetes mellitus: Parameters associated with adiponectin complex distribution,” Diabetes and Vascular Disease Research, vol. 8, no. 3, pp. 190–194, 2011.

R. Drolet, C. Bélanger, M. Fortier et al., “Fat depot-specific impact of visceral obesity on adipocyte adiponectin release in women,” Obesity, vol. 17, no. 3, pp. 424–430, 2009.

K. Ramya, K. A. Ayyappa, S. Ghosh, V. Mohan, and V. Radha, “Genetic association of ADIPOQ gene variants with type 2 diabetes, obesity and serum adiponectin levels in south Indian population,” Gene, vol. 532, no. 2, pp. 253–262, 2013.

T. I. Pollin, K. Tanner, J. R. O'Connell et al., “Linkage of plasma adiponectin levels to 3q27 explained by association with variation in the APM1 gene,” Diabetes, vol. 54, no. 1, pp. 268–274, 2005.

M. Stumvoll, O. Tschritter, A. Fritsche et al., “Association of the T-G polymorphism in adiponectin (Exon 2) with obesity and insulin sensitivity: interaction with family history of type 2 diabetes,” Diabetes, vol. 51, no. 1, pp. 37–41, 2002.

J. G. Woo, L. M. Dolan, R. Deka et al., “Interactions between noncontiguous haplotypes in the adiponectin gene ACDC are associated with plasma adiponectin,” Diabetes, vol. 55, no. 2, pp. 523–529, 2006.

G. de Pergola and F. Silvestris, “Obesity as a major risk factor for cancer,” Journal of Obesity, vol. 2013, Article ID 291546, 11 pages, 2013.

A. Avogaro and S. V. de Kreutzenberg, “Mechanisms of endothelial dysfunction in obesity,” Clinica Chimica Acta, vol. 360, no. 1-2, pp. 9–26, 2005.

C. M. Diaz-Melean, V. K. Somers, and J. P. Rodriguez-Escudero, “Mechanisms of adverse cardiometabolic consequences of obesity,” Current Atherosclerosis Reports, vol. 15, no. 11, p. 364, 2013.

M. Matsuda and I. Shimomura, “Roles of adiponectin and oxidative stress in obesity-associated metabolic and cardiovascular diseases,” Reviews in Endocrine and Metabolic Disorders, vol. 15, no. 1, pp. 1–10, 2014.

M. Cnop, P. J. Havel, K. M. Utzschneider et al., “Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex,” Diabetologia, vol. 46, no. 4, pp. 459–469, 2003.

N. H. Kim, N. H. Cho, C. H. Yun, et al., “Association of obstructive sleep apnea and glucose metabolism in subjects with or without obesity,” Diabetes Care, vol. 36, no. 12, pp. 3909–3915, 2013.

A. M. Wolf, D. Wolf, H. Rumpold, B. Enrich, and H. Tilg, “Adiponectin induces the anti-inflammatory cytokines IL-10 and IL-1RA in human leukocytes,” Biochemical and Biophysical Research Communications, vol. 323, no. 2, pp. 630–635, 2004.

H. Demirci, C. Nuhoglu, I. S. Ursavas, S. Isildak, E. O. Basaran, and M. Y. Kilic, “Obesity and asymptomatic hypertension among children aged 6–13 years living in Bursa, Turkey,” Family Practice, vol. 30, no. 6, pp. 629–633, 2013.

N. Ouchi, S. Kihara, T. Funahashi, Y. Matsuzawa, and K. Walsh, “Obesity, adiponectin and vascular inflammatory disease,” Current Opinion in Lipidology, vol. 14, no. 6, pp. 561–566, 2003.

Y. Iwashima, T. Katsuya, K. Ishikawa et al., “Hypoadiponectinemia is an independent risk factor for hypertension,” Hypertension, vol. 43, no. 6, pp. 1318–1323, 2004.

T. Di Chiara, A. Licata, C. Argano, G. Duro, S. Corrao, and R. Scaglione, “Plasma adiponectin: a contributing factor for cardiac changes in visceral obesity-associated hypertension,” Blood Pressure, vol. 23, no. 3, pp. 147–153, 2014.

N. Ouchi, S. Kihara, Y. Arita et al., “Adipocyte-derived plasma protein, adiponectin, suppresses lipid accumulation and class A scavenger receptor expression in human monocyte-derived macrophages,” Circulation, vol. 103, no. 8, pp. 1057–1063, 2001.

Z. Chen, I. Peng, W. Sun et al., “AMP-activated protein kinase functionally phosphorylates endothelial nitric oxide synthase ser633,” Circulation Research, vol. 104, no. 4, pp. 496–505, 2009.

A. V. Mathew, S. Okada, and K. Sharma, “Obesity related kidney disease,” Current Diabetes Reviews, vol. 7, no. 1, pp. 41–49, 2011.

M. Tesauro, A. Mascali, O. Franzese, S. Cipriani, C. Cardillo, and N. di Daniele, “Chronic kidney disease, obesity, and hypertension: the role of leptin and adiponectin,” International Journal of Hypertension, vol. 2012, Article ID 943605, 7 pages, 2012.

V. Menon, L. Li, X. Wang et al., “Adiponectin and mortality in patients with chronic kidney disease,” Journal of the American Society of Nephrology, vol. 17, no. 9, pp. 2599–2606, 2006.

S. A. Bakkaloglu, O. Soylemezoglu, N. Buyan et al., “High serum adiponectin levels during steroid-responsive nephrotic syndrome relapse,” Pediatric Nephrology, vol. 20, no. 4, pp. 474–477, 2005.

N. Komura, S. Kihara, M. Sonoda et al., “Increment and impairment of adiponectin in renal failure,” Cardiovascular Research, vol. 86, no. 3, pp. 471–477, 2010.

K. Sharma, S. RamachandraRao, G. Qiu et al., “Adiponectin regulates albuminuria and podocyte function in mice,” The Journal of Clinical Investigation, vol. 118, no. 5, pp. 1645–1656, 2008.

Y. Shimamoto, M. Mizukoshi, A. Kuroi, et al., “Is visceral fat really a coronary risk factor?” International Heart Journal, vol. 54, no. 5, pp. 273–278, 2013.

S. H. Choi, E. S. Hong, and S. Lim, “Clinical implications of adipocytokines and newly emerging metabolic factors with relation to insulin resistance and cardiovascular health,” Frontiers in Endocrinology, vol. 4, article 97, 2013.

N. Sattar, P. Watt, L. Cherry, S. Ebrahim, G. D. Smith, and D. A. Lawlor, “High molecular weight adiponectin is not associated with incident coronary heart disease in older women: a nested prospective case-control study,” The Journal of Clinical Endocrinology and Metabolism, vol. 93, no. 5, pp. 1846–1849, 2008.

M. Matsuda, I. Shimomura, M. Sata et al., “Role of adiponectin in preventing vascular stenosis. The missing link of adipo-vascular axis,” Journal of Biological Chemistry, vol. 277, no. 40, pp. 37487–37491, 2002.

N. Ouchi and K. Walsh, “Cardiovascular and metabolic regulation by the adiponectin/C1q/tumor necrosis factor-related protein family of proteins,” Circulation, vol. 125, no. 25, pp. 3066–3068, 2012.

G. Mazzarella, V. Esposito, A. Bianco et al., “Inflammatory effects on human lung epithelial cells after exposure to diesel exhaust micron sub particles (PM1.0) and pollen allergens,” Environmental Pollution, vol. 161, pp. 64–69, 2012.

V. Esposito, A. Lucariello, L. Savarese et al., “Morphology changes in human lung epithelial cells after exposure to diesel exhaust micron sub particles (PM1.0) and pollen allergens,” Environmental Pollution, vol. 171, pp. 162–167, 2012.

G. Mazzarella, F. Ferraraccio, M. V. Prati et al., “Effects of diesel exhaust particles on human lung epithelial cells: an in vitro study,” Respiratory Medicine, vol. 101, no. 6, pp. 1155–1162, 2007.

E. Grella, G. Paciocco, U. Caterino, and G. Mazzarella, “Respiratory function and atmospheric pollution,” Monaldi Archives for Chest Disease, vol. 57, no. 3-4, pp. 196–199, 2002.

G. de Laurentiis, D. Paris, D. Melck et al., “Separating smoking-related diseases using NMR-based metabolomics of exhaled breath condensate,” Journal of Proteome Research, vol. 12, no. 3, pp. 1502–1511, 2013.

G. Corbi, A. Bianco, V. Turchiarelli et al., “Potential mechanisms linking atherosclerosis and increased cardiovascular risk in COPD: focus on sirtuins,” International Journal of Molecular Sciences, vol. 14, no. 6, pp. 12696–12713, 2013.

L. M. Cecere, A. J. Littman, C. G. Slatore et al., “Obesity and COPD: associated symptoms, health-related quality of life, and medication use,” Journal of Chronic Obstructive Pulmonary Disease, vol. 8, no. 4, pp. 275–284, 2011.

F. M. E. Franssen, D. E. O'Donnell, G. H. Goossens, E. E. Blaak, and A. M. W. J. Schols, “Obesity and the lung: 5 · Obesity and COPD,” Thorax, vol. 63, no. 12, pp. 1110–1117, 2008.

A. Bianco, G. Mazzarella, V. Turchiarelli, et al., “Adiponectin: an attractive marker for metabolic disorders in Chronic Obstructive Pulmonary Disease (COPD),” Nutrients, vol. 5, no. 10, pp. 4115–4125, 2013.

K. H. Chan, S. C. Yeung, T. J. Yao et al., “Elevated plasma adiponectin levels in patients with chronic obstructive pulmonary disease,” International Journal of Tuberculosis and Lung Disease, vol. 14, no. 9, pp. 1193–1200, 2010.

H. Liu, J. S. Liu, J. Huang, L. W. Zhong, and J. Y. Xu, “Unique association of adiponectin isoforms with serum cytokines and redox molecules in patients with chronic obstructive pulmonary disease,” Chinese Medical Journal (English Edition), vol. 126, no. 17, pp. 3383–3384, 2013.

R. Summer, C. A. Fiack, Y. Ikeda et al., “Adiponectin deficiency: a model of pulmonary hypertension associated with pulmonary vascular disease,” American Journal of Physiology—Lung Cellular and Molecular Physiology, vol. 297, no. 3, pp. L432–L438, 2009.

J. L. Mathew and I. Narang, “Sleeping too close together: obesity and obstructive sleep apnea in childhood and adolescence,” Paediatric Respiratory Reviews, 2013.

T. A. Hargens, S. G. Guill, A. S. Kaleth et al., “Insulin resistance and adipose-derived hormones in young men with untreated obstructive sleep apnea,” Sleep and Breathing, vol. 17, no. 1, pp. 403–409, 2013.

Y. Nakagawa, K. Kishida, S. Kihara, R. Yoshida, T. Funahashi, and I. Shimomura, “Nocturnal falls of adiponectin levels in sleep apnea with abdominal obesity and impact of hypoxia-induced dysregulated adiponectin production in obese murine mesenteric adipose tissue,” Journal of Atherosclerosis and Thrombosis, vol. 18, no. 3, pp. 240–247, 2011.

U. J. Magalang, J. P. Cruff, R. Rajappan et al., “Intermittent hypoxia suppresses adiponectin secretion by adipocytes,” Experimental and Clinical Endocrinology and Diabetes, vol. 117, no. 3, pp. 129–134, 2009.

B. E. K. Klein, “Overview of epidemiologic studies of diabetic retinopathy,” Ophthalmic Epidemiology, vol. 14, no. 4, pp. 179–183, 2007.

M. I. Yilmaz, A. Sonmez, C. Acikel et al., “Adiponectin may play a part in the pathogenesis of diabetic retinopathy,” European Journal of Endocrinology, vol. 151, no. 1, pp. 135–140, 2004.

H. Misu, K. Ishikura, S. Kurita et al., “Inverse correlation between serum levels of selenoprotein p and adiponectin in patients with type 2 diabetes,” PLoS ONE, vol. 7, no. 4, Article ID e34952, 2012.

C. Costagliola, A. Daniele, R. dell'Omo et al., “Aqueous humor levels of vascular endothelial growth factor and adiponectin in patients with type 2 diabetes before and after intravitreal bevacizumab injection,” Experimental Eye Research, vol. 110, pp. 50–54, 2013.

D. Mao, H. Peng, Q. Li et al., “Aqueous humor and plasma adiponectin levels in proliferative diabetic retinopathy patients,” Current Eye Research, vol. 37, no. 9, pp. 803–808, 2012.

J. Cunha-Vaz, J. R. F. De Abreu, A. J. Campos, and G. M. Figo, “Early breakdown of the blood retinal barrier in diabetes,” British Journal of Ophthalmology, vol. 59, no. 11, pp. 649–656, 1975.

H. Chen, M. Montagnani, T. Funahashi, I. Shimomura, and M. J. Quon, “Adiponectin stimulates production of nitric oxide in vascular endothelial cells,” Journal of Biological Chemistry, vol. 278, no. 45, pp. 45021–45026, 2003.

D. Fukumura, A. Ushiyama, D. G. Duda et al., “Paracrine regulation of angiogenesis and adipocyte differentiation during in vivo adipogenesis.,” Circulation Research, vol. 93, no. 9, pp. e88–e97, 2003.

K. Iskander, R. Farhour, M. Ficek, and A. Ray, “Obesity-related complications: Few biochemical phenomena with reference to tumorigenesis,” Malaysian Journal of Pathology, vol. 35, no. 1, pp. 1–15, 2013.

M. L. Kwan, E. M. John, B. J. Caan, et al., “Obesity and mortality after Breast Cancer by Race/Ethnicity: the California Breast Cancer Survivorship Consortium,” American Journal of Epidemiology, vol. 179, no. 1, pp. 95–111, 2013.

E. Surmacz and J. Mammary, “Leptin and adiponectin: emerging therapeutic targets in breast cancer,” Journal of Mammar Gland Biology and Neoplasia, vol. 18, no. 3-4, pp. 321–332, 2013.

Y. Ohbuchi, Y. Suzuki, I. Hatakeyama et al., “A lower serum level of middle-molecular-weight adiponectin is a risk factor for endometrial cancer,” International Journal of Clinical Oncology, 2014.

T. Kerenidi, M. Lada, A. Tsaroucha, P. Georgoulias, P. Mystridou, and K. I. Gourgoulianis, “Clinical significance of serum adipokines levels in lung cancer,” Medical Oncology, vol. 30, no. 2, article 507, 2013.

F. Kosova, T. Coskun, Y. Kaya, E. Kara, and Z. Ari, “Adipocytokine levels of colon cancer patients before and after treatment,” Bratislava Medical Journal, vol. 114, no. 7, pp. 394–397, 2013.

L. M. Liao, K. Schwartz, M. Pollak et al., “Serum leptin and adiponectin levels and risk of renal cell carcinoma,” Obesity, vol. 21, no. 7, pp. 1478–1485, 2013.

E. T. Petridou, N. Mitsiades, S. Gialamas et al., “Circulating adiponectin levels and expression of adiponectin receptors in relation to lung cancer: two case-control studies,” Oncology, vol. 73, no. 3-4, pp. 261–269, 2007.

M. E. Grossmann, K. J. Nkhata, N. K. Mizuno, A. Ray, and M. P. Cleary, “Effects of adiponectin on breast cancer cell growth and signaling,” British Journal of Cancer, vol. 98, no. 2, pp. 370–379, 2008.

S. Nakayama, Y. Miyoshi, H. Ishihara, and S. Noguchi, “Growth-inhibitory effect of adiponectin via adiponectin receptor 1 on human breast cancer cells through inhibition of S-phase entry without inducing apoptosis,” Breast Cancer Research and Treatment, vol. 112, no. 3, pp. 405–410, 2008.

A. P. Courcoulas, N. J. Christian, S. H. Belle, et al., “Weight change and health outcomes at 3 years after bariatric surgery among individuals with severe obesity,” The Journal of the American Medical Association, vol. 310, no. 22, pp. 2416–2425, 2013.

S. F. Noria and T. Grantcharov, “Biological effects of bariatric surgery on obesity-related comorbidities,” Canadian Journal of Surgery, vol. 56, no. 1, pp. 47–57, 2013.

J. Salas-Salvadó, M. Bulló, P. García-Lorda et al., “Subcutaneous adipose tissue cytokine production is not responsible for the restoration of systemic inflammation markers during weight loss,” International Journal of Obesity, vol. 30, no. 12, pp. 1714–1720, 2006.

E. P. Weiss, S. B. Racette, D. T. Villareal et al., “Improvements in glucose tolerance and insulin action induced by increasing energy expenditure or decreasing energy intake: a randomized controlled trial,” The American Journal of Clinical Nutrition, vol. 84, no. 5, pp. 1033–1042, 2006.

K. A. Simpson and M. A. F. Singh, “Effects of exercise on adiponectin: a systematic review,” Obesity, vol. 16, no. 2, pp. 241–256, 2008.

M. H. Rokling-Andersen, J. E. Reseland, M. B. Veierød et al., “Effects of long-term exercise and diet intervention on plasma adipokine concentrations,” The American Journal of Clinical Nutrition, vol. 86, no. 5, pp. 1293–1301, 2007.

T. Christiansen, S. K. Paulsen, J. M. Bruun, T. Ploug, S. B. Pedersen, and B. Richelsen, “Diet-induced weight loss and exercise alone and in combination enhance the expression of adiponectin receptors in adipose tissue and skeletal muscle, but only diet-induced weight loss enhanced circulating adiponectin,” The Journal of Clinical Endocrinology & Metabolism, vol. 95, no. 2, pp. 911–919, 2010.

Y. Yamazaki, Y. Kawano, and M. Uebayasi, “Induction of adiponectin by natural and synthetic phenolamides in mouse and human preadipocytes and its enhancement by docosahexaenoic acid,” Life Sciences, vol. 82, no. 5-6, pp. 290–300, 2008.

T. Tsuda, Y. Ueno, H. Aoki et al., “Anthocyanin enhances adipocytokine secretion and adipocyte-specific gene expression in isolated rat adipocytes,” Biochemical and Biophysical Research Communications, vol. 316, no. 1, pp. 149–157, 2004.

H. Nozawa, “Xanthohumol, the chalcone from beer hops (Humulus lupulus L.), is the ligand for farnesoid X receptor and ameliorates lipid and glucose metabolism in KK-Ay mice,” Biochemical and Biophysical Research Communications, vol. 336, no. 3, pp. 754–761, 2005.

A. Moriuchi, H. Yamasaki, M. Shimamura et al., “Induction of human adiponectin gene transcription by telmisartan, angiotensin receptor blocker, independently on PPAR-γ activation,” Biochemical and Biophysical Research Communications, vol. 356, no. 4, pp. 1024–1030, 2007.

A. Hiuge, A. Tenenbaum, N. Maeda et al., “Effects of peroxisome proliferator-activated receptor ligands, bezafibrate and fenofibrate, on adiponectin level,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 27, no. 3, pp. 635–641, 2007.

J. M. Bruun, A. Roeske-Nielsen, B. Richelsen, P. Fredman, and K. Buschard, “Sulfatide increases adiponectin and decreases TNF-α, IL-6, and IL-8 in human adipose tissue in vitro,” Molecular and Cellular Endocrinology, vol. 263, no. 1-2, pp. 142–148, 2007.

N. Adamia, D. Virsaladze, N. Charkviani, M. Skhirtladze, and M. Khutsishvili, “Effect of metformin therapy on plasma adiponectin and leptin levels in obese and insulin resistant postmenopausal females with type 2 diabetes,” Georgian Medical News, no. 145, pp. 52–55, 2007.

A. Sahebkar, “Head-to-head comparison of fibrates versus statins for elevation of circulating adiponectin concentrations: a systematic review and meta-analysis,” Metabolism, vol. 62, no. 12, pp. 1876–1885, 2013.

A. Tsuchida, T. Yamauchi, S. Takekawa et al., “Peroxisome proliferator-activated receptor (PPAR)α activation increases adiponectin receptors and reduces obesity-related inflammation in adipose tissue: comparison of activation of PPARα, PPARγ, and their combination,” Diabetes, vol. 54, no. 12, pp. 3358–3370, 2005.

S. A. Phillips, T. P. Ciaraldi, D. K. Oh, M. K. Savu, and R. R. Henry, “Adiponectin secretion and response to pioglitazone is depot dependent in cultured human adipose tissue,” The American Journal of Physiology: Endocrinology and Metabolism, vol. 295, no. 4, pp. E842–E850, 2008.

M. Liu and F. Liu, “Transcriptional and post-translational regulation of adiponectin,” Biochemical Journal, vol. 425, no. 1, pp. 41–52, 2009.

Y. Liu, S. Turdi, T. Park et al., “Adiponectin corrects high-fat diet-induced disturbances in muscle metabolomic profile and whole-body glucose homeostasis,” Diabetes, vol. 62, no. 3, pp. 743–752, 2013.

K. Kondo, R. Shibata, K. Unno et al., “Impact of a single intracoronary administration of adiponectin on myocardial ischemia/reperfusion injury in a pig model,” Circulation: Cardiovascular Interventions, vol. 3, no. 2, pp. 166–173, 2010.

T. Yamauchi, J. Kamon, H. Waki et al., “Globular adiponectin protected ob/ob mice from diabetes and ApoE-deficient mice from atherosclerosis,” Journal of Biological Chemistry, vol. 278, no. 4, pp. 2461–2468, 2003.

L. Otvos, E. Haspinger, F. LaRussa et al., “Design and development of a peptide-based adiponectin receptor agonist for cancer treatment,” BMC Biotechnology, vol. 11, article 90, 2011.

Y. Sun, Z. Zang, L. Zhong et al., “Identification of adiponectin receptor agonist utilizing a fluorescence polarization based high throughput assay,” PLoS ONE, vol. 8, no. 5, Article ID e63354, 2013.

M. Okada-Iwabu, T. Yamauchi, M. Iwabu, et al., “A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity,” Nature, vol. 503, no. 7477, pp. 493–499, 2013.

S. E. Kasim-Karakas, A. Tsodikov, U. Singh, and I. Jialal, “Responses of inflammatory markers to a low-fat, high-carbohydrate diet: effects of energy intake,” The American Journal of Clinical Nutrition, vol. 83, no. 4, pp. 774–779, 2006.

K. He, F. B. Hu, G. A. Colditz, J. E. Manson, W. C. Willett, and S. Liu, “Changes in intake of fruits and vegetables in relation to risk of obesity and weight gain among middle-aged women,” International Journal of Obesity, vol. 28, no. 12, pp. 1569–1574, 2004.

T. L. Nelson, J. R. Stevens, and M. S. Hickey, “Adiponectin levels are reduced, independent of polymorphisms in the adiponectin gene, after supplementation with α-linolenic acid among healthy adults,” Metabolism: Clinical and Experimental, vol. 56, no. 9, pp. 1209–1215, 2007.

M. A. Micallef and M. L. Garg, “Anti-inflammatory and cardioprotective effects of n-3 polyunsaturated fatty acids and plant sterols in hyperlipidemic individuals,” Atherosclerosis, vol. 204, no. 2, pp. 476–482, 2009.

G. Grunberger, K. L. Jen, and J. D. Artiss, “The benefits of early intervention in obese diabetic patients with FBCx: a new dietary fibre,” Diabetes/Metabolism Research and Reviews, vol. 23, no. 1, pp. 56–62, 2007.

M. W. Hulver, D. Zheng, C. J. Tanner et al., “Adiponectin is not altered with exercise training despite enhanced insulin action,” American Journal of Physiology: Endocrinology and Metabolism, vol. 283, no. 4, pp. E861–E865, 2002.

M. Blüher, J. W. Bullen Jr., J. H. Lee et al., “Circulating adiponectin and expression of adiponectin receptors in human skeletal muscle: associations with metabolic parameters and insulin resistance and regulation by physical training,” The Journal of Clinical Endocrinology & Metabolism, vol. 91, no. 6, pp. 2310–2316, 2006.

M. Zhu, J. Miura, L. X. Lu et al., “Circulating adiponectin levels increase in rats on caloric restriction: the potential for insulin sensitization,” Experimental Gerontology, vol. 39, no. 7, pp. 1049–1059, 2004.