Adiponectin and leptin exert antagonizing effects on proliferation and motility of papillary thyroid cancer cell lines.

Adiponectin (Acrp30) and leptin, adipokines produced and secreted mainly by the adipose tissue, are involved in human carcinogenesis. Thyroid carcinomas are frequent endocrine cancers, and several evidences suggest that they are correlated with obesity. In this study, we first analyzed the expression levels and prognostic values of Acrp30, leptin, and their receptors in thyroid cancer cells. Then, we investigated the role of Acrp30 and leptin in proliferation, migration, and invasion. We found that Acrp30 treatment alone inhibits cell proliferation and cell viability in a time and dose-dependent manner; leptin alone does not influence thyroid cancer cells (BCPAP and K1) proliferation, but the combined treatment reverts Acrp30-induced effects on cell proliferation. Additionally, through wound healing and Matrigel Matrix invasion assays, we unveiled that Acrp30 inhibits thyroid cancer cell motility, while leptin induces the opposite effect. Importantly, in the combined treatment, Acrp30 and leptin exert antagonizing effects on papillary thyroid cancer cells' migration and invasion in both BCPAP and K1 cell lines. Highlights of these studies suggest that Acrp30 and leptin could represent therapeutic targets and biomarkers for the management of thyroid cancer.

Adiponectin in Cerebrospinal Fluid from Patients Affected by Multiple Sclerosis Is Correlated with the Progression and Severity of Disease.

Adiponectin exerts relevant actions in immunity and is modulated in several disorders, such as multiple sclerosis (MS). In this study, we characterized adiponectin expression and profiles in cerebrospinal fluid (CSF) from MS patients to investigate its potential relationship with the severity and progression of the disease. Total adiponectin in CSF was measured by ELISA in 66 unrelated CSF MS patients and compared with 24 age- and sex-matched controls. Adiponectin oligomer profiles were analysed by Western blotting and FPLC chromatography. Total CSF adiponectin was significantly increased in MS patients compared with controls (9.91 ng/mL vs 6.02 ng/mL) (p < 0.001). Interestingly, CSF adiponectin positively correlated with CSF IgG, and CSF/serum albumin directly correlated with CSF/serum adiponectin. Our data demonstrated that CSF adiponectin predicts a worse prognosis: patients with the progressive form of MS had higher levels compared with the relapsing remitting form; patients with higher EDSS at baseline and a higher MS severity score at 4.5-year follow-up had significantly elevated adiponectin levels with respect to patients with a less severe phenotype. Finally, the adiponectin oligomerization profile was altered in CSF from MS patients, with a significant increase in HMW and MMW. The correlation of CSF adiponectin with the severity and prognosis of MS disease confirmed the role of this adipokine in the inflammatory/immune processes of MS and suggested its use as a complementary tool to assess the severity, progression and prognosis of the disease. Further studies on larger MS cohorts are needed to clarify the contribution of adiponectin to the etiopathogenesis of MS.

Adiponectin Is Inversely Associated With Tumour Grade in Colorectal Cancer Patients.

BACKGROUND/AIM: Colorectal cancer is frequently associated with metabolic diseases. Adiponectin (APN) is an insulin-sensitizing adipokine circulating as low molecular weight (LMW), medium molecular weight (MMW) and high molecular weight (HMW) oligomers; the latter are the most bio-active oligomers. APN, through AdipoR1, AdipoR2 and T-cadherin receptors, regulates inflammation, and proliferation. Considering the anti-proliferative and anti-inflammatory properties of APN, we investigated the involvement of the "APN system" in colorectal cancer. MATERIALS AND METHODS: A total of 44 colorectal cancer patients and 51 healthy controls were recruited. We analysed APN and HMW oligomers in sera, AdipoR1, AdipoR2 and T-cadherin expression in non-cancerous and cancerous colon tissues. RESULTS: we found statistically lower levels of APN in patients compared to controls, with a specific decrease of HMW oligomers. Importantly, APN correlated to cancer grade. AdipoR1 was found overexpressed in cancerous compared to non-cancerous tissues while AdipoR2 and T-cadherin were down-regulated. CONCLUSION: The deregulated expression of the "APN system" in colorectal cancer with a specific correlation to tumor grade suggests APN as a promising biomarker in colorectal cancer.

Implications of the Adiponectin System in Non-Small Cell Lung Cancer Patients: A Case-Control Study.

Alterations of adipose tissue occurring in obesity have been recognized as a major risk factor for several cancers. The relationship between adipose tissue and lung cancer, which is the main cancer-related cause of death worldwide, still requires investigation. Perturbations in the adipokine system are likely to interfere with inter-organ crosstalk in lung cancer, which may influence the lung tumor microenvironment. Adiponectin (Acrp30) expression is deregulated in several cancer types. Acrp30 circulates as oligomers with a Low (LMW), Medium (MMW), and High Molecular Weight (HMW), with the latter mediating the main biological effects. Acrp30 acts through AdipoR1 and AdipoR2 receptors. T-cadherin has been described as a non-signaling receptor. This study's aim was to investigate the regulation of serum Acrp30 and its receptors in sample tissue from non-small cell lung cancer (NSCLC) patients. We recruited 72 NSCLC patients and 60 healthy controls, whom we evaluated in terms of their Acpr30 levels and oligomeric profile. In addition, the expression of AdipoRs in tissues from lung cancer specimens was also measured and compared to coupled healthy lung samples. Our findings show a significant reduction of total Acrp30 levels in NSCLC patients compared to normal subjects, with a specific down-regulation of HMW oligomers. Acrp30 expression was lower in lung adenocarcinoma than other subtypes, regardless of other factors. A significantly higher expression of AdipoR1 was observed, while no differences in R2 and a lower expression of T-cadherin were found in lung cancer specimens compared to normal healthy lung tissues. Involvement of the Acrp30 system in lung cancer may provide new insight into the interaction between adipose tissue and lung and sheds light on its potential ability to influence the lung tumor microenvironment.

Adiponectin Receptors and Pro-inflammatory Cytokines Are Modulated in Common Variable Immunodeficiency Patients: Correlation With Ig Replacement Therapy.

Adiponectin exerts beneficial pleiotropic effects through three receptors, AdipoR1, AdipoR2, and T-cadherin; it also exerts immunomodulatory effects. We previously demonstrated that adiponectin levels are altered in common variable immunodeficiency disease (CVID). The purpose of the present study was to investigate further the specific involvement of adiponectin in CVID by characterizing (i) the expression profile of adiponectin receptors on peripheral blood mononuclear cells; (ii) the levels of another relevant adipokine, namely leptin; (iii) the levels of five other cytokines (IL-2, IL-6, IL-10, TNFα, and IFNγ) in 24 patients on maintenance therapy, in 18 treatment-naïve patients (before and 24 h after the first Ig infusion) and in 28 healthy controls. We found that (i) adiponectin was down-expressed in patients on maintenance therapy and in treatment-naïve patients, and that it increased in treatment-naïve patients 24 h after the first Ig infusion; (ii) leptin expression did not differ between maintenance patients and controls either before or after the first Ig infusion; (iii) AdipoR1 expression was significantly higher on B lymphocytes, monocytes and NK cells of CVID patients than in controls; (iv) the expression of AdipoR1 and AdipoR2 on B lymphocytes, monocytes and NK cells was higher after the first Ig infusion than in treatment-naïve patients; (v) T-cadherin expression did not differ between treatment- naïve CVID patients and controls, and was not affected by Ig infusion; and (vi) IL-6, IL-8, IL-10, and TNFα levels were differently expressed in CVID patients on therapy maintenance and were not affected by the first Ig replacement therapy. This is the first study to demonstrate that the expression of AdipoRs in peripheral blood mononuclear cells from CVID patients differs from that of controls, and changes after the first Ig infusion. The specificity of adiponectin involvement in CVID is supported by the absence of changes in leptin levels and in the levels of the cytokines investigated. Taken together, these results suggest that the adiponectin system plays an important and specific role in CVID. A better understanding of adiponectin as a link in the cross-talk between the immune system and adipose tissue may provide additional benefits for the management of CVID patients.

Adiponectin Expression Is Modulated by Long-Term Physical Activity in Adult Patients Affected by Cystic Fibrosis.

Cystic fibrosis (CF) is a genetic disease characterized by progressive decline of lung function and chronic airway inflammation. Adipose tissue, through adiponectin and leptin, exerts several effects on energy metabolism and inflammatory processes. This study evaluated the levels of adiponectin and leptin in adult healthy subjects, in patients with CF and their correlation with long-term physical activity. CF patients were divided into two groups (sedentary versus active) based on their regular physical activity over 3 years. Anthropometric and serum biochemical profiles of CF patients and controls were evaluated and compared. Total serum adiponectin and leptin levels were measured by ELISA; adiponectin oligomeric profiles were analysed by western blot. Adiponectin levels were significantly higher while leptin levels were lower in patients with CF than in healthy controls. Furthermore, adiponectin was significantly lower in active compared to sedentary CF (p = 0.047), while leptin was slightly increased in active compared to sedentary CF. In addition, C-reactive protein levels were significantly lower in active than in sedentary CF patients (p = 0.048). Interestingly, only in the active group adiponectin levels were inversely correlated with forced expiratory volume (FEV) 1% decrease/year and FEV1% decrease. Moreover, adiponectin levels negatively correlated with lipid profiles. Our findings indicated that regular, long-term physical activity in CF improves respiratory function, metabolism, and inflammation status. These improvements in patients' conditions are associated with immunometabolic processes involving adiponectin, leptin, and C-reactive protein. Therefore, we propose that both adipokines may be a useful biomarker in the evaluation of metabolic and inflammatory status in patients with CF.

Adiponectin Expression and Genotypes in Italian People with Severe Obesity Undergone a Hypocaloric Diet and Physical Exercise Program.

Adiponectin exerts positive effects on metabolic and inflammatory processes. Adiponectin levels and some single-nucleotide polymorphisms (SNPs) seem to be associated with obesity. Here, we investigated the effects of a 4-week Hypocaloric diet and Physical exercise Program (HPP) on 268 young people with severe obesity. We evaluated the relationship between adiponectin levels and anthropometric and biochemical parameters, at baseline and after a 4-week HPP. Finally, we investigated some adiponectin gene variants and their correlation to biochemical parameters. Adiponectin levels were statistically lower in people with severe obesity than in controls. At the end of the HPP, all the people with severe obesity showed a Body Mass Index (BMI) reduction with a statistically significant increase in adiponectin levels. Genotyping, the adiponectin gene demonstrated a significant difference in 3 polymorphisms within the people with severe obesity. Besides, c.11377C>G and c.11391G>A homozygous subjects experienced more advantages by HPP. Furthermore, c.268G>A heterozygous subjects showed an enhancement in lipid profile as well in adiponectin levels. The best predictor of the changes in adiponectin levels was represented by the c.268G>A WT allele. Our study confirmed that a 4-weeks HPP in people with severe obesity results in metabolic amelioration associated with a significant increase of adiponectin levels. Importantly, we found that a specific genetic background in the ADIPOQ gene can predispose toward a more significant weight loss.

Total and High Molecular Weight Adiponectin Expression Is Decreased in Patients with Common Variable Immunodeficiency: Correlation with Ig Replacement Therapy.

Adiponectin (Acrp30) is an adipokine widely studied for its beneficial metabolic properties. It circulates as low molecular weight (LMW), medium molecular weight (MMW), and high molecular weight (HMW) oligomers. The latter exerts the most potent biological effects. Acrp30 attracted renewed interest with the finding that it was associated with the development and progression of immune disorders. The mechanisms underlying this association and the role of Acrp30 in the pathophysiology of immune-mediated conditions remain unknown. Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by chronic activation of the immune system, impaired antibody production, and imbalanced cytokine production. In the attempt to shed light on the expression of Acrp30 in CVID, we: (a) investigated total Acrp30 and its oligomerization state in CVID patients undergoing maintenance Ig replacement therapy; (b) assessed the effects of Ig replacement therapy on Acrp30 expression in treatment-naïve CVID patients, namely, patients not treated before diagnosis, before and after the first Ig administration; and (c) evaluated the correlation between Acrp30 levels and clinical phenotypes of the disease. As controls, we analyzed healthy subjects and patients affected by a non-immunodeficiency chronic inflammatory demyelinating polyneuropathy (CIDP), before and after Ig infusion. We found that total Acrp30 and HMW oligomers were decreased in CVID but not in CIDP patients versus controls. Moreover, Acrp30 levels were correlated with IgA levels and were associated with two CVID phenotypes, namely, autoimmune cytopenia and enteropathy. Receiver operating characteristic curve analysis indicated that Acrp30 modulation is specific for CVID patients. Acrp30 and HMW levels quickly and dramatically increased after Ig infusion only in eight treatment-naïve CVID patients but not in five CIDP patients. This finding indicates that Ig administration per se is not able to induce an increase of Acrp30, but the specific cellular and/or molecular background proper of CVID seems to be essential. In conclusion, our data indicate that Acrp30 is specifically related to CVID activity. Further studies are required to understand the biological role of Acrp30 and its possible use as disease biomarker in CVID.

The burden of obesity in asthma and COPD: Role of adiponectin.

The influence of obesity on development, severity and prognosis of both asthma and COPD is attracting growing interest. The impact of obesity on the respiratory system ranges from structural modifications (decline of total lung capacity) to humoral alterations. Adipose tissue strongly contributes to the establishment of an inflammatory state being an important source of adipokines. Amongst adipokines, adiponectin is an important component of organ cross talk with adipose tissue exerting protective effects on a variety of pathophysiological processes. Adiponectin is secreted in serum where it abundantly circulates as complexes of different molecular weight. Adiponectin properties are mediated by specific receptors that are widely expressed with AdipoR1, AdipoR2, and T-cadherin being present on epithelial and endothelial pulmonary cells indicating a functional role on lung physiology. In COPD, mild to moderate obesity has been shown to have protective effects on patient's survival, while a higher mortality rate has been observed in patients with low BMI. A specific cluster of obese patients has been identified; in this group, asthma features are particularly severe and difficult to treat. Better understanding of the molecular mechanisms at the base of cross talk among different tissues and organs will lead to identification of new targets for both diagnosis and treatment of asthma and COPD.

Evaluation of adiponectin profile in Italian patients affected by obstructive sleep apnea syndrome.

Obstructive sleep apnea syndrome (OSAS) is a common breathing disorder; obesity represents a major risk factor for the development and progression of OSAS although obese patients do not necessarily suffer from OSAS. Adipose tissue communicates with lung in both physiologic and pathologic conditions through the production of adipokines, hormones active in metabolic and inflammatory processes. To explore the extent to which Acrp30 impacts on pathophysiology of OSAS and whether these proteins could be considered as targets for both diagnosis and therapy through enzyme-linked immunosorbent assay, western blotting analysis and fast protein liquid chromatography we have analyzed total levels as well as oligomer distribution in OSAS patients. Our data demonstrated that total Acrp30 serum levels were statistically reduced in OSAS patients compared to controls (p value = 0.02). Within a selected subgroup of OSAS patients with a BMI<30, Acrp30 levels were still statistically lower in OSAS than in control group (p value < 0.05). In addition, more severe patients (AHI>15) exhibited a more pronounced reduction of Acrp30 levels. Interestingly, this reduction is mainly due to a specific decrease of the HMW oligomers, those exhibiting major biological significance. In conclusion, our results strongly suggest a role for Acrp30 oligomerization in OSAS; in fact, the down-regulation of Acpr30 and its HMW oligomers seems to be correlated to illness status independently of concomitant presence of obesity. In addition, this reduction is mainly due to the high-weight oligomers of Acrp30 suggesting a functional role of this adipokine in OSAS.

Gene molecular analysis and Adiponectin expression in professional Water Polo players.

Metabolic Syndrome prevalence has reaching epidemic proportions worldwide. Adiponectin (Acrp30), and in particular its High Molecular Weight (HMW) oligomers, contributes to enhance insulin sensitivity and to reduce inflammation levels. Physical exercise improves body's biochemical balance and metabolism resulting effective in prevention of metabolic diseases. Whether improvement of metabolic features mediated by physical exercise is associated with changes in Acrp30 serum composition is not yet clarified. In the present study, we investigated total Acrp30 expression, its oligomeric status and genetic variants in adiponectin gene (ACDC) in twenty-two professional Water Polo (WP) Players and 40 age- and sex-matched controls. Anthropometric, metabolic parameters and total Acrp30 were assessed; Acrp30 oligomeric profile was characterized by Western blot as well as by FPLC analysis. ACDC gene was analyzed by direct-sequencing analysis. Significant elevated body mass index, aspartate aminotransferase and lactate dehydrogenase levels and, conversely, significantly lower concentrations of total and cholesterol low density lipoprotein were present in WP players. No significant difference was found in total Acrp30 and/or HMW oligomers. Interestingly, in WP players, a direct relationship between total Acrp30 and monocytes as well as an inverse relationship between total Acrp30 and AST levels were found. ACDC screening revealed previously described SNPs. In conclusion, our study confirms the long-term beneficial effects of high physical training on metabolism and suggests that they are not associated with Acrp30 and/or HMW oligomers changes. Moreover, the correlation of Acrp30 with monocytes in WP athletes could represent a mechanism by which Acrp30 participates in exercise-induced anti-inflammatory functions and/or cardiovascular health.

New synthetic AICAR derivatives with enhanced AMPK and ACC activation.

5-Aminoimidazole-4-carboxamide riboside (AICAR) has an important role in the regulation of the cellular metabolism showing a broad spectrum of therapeutic activities against different metabolic processes. Due to these proven AICAR properties, we have designed, synthesized and tested the biological activity of two ribose-modified AICAR derivatives, named A3 and A4, in comparison to native AICAR and its 5'-phosphorylated counterpart ZMP. Our findings have shown that A3 and A4 derivatives induce the phosphorylation of 5'-AMP activated protein kinase α (AMPKα), which leads to the inhibition of acetyl-CoA carboxylase (ACC), and down-regulate the activity of the extracellular signal-regulated kinases (ERK1/2). Cytotoxicity tests demonstrated that A3 and A4 do not significantly reduce cell viability up to 24 h. Taken together our results indicate that A3 and A4 have a comparable activity to AICAR and ZMP at 0.5 and 1 mM suggesting their potential use in future pharmacological strategies relating to metabolic diseases.

New insight into adiponectin role in obesity and obesity-related diseases.

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.

Adiponectin as novel regulator of cell proliferation in human glioblastoma.

Adiponectin (Acrp30) is an adipocyte-secreted hormone with pleiotropic metabolic effects, whose reduced levels were related to development and progression of several malignancies. We looked at the presence of Acrp30 receptors in human glioblastomas (GBM), hypothesizing a role for Acrp30 also in this untreatable cancer. Here we demonstrate that human GBM express Acrp30 receptors (AdipoR1 and AdipoR2), which are often co-expressed in GBM samples (70% of the analyzed tumors). To investigate the effects of Acrp30 on GBM growth, we used human GBM cell lines U87-MG and U251, expressing both AdipoR1 and AdipoR2 receptors. In these cells, Acrp30 treatment inhibits DNA synthesis and cell proliferation rate, inducing arrest in G1 phase of the cell cycle. These effects were correlated to a sustained activation of ERK1/2 and Akt kinases, upon Acrp30 treatment. Our results suggest that Acrp30 may represent a novel endogenous negative regulator of GBM cell proliferation, to be evaluated for the possible development of novel pharmacological approaches.

Mannose-binding lectin genetic analysis: possible protective role of the HYPA haplotype in the development of recurrent urinary tract infections in men.

Factors related to bacterial virulence and/or to the host have been implicated in the pathogenesis of recurrent urinary tract infections (rUTI), but in most cases the cause is unknown. Mannose binding lectin (MBL) is an acute phase glycoprotein that exerts immunological functions by binding to the surface of a variety of pathogens. Some human gene variants reduce MBL activity thereby predisposing the host to bacterial and viral infections. The aim of this study was to investigate MBL2 gene variants in relation to rUTI risk. Six MBL gene variants and seven haplotypes were analyzed by PCR and direct sequencing in rUTI patients (n = 83) and in healthy subjects from southern Italy (n = 642). The frequencies of the L allele (-550) and the HYPA haplotype were higher in controls than in patients stratified according to sex (p < 0.05). Our data indicate that the HYPA haplotype in the MBL2 gene could be associated with a minor risk of developing rUTI in males.

Adiponectin oligomers as potential indicators of adipose tissue improvement in obese subjects.

OBJECTIVE: Adiponectin is an adipocytokine that exerts beneficial effects on obesity and related disorders by two receptors (ADIPORs). Adiponectin is produced as a monomer that circulates in serum as different oligomers. The oligomerization state and the tissue expression of adiponectin and ADIPORs are linked to its biological activities. In this study, the levels of total adiponectin and its oligomers were evaluated in relation to obesity and surgical weight loss. The expression of adiponectin and ADIPORs was analyzed in visceral and subcutaneous adipose tissues of obese patients. DESIGN AND METHODS: In 25 obese patients and 44 age- and sex-matched controls, the serum levels of adiponectin and its oligomers were measured and compared by ELISA, western blotting, and gel filtration. The expression of adiponectin and ADIPORs in both adipose tissues was evaluated by real-time quantitative PCR and western blotting. RESULTS: The amount of each adiponectin oligomer, including the monomer, increases after weight loss. The reduced circulating levels of adiponectin and its oligomers are not associated with the adipose tissue depot-specific expression of adiponectin and ADIPORs. CONCLUSIONS: Our results suggest that in patients, adiposity is associated with the serum concentrations of adiponectin and its oligomers but not with adipose tissue depot-specific expression of adiponectin and ADIPORs. In particular, the increase in adiponectin monomer levels could probably be related to the improvement of the whole-body energy metabolism then being involved in the improvement of adipose tissue function after weight loss. This work indicates the importance of assessing the whole adiponectin oligomeric profile as further potential indicators of adipose tissue functions in obesity.

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.

OBJECTIVE: The hormone adiponectin exerts beneficial pleiotropic effects on biological and metabolic processes. Although a well-recognized insulin sensitizer, its characteristic has yet to be clearly defined. Myotonic dystrophy type 1 (DM1) is a rare genetic disorder that features muscle wasting and metabolic comorbidity, and patients have an increased risk of developing type 2 diabetes. We analyzed circulating levels of adiponectin and its oligomers to determine whether their expression correlates with metabolic alterations in DM1 patients. DESIGN AND METHODS: We measured the anthropometric and biochemical features and three insulin resistance (IR) indices (homeostasis model assessment, quantitative insulin sensitivity check index, and McAuley) of 21 DM1 patients and of 82 age-, sex-, and weight-matched controls. In the blood samples of patients and controls, adiponectin levels were measured by ELISA, and its oligomers were characterized by using western blotting and gel filtration. The adiponectin gene was molecularly analyzed in patients. RESULTS: DM1 patients had significantly higher body mass index, waist circumference, triglycerides (TGs), glucose, tumor necrosis factor α, and IR; conversely, they had significantly lower concentrations of total serum adiponectin with a selective, pronounced decrease of its high molecular weight (HMW) oligomers. There was a strong negative correlation between adiponectin and TGs in DM1 patients. CONCLUSIONS: Our results endorse the hypothesis that decreased expression of adiponectin together with a selective reduction of its HMW oligomers contributes to the worsening of IR and its metabolic complications in DM1 patients. These findings suggest that adiponectin and HMW oligomers may serve as biomarkers and are promising therapeutic agents for IR and its consequences in DM1.