Maria Ludovica Monaco

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 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.

Adiponectin in Asthma: Implications for Phenotyping

Asthma is a heterogeneous inflammatory airway disease, which exhibits multiple phenotypes, mainly defined by a combination of different clinical features. Asthma phenotypes include age at onset, smoking status, exacerbations frequency, and co-existence of obesity. Links between specific biological pathways and phenotypes are emerging. The genetic background together with detectable biomarkers could more accurately identify asthma phenotypes consistent with clinical-physiological characteristics and response to therapies. Several cross-sectional studies indicate a strict correlation between adipose tissue, obesity, and asthma suggesting that obesity is not only a risk factor for asthma but also a predictor of poor prognosis. Despite the strong clinical correlation between obesity and asthma, the underlying biological pathways have not been extensively investigated. Recently, a pivotal role for adiponectin has been recognized in physio-pathological conditions of lung. Adiponectin is expressed as a 247 residues long protein and secreted as oligomers of low, medium and high molecular weight. The larger oligomers seem to have a more pronounced insulinsensitizing, anti-atherogenic, and anti-inflammatory effects. Interestingly, the three receptors AdipoR1, AdipoR2, and Tcadherin mediating adiponectin activity are expressed on lung cells mediating adiponectin beneficial effects. Recently, different studies demonstrated the involvement of adiponectin in asthma since its levels and the expression of AdipoR1, AdipoR2 and T-cadherin are modulated in asthma patients and in asthma mouse models. In the present study, we review the literature reporting adiponectin impact on expression of specific clinical asthma phenotypes.

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.

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. J. Cell. Physiol. 229: 1444–1454, 2014.

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 patients 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.

Tissue-specific downregulation of the adiponectin "system": possible implications for fat accumulation tendency in the pig

Adiponectins beneficial effects are mediated by the AdipoR1 and AdipoR2 receptors (AdipoRs). The pig is a good model to study complex disorders such as obesity. We analyzed the expression of adiponectin, AdipoRs and some key molecules of energy metabolism (AMP-activated protein kinase α [AMPKα], p38 mitogen-activated protein kinase [p38 MAPK], and PPARα) in 2 pig breeds that displayed an opposite genetic behavior for energy metabolism: Casertana (CE), a fat-type animal, and Large White (LW), a lean-type animal. Muscle, liver, visceral and subcutaneous adipose tissues, and brain tissues were examined. The AdipoRs cDNA sequences were identical in the 2 breeds. AdipoRs mRNA expression, measured in all tissues, was significantly lower only in the 2 adipose tissues of CE pigs (P < 0.05). The muscle expression of AdipoRs, AMPKα, p38 MAPK, and PPARα was lower in CE than in LW animals (P < 0.01, P < 0.05, P < 0.01, P < 0.01, respectively). In liver, no molecule differed between breeds. The expression of both AdipoRs in visceral and subcutaneous adipose tissues was lower in CE pigs (P < 0.01). In brain, AdipoR1 and AMPKα expression was lower in CE pigs (P < 0.01), whereas AdipoR2 tended to be lower in CE than LW pigs (P = 0.05). In conclusion, our results suggest that tissue-specific downregulation of Adiponectin, AdipoRs, and of the key molecules of energy metabolism may be associated with the tendency of CE pigs to accumulate fat.

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 bodys 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.

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.

Adiponectin profile and Irisin expression in Italian obese children: Association with insulin-resistance

HighlightsTotal Acrp30 and HMW oligomers were lower in obese children than in controls.Irisin levels were significantly higher in obese children than in controls.Irisin levels were inversely correlated to total Acrp30 and HMW oligomer levels. ABSTRACT Adiponectin (Acrp30), its high molecular weight (HMW) oligomers, and Irisin are molecules involved in several metabolic processes. To investigate if these cytokines could represent new metabolic markers, we evaluated the expression of Acrp30 and Irisin in serum of obese children from South Italy affected by different degrees of insulin resistance (IR). The anthropometric and metabolic features were evaluated in 27 obese children versus 13 age‐matched controls. The expression of Acrp30, its pattern and Irisin were investigated by ELISA, western blotting and fast protein liquid chromatography. The HOMA index was significantly higher in obese children versus controls, and metabolic syndrome was more prevalent in obese children with elevated IR versus those with normal HOMA (38% vs 16%). Total Acrp30 and HMW oligomers were significantly lower in obese than in control children, and the difference was more pronounced in children with HOMA >3.4. In control and obese children, total Acrp30 and HMW oligomers were inversely related to HOMA (r‐0.38, p 0.02; r‐0.35, p 0.03). Irisin was significantly higher in obese than in control children, and was inversely correlated with Acrp30 and HMW (r‐0.32, p 0.04; r‐0.39, p 0.01). The inverse correlation of Acpr30 and HMW oligomers with HOMA indicates that Acpr30 is directly involved in IR status. Moreover, the inverse correlation between Irisin and Acrp30 and, more significantly, between Irisin and HMW oligomers suggests that the two cytokines are closely connected. The use of Acrp30, HMW oligomers and Irisin as predictive factors of IR in obese children remains to be further elucidated.