Association of recently described adipokines with liver histology in biopsy-proven non-alcoholic fatty liver disease: a systematic review.
Bekaert M,Verhelst X,Geerts A,Lapauw B,Calders P
Obesity reviews : an official journal of the International Association for the Study of Obesity
The prevalence of non-alcoholic fatty liver disease (NAFLD) is rising, as is the prevalence of obesity and type 2 diabetes. It is increasingly recognized that an impaired pattern in adipokine secretion could play a pivotal role in the development of NAFLD. We performed a systematic review to evaluate the potential link between newly described adipokines and liver histology in biopsy-proven NAFLD patients. A computerized literature search was performed in PubMed, EMBASE and Web of Science electronic databases. Thirty-one cross-sectional studies were included, resulting in a total of seven different investigated adipokines. Studies included in this review mainly had a good methodological quality. Most adipokines were suggested to be involved in the inflammatory response that develops within the context of NAFLD, either at hepatic or systemic level, and/or hepatic insulin resistance. Based on literature, clinical studies suggest that chemerin, resistin and adipocyte-fatty-acid-binding protein potentially are involved in NAFLD pathogenesis and/or progression. However, major inconsistency still exists, and there is a high need for larger studies, together with the need of standardized assays to determine adipokine levels.
Adipokines in Healthy Skeletal Muscle and Metabolic Disease.
Coles C A
Advances in experimental medicine and biology
Adipose tissue not only functions as a reserve to store energy but has become of major interest as an endocrine organ, releasing signalling molecules termed adipokines which impact on other tissues, such as skeletal muscle. Adipocytes, within skeletal muscle and adipose tissue, secrete adipokines to finely maintain the balance between feed intake and energy expenditure. This book chapter focuses on the three adipokines, adiponectin, leptin and IL-6, which have potent effects on skeletal muscle during rest and exercise. Similarly, adiponectin, leptin and IL-6 enhance glucose uptake and increase fatty acid oxidation in skeletal muscle. Fatty acid oxidation is increased through activation of AMPK (adenosine monophosphate-activated protein kinase signalling) causing phosphorylation and inhibition of ACC (acetyl-coenzyme A carboxylase), decreasing availability of malonyl CoA. Leptin and adiponectin also control feed intake via AMPK signalling in the hypothalamus. Adipokines function to maintain energy homeostasis, however, when feed intake exceeds energy expenditure adipokines can become dysregulated causing lipotoxicity in skeletal muscle and metabolic disease can prevail. Cross-talk between adipocytes and skeletal muscle via correct control by adipokines is important in controlling energy homeostasis during rest and exercise and can help prevent metabolic disease.
Multiple Sclerosis and Obesity: Possible Roles of Adipokines.
Guerrero-García José de Jesús,Carrera-Quintanar Lucrecia,López-Roa Rocío Ivette,Márquez-Aguirre Ana Laura,Rojas-Mayorquín Argelia Esperanza,Ortuño-Sahagún Daniel
Mediators of inflammation
Multiple Sclerosis (MS) is an autoimmune disorder of the Central Nervous System that has been associated with several environmental factors, such as diet and obesity. The possible link between MS and obesity has become more interesting in recent years since the discovery of the remarkable properties of adipose tissue. Once MS is initiated, obesity can contribute to increased disease severity by negatively influencing disease progress and treatment response, but, also, obesity in early life is highly relevant as a susceptibility factor and causally related risk for late MS development. The aim of this review was to discuss recent evidence about the link between obesity, as a chronic inflammatory state, and the pathogenesis of MS as a chronic autoimmune and inflammatory disease. First, we describe the main cells involved in MS pathogenesis, both from neural tissue and from the immune system, and including a new participant, the adipocyte, focusing on their roles in MS. Second, we concentrate on the role of several adipokines that are able to participate in the mediation of the immune response in MS and on the possible cross talk between the latter. Finally, we explore recent therapy that involves the transplantation of adipocyte precursor cells for the treatment of MS.
The Cross-Link between Adipokines, Insulin Resistance and Obesity in Offspring of Diabetic Pregnancies.
Bozkurt Latife,Göbl Christian S,Rami-Merhar Birgit,Winhofer Yvonne,Baumgartner-Parzer Sabina,Schober Edith,Kautzky-Willer Alexandra
Hormone research in paediatrics
BACKGROUND/AIMS:Intrauterine exposure to hyperglycemia might impact the risk for future metabolic deteriorations. The aim was to characterize the association between different adipokines and neuropeptides and insulin resistance and BMI-SDS in children affected by diabetes during pregnancy. METHODS:76 children (mean age: 6 years, male:female = 36:40) born to mothers with gestational or pregestational diabetes and nondiabetic women were consecutively included for clinical assessments comprising anthropometrics and metabolic characterization [2-hour glucose tolerance test, leptin, peptide YY (PYY), neuropeptide Y (NPY), ghrelin, growth differentiation factor 15 (GDF-15), and adiponectin]. RESULTS:The level of insulin resistance was associated with BMI-SDS (p < 0.001), leptin (p < 0.001), ghrelin (p = 0.002), age (p < 0.002) and negatively with GDF-15 (p = 0.005). BMI-SDS, leptin and GDF-15 were shown to have independent effects on insulin resistance by using a multiple regression model (additionally including age, and maternal diabetes status), whereas ghrelin lost significance (p = 0.345). No differences were present in adipokines and insulin resistance when children were evaluated by maternal glucometabolic status. However, we observed more strengthened associations between insulin resistance and covariates BMI-SDS and leptin in offspring of diabetic pregnancies. CONCLUSIONS:Young children with elevated BMI or leptin are affected by higher indices of insulin resistance, particularly those who were born to mothers with diabetes during pregnancy. The impact of this special risk constellation should be considered in future studies.
Serum adipokines might predict liver histology findings in non-alcoholic fatty liver disease.
Jamali Raika,Razavizade Mohsen,Arj Abbas,Aarabi Mohammad Hossein
World journal of gastroenterology
AIM:To assess significance of serum adipokines to determine the histological severity of non-alcoholic fatty liver disease. METHODS:Patients with persistent elevation in serum aminotransferase levels and well-defined characteristics of fatty liver at ultrasound were enrolled. Individuals with a history of alcohol consumption, hepatotoxic medication, viral hepatitis or known liver disease were excluded. Liver biopsy was performed to confirm non-alcoholic liver disease (NAFLD). The degrees of liver steatosis, lobular inflammation and fibrosis were determined based on the non-alcoholic fatty liver activity score (NAS) by a single expert pathologist. Patients with a NAS of five or higher were considered to have steatohepatitis. Those with a NAS of two or lower were defined as simple fatty liver. Binary logistic regression was used to determine the independent association of adipokines with histological findings. Receiver operating characteristic (ROC) analysis was employed to determine cut-off values of serum adipokines to discriminate the grades of liver steatosis, lobular inflammation and fibrosis. RESULTS:Fifty-four participants aged 37.02 ± 9.82 were enrolled in the study. Higher serum levels of visfatin, IL-8, TNF-α levels were associated independently with steatosis grade of more than 33% [β = 1.08 (95%CI: 1.03-1.14), 1.04 (95%CI: 1.008-1.07), 1.04 (95%CI: 1.004-1.08), P < 0.05]. Elevated serum IL-6 and IL-8 levels were associated independently with advanced lobular inflammation [β = 1.4 (95%CI: 1.09-1.8), 1.07 (95%CI: 1.003-1.15), P < 0.05]. Similarly, higher TNF-α, resistin, and hepcidin levels were associated independently with advanced fibrosis stage [β = 1.06 (95%CI: 1.002-1.12), 19.86 (95%CI: 2.79-141.19), 560.72 (95%CI: 5.98-5255.33), P < 0.05]. Serum IL-8 and TNF-α values were associated independently with the NAS score, considering a NAS score of 5 as the reference value [β = 1.05 (95%CI: 1.01-1.1), 1.13 (95%CI: 1.04-1.22), P < 0.05]. CONCLUSION:Certain adipokines may determine the severity of NAFLD histology accurately.
Prognostic Value of Adipokines in Predicting Cardiovascular Outcome: Explaining the Obesity Paradox.
Wolk Robert,Bertolet Marnie,Singh Prachi,Brooks Maria M,Pratley Richard E,Frye Robert L,Mooradian Arshag D,Rutter Martin K,Calvin Andrew D,Chaitman Bernard R,Somers Virend K,
Mayo Clinic proceedings
OBJECTIVE:To evaluate the cardiovascular (CV) prognostic value of adipokines in a large prospective cohort of patients participating in the Bypass Angioplasty Revascularization Investigation 2 Diabetes trial. PATIENTS AND METHODS:The effects of the adipokine levels at baseline and change from baseline on the composite outcome (CV death, myocardial infarction, and stroke) were analyzed using unadjusted and fully adjusted Cox models in 2330 patients with type 2 diabetes and coronary artery disease who had participated in the Bypass Angioplasty Revascularization Investigation 2 Diabetes trial (from January 1, 2001, through December 1, 2008). RESULTS:In a fully adjusted model, baseline leptin and change from baseline leptin were protective for CV events, whereas baseline adiponectin, baseline tumor necrosis factor α (TNF-α), change from baseline TNF-α, baseline C-reactive protein (CRP), and change from baseline CRP were harmful. The effect of baseline leptin on CV events depended on the body mass index (BMI), such that the hazard ratios (HRs) varied between 0.6 and 1.4 across the BMI quintiles (interaction P=.03). The same was true for baseline adiponectin (HR varied from 0.7 to 1.7; interaction P=.01), change from baseline monocyte chemoattractant protein-1 (HR varied from 0.8 to 1.8; interaction P=.03), change from baseline TNF-α (HR varied from 0.9 to 1.4; interaction P=.02), and change from baseline IL-6 (HR varied from 0.7 to 1.8; interaction P=.005). CONCLUSION:Adipokines are independent predictors of CV events in patients with type 2 diabetes and coronary artery disease. The association between the specific adipokines and CV outcome varies depending on BMI. This reflects the complex pathophysiology of CV disease in obesity and may help explain the "obesity paradox." TRIAL REGISTRATION:clinicaltrials.gov Identifier: NCT00006305.
Emerging role of adipokines in systemic lupus erythematosus.
Li Hong-Miao,Zhang Tian-Ping,Leng Rui-Xue,Li Xiang-Pei,Li Xiao-Mei,Liu Hai-Rong,Ye Dong-Qing,Pan Hai-Feng
Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by multisystem organ involvement and unclear pathogenesis. Several adipokines synthesized in the adipose tissue, including leptin, adiponectin, resistin, and chemerin, have been explored in autoimmune rheumatic diseases, especially SLE, and results suggest that these mediators may be implicated in the pathogenesis of SLE. However, the current results are controversial. In this review, we will briefly discuss the expression and possible pathogenic role of several important adipokines, including leptin, adiponectin, resistin, and chemerin in SLE.
The clinical value of adipokines in predicting the severity and outcome of acute pancreatitis.
Karpavicius Andrius,Dambrauskas Zilvinas,Gradauskas Audrius,Samuilis Arturas,Zviniene Kristina,Kupcinskas Juozas,Brimas Gintautas,Meckovski Artur,Sileikis Audrius,Strupas Kestutis
BACKGROUND:Recent data shows that patients with severe acute pancreatic might benefit from early intensive therapy, enteral nutrition and timely transfer to specialized centers. The early prophylactic use of antibiotics in AP remains controversial. The role and need for new markers in stratification of acute pancreatitis is also uncertain. This study aims to evaluate the prognostic usefulness of adipokines in prediction of the severity and outcome of acute pancreatitis (AP). METHODS:Prospective study was conducted in four clinical centers. The diagnosis and severity assessment of AP was established according to the revised 2012 Atlanta classification. Adipokines, IL-6 and CRP levels were measured at admission and on 3rd day of hospital stay and compared with the control group. The predictive accuracy of each marker was measured by area under the receiver operating curve. RESULTS:Forty healthy controls and 102 patients were enrolled in to the study. Twenty seven (26.5 %) patients had mild, 55 (53.9 %) - moderate and 20 (19.6 %) - severe AP. Only resistin (cut-off value 13.7 ng/ml) and IL-6 (cut-off value 473.4 pg/ml) were reliable early markers of SAP. IL-6 with cut-off value of 157.0 pg/ml was a predictor of necrosis. The peripancreatic necrosis volume of 112.5 ml was a marker of SAP and 433.0 ml cut-off value could be used to predict the need of interventions. CONCLUSIONS:The prognostic value of adipokines in AP is limited. Only admission resistin levels could serve as an early predictor for SAP. The Lithuanian Regional Ethics Committee approved the study protocol (permission No. L-12-02/1/2/3/4) and all the patients and the control group provided written informed consent.
The Roles of Adipokines, Proinflammatory Cytokines, and Adipose Tissue Macrophages in Obesity-Associated Insulin Resistance in Modest Obesity and Early Metabolic Dysfunction.
Kang Yea Eun,Kim Ji Min,Joung Kyong Hye,Lee Ju Hee,You Bo Ram,Choi Min Jeong,Ryu Min Jeong,Ko Young Bok,Lee Min A,Lee Junguee,Ku Bon Jeong,Shong Minho,Lee Ki Hwan,Kim Hyun Jin
The roles of adipokines, proinflammatory cytokines, and adipose tissue macrophages in obesity-associated insulin resistance have been explored in both animal and human studies. However, our current understanding of obesity-associated insulin resistance relies on studies of artificial metabolic extremes. The purpose of this study was to explore the roles of adipokines, proinflammatory cytokines, and adipose tissue macrophages in human patients with modest obesity and early metabolic dysfunction. We obtained omental adipose tissue and fasting blood samples from 51 females undergoing gynecologic surgery. We investigated serum concentrations of proinflammatory cytokines and adipokines as well as the mRNA expression of proinflammatory and macrophage phenotype markers in visceral adipose tissue using ELISA and quantitative RT-PCR. We measured adipose tissue inflammation and macrophage infiltration using immunohistochemical analysis. Serum levels of adiponectin and leptin were significantly correlated with HOMA-IR and body mass index. The levels of expression of MCP-1 and TNF-α in visceral adipose tissue were also higher in the obese group (body mass index ≥ 25). The expression of mRNA MCP-1 in visceral adipose tissue was positively correlated with body mass index (r = 0.428, p = 0.037) but not with HOMA-IR, whereas TNF-α in visceral adipose tissue was correlated with HOMA-IR (r = 0.462, p = 0.035) but not with body mass index. There was no obvious change in macrophage phenotype or macrophage infiltration in patients with modest obesity or early metabolic dysfunction. Expression of mRNA CD163/CD68 was significantly related to mitochondrial-associated genes and serum inflammatory cytokine levels of resistin and leptin. These results suggest that changes in the production of inflammatory biomolecules precede increased immune cell infiltration and induction of a macrophage phenotype switch in visceral adipose tissue. Furthermore, serum resistin and leptin have specific roles in the regulation of adipose tissue macrophages in patients with modest obesity or early metabolic dysfunction.
Changes in profile of lipids and adipokines in patients with newly diagnosed hypothyroidism and hyperthyroidism.
Chen Yanyan,Wu Xiafang,Wu Ruirui,Sun Xiance,Yang Boyi,Wang Yi,Xu Yuanyuan
Changes in profile of lipids and adipokines have been reported in patients with thyroid dysfunction. But the evidence is controversial. The present study aimed to explore the relationships between thyroid function and the profile of lipids and adipokines. A cross-sectional study was conducted in 197 newly diagnosed hypothyroid patients, 230 newly diagnosed hyperthyroid patients and 355 control subjects. Hypothyroid patients presented with significantly higher serum levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDLC), fasting insulin, resistin and leptin than control (p < 0.05). Hyperthyroid patients presented with significantly lower serum levels of high-density lipoprotein cholesterol, LDLC and leptin, as well as higher levels of fasting insulin, resistin, adiponectin and homeostasis model insulin resistance index (HOMA-IR) than control (p < 0.05). Nonlinear regression and multivariable linear regression models all showed significant associations of resistin or adiponectin with free thyroxine and association of leptin with thyroid-stimulating hormone (p < 0.001). Furthermore, significant correlation between resistin and HOMA-IR was observed in the patients (p < 0.001). Thus, thyroid dysfunction affects the profile of lipids and adipokines. Resistin may serve as a link between thyroid dysfunction and insulin resistance.
The role of adipokines in ischemic stroke risk stratification.
Bouziana Styliani,Tziomalos Konstantinos,Goulas Antonios,Ηatzitolios Apostolos Ι
International journal of stroke : official journal of the International Stroke Society
BACKGROUND:Adiponectin, leptin, and resistin are the most well-studied adipokines and play important roles in the regulation of glucose metabolism, subclinical inflammation, and cardiovascular homeostasis. Accordingly, measurement of adipokine levels might be useful in cardiovascular risk stratification. Moreover, the study of single-nucleotide polymorphisms of genes that encode these adipokines might also represent a valuable predictive tool in cardiovascular disease prevention strategies. AIMS:To summarize the biologic role of the adipokines adiponectin, leptin, and resistin and the prognostic value of their serum levels regarding the occurrence and outcome of ischemic stroke. We also discuss the relationship of single-nucleotide polymorphisms of the adiponectin, leptin genes, and the -420C > G polymorphism of resistin gene with stroke risk. SUMMARY OF REVIEW:Several studies in the general population evaluated the association between these adipokines and stroke risk, yielding conflicting results. There are more limited data regarding the effect of these adipokines on stroke severity and outcome. A small number of studies also assessed the predictive role of single-nucleotide polymorphisms of the adiponectin, leptin, and resistin genes regarding stroke risk, but the findings were also controversial. CONCLUSIONS:It is unclear whether adiponectin, leptin, and resistin levels or the single-nucleotide polymorphisms of their encoding genes are independently associated with stroke risk. However, given the role of these adipokines in the pathogenesis of atherosclerosis, larger prospective studies, both in the general population and in patients with a history of stroke, are needed to determine whether the measurement of serum levels of these adipokines or the evaluation of single-nucleotide polymorphisms in their encoding genes could improve stroke risk prediction. If this relationship is proven, therapeutic interventions targeting adipokine levels might represent a novel approach to reduce stroke-related mortality and disability.
Association between circulatory levels of adipokines and bone mineral density in postmenopausal women.
Cervellati Carlo,Bonaccorsi Gloria,Bergamini Carlo M,Fila Enrica,Greco Pantaleo,Valacchi Giuseppe,Massari Leo,Gonelli Arianna,Tisato Veronica
Menopause (New York, N.Y.)
OBJECTIVE:Epidemiological evidence indicates that excess fat may be beneficial for bone health, offering protective effects against the onset of postmenopausal osteoporosis. Experimental data suggest that this link might be due to the direct effect of adipokines on bone tissue. Confirmatory evidence of this association, however, remains limited. METHODS:The levels of a panel of selected adipokines including interleukin (IL)-6, -8, -1β, adipsin, lipocalin-2/neutrophil gelatinase-associated ipocalin, tumor necrosis factor alpha, monocyte chemoattractant protein-1, plasminogen activator inhibitor-1, hepatocyte growth factor, resistin, leptin, and adiponectin in a group of osteopenic and osteoporotic postmenopausal women were compared with those of unaffected women (n = 127). RESULTS:Univariate analysis revealed that leptin and adiponectin were significantly correlated with bone mineral density (BMD). In particular, leptin was positively associated with BMD of the spine (r = 0.22, P < 0.05), femoral neck (r = 0.23, P < 0.05), trochanter (r = 0.20, P < 0.05), and total hip (r = 0.27, P < 0.01), whereas adiponectin was inversely correlated with BMD at the trochanter (r = -0.21, P < 0.05). No correlations were, however, significant after adjusting for body fat variables. Stratification of the sample according to IL-6 levels revealed that adiponectin remained significantly inversely associated with BMD, regardless of fat levels and age (β=-0.29, P < 0.05; r = 0.198) in the subgroup of participants with low levels of IL-6. CONCLUSIONS:Our data suggest that circulating adiponectin is inversely associated with markers of bone health in postmenopausal women, and that the interaction is influenced by IL-6 levels.
Plasma levels of adipokines in systemic lupus erythematosus patients.
Zhang Tian-Ping,Li Hong-Miao,Leng Rui-Xue,Li Xiang-Pei,Li Xiao-Mei,Pan Hai-Feng,Ye Dong-Qing
OBJECTIVE:To evaluate the plasma levels of six adipokines, including chemerin, omentin-1, lipocalin-2, cathepsin-S, cathepsin-L and adipsin, in patients with SLE. METHODS:Ninety SLE patients and ninety control subjects were recruited, plasma adipokines levels were measured by enzyme-linked immunosorbent assay, and their associations with major clinical and laboratory indexes were analyzed. RESULTS:There were no significant differences in plasma chemerin, omentin-1, lipocalin-2, cathepsin-S, cathepsin-L and adipsin levels between SLE patients and controls. Further subgroup analyses by major clinical and laboratory indexes showed that plasma omentin-1 level was significantly lower in SLE patients without nephritis when compared with those patients with nephritis (P=0.002). Plasma chemerin, cathepsin-S levels in SLE patients without nervous system disorder were significantly lower in comparison with SLE patients with nervous system disorder (P=0.035, P=0.029). No significant associations of other adipokines with any major clinical and laboratory indexes were observed. CONCLUSIONS:Plasma levels of chemerin, omentin-1, lipocalin-2, cathepsin-S, cathepsin-L and adipsin in SLE patients were not markedly different from the normal controls. The presence of nephritis was connected with higher plasma omentin-1 levels in SLE patients, and the presence of nervous system disorder was associated with higher plasma chemerin, cathepsin-S levels in SLE patients. However, functional studies are awaited to further explore the potential roles of these cytokines in SLE.
Elevated levels of adipokines predict outcome after acute myocardial infarction: A long-term follow-up of the Glucose Tolerance in Patients with Acute Myocardial Infarction cohort.
Ritsinger Viveca,Brismar Kerstin,Malmberg Klas,Mellbin Linda,Näsman Per,Rydén Lars,Söderberg Stefan,Tenerz Åke,Norhammar Anna
Diabetes & vascular disease research
OBJECTIVE:Adiponectin and leptin are associated with insulin resistance and cardiovascular disease. Information on the prognostic value after an acute myocardial infarction is still conflicting. METHODS:Patients (n = 180) without known diabetes and with admission glucose of <11 mmol/L admitted for an acute myocardial infarction in 1998-2000 were followed for mortality and cardiovascular events (first of cardiovascular mortality/acute myocardial infarction/stroke/heart failure) until the end of 2011 (median: 11.6 years). Plasma adiponectin and leptin were related to outcome in Cox proportional-hazard regression analyses. RESULTS:Median age was 64 years and 69% were male. Total mortality was 34% (n = 61) and 44% (n = 80) experienced a cardiovascular event. Adiponectin at discharge predicted cardiovascular events (hazard ratio; 95% confidence interval; 1.45; 1.02-2.07, p = 0.038), total mortality (2.53; 1.64-3.91, p < 0.001) and cancer mortality (3.64; 1.51-8.74, p = 0.004). After adjustment for age, sex, body mass index, previous myocardial infarction and heart failure, adiponectin predicted total mortality (1.79; 1.07-3.00, p = 0.027) but not cardiovascular events. High levels of leptin were associated with cardiovascular events during the first 7 years, after which the association was attenuated. Leptin did not predict total mortality. CONCLUSION:In patients with acute myocardial infarction but without previously known diabetes, high levels of adiponectin at discharge predicted total mortality. The present results support the hypothesis that high rather than low levels of adiponectin predict mortality after acute myocardial infarction.
Adipokines in connective tissue diseases.
Sawicka Karolina,Krasowska Dorota
Clinical and experimental rheumatology
Adipokines, pleiotropic molecules produced by white adipose tissue (WAT) have attracted the attention of scientists since 1994. The role of adipokines in metabolic syndrome is known and fixed. Adipokines exerting a variety of metabolic activities have contributed to the ethiopathogenesis and the consequences of metabolic syndrome. Furthermore, adipokines are involved in the regulation of inflammatory processes and autoimmunity in the light of pathogenesis of connective tissue diseases. Given some evidence for the influence of adipokines in metabolic syndrome, there may be a link between CVDs and rheumatic diseases. This review provides an overview of the literature focusing on the role of adipokines in rheumatic diseases by putting special emphasis on the potential role of leptin, resistin, adiponectin, chemerin, visfatin and novel adipokines in connective tissue diseases.
Potential beneficial effect of some adipokines positively correlated with the adipose tissue content on the cardiovascular system.
Sawicka Magdalena,Janowska Joanna,Chudek Jerzy
International journal of cardiology
Obesity is a risk factor of cardiovascular diseases. However, in the case of heart failure, obese and overweight patients have a more favourable prognosis compared to patients who have a normal body weight. This phenomenon is referred to as the "obesity paradox," and it is explained by, among others, a positive effect of adipokines produced by adipose tissue, particularly by the tissue located in the direct vicinity of the heart and blood vessels. The favourable effect on the cardiovascular system is mostly associated with adiponectin and omentin, but the levels of these substances are reduced in obese patients. Among the adipokines which levels are positively correlated with the adipose tissue content, favourable activity is demonstrated by apelin, progranulin, chemerin, TNF-α (tumour necrosis factor-)α, CTRP-3 (C1q/tumour necrosis factor (TNF) related protein), leptin, visfatin and vaspin. This activity is associated with the promotion of regeneration processes in the damaged myocardium, formation of new blood vessels, reduction of the afterload, improvement of metabolic processes in cardiomyocytes and myocardial contractile function, inhibition of apoptosis and fibrosis of the myocardium, as well as anti-inflammatory and anti-atheromatous effects. The potential use of these properties in the treatment of heart failure and ischaemic heart disease, as well as in pulmonary hypertension, arterial hypertension and the limitation of the loss of cardiomyocytes during cardioplegia-requiring cardiosurgical procedures, is studied. The most advanced studies focus on analogues of apelin and progranulin.
Serum fibroblast growth factor 21 is a superior biomarker to other adipokines in predicting incident diabetes.
Woo Yu Cho,Lee Chi Ho,Fong Carol H Y,Xu Aimin,Tso Annette W K,Cheung Bernard M Y,Lam Karen S L
OBJECTIVE:Fibroblast growth factor 21 (FGF21) improves glucose and lipid metabolism, but high circulating levels are found in type 2 diabetes, suggesting FGF21 resistance. Serum FGF21 predicts incident diabetes, but its performance compared to established and emerging predictors is not known. We aimed to study the performance of FGF21 in diabetes prediction, relative to other adipokines and established risk factors including 2-h plasma glucose (2hG) during the oral glucose tolerance test (OGTT). DESIGN/PARTICIPANTS/MEASUREMENTS:We studied 1380 nondiabetic subjects from the Hong Kong Cardiovascular Risk Factor Prevalence Study using the second visit (2000-2004) as baseline when serum levels of FGF21 and other adipokines were measured. Glycaemic status was assessed by OGTT. Incident diabetes was defined as fasting glucose level (FG) ≥ 7 mmol/l or 2hG ≥ 11·1 mmol/l or use of antidiabetic agents, at subsequent visits. RESULTS:A total of 123 participants developed diabetes over 9·0 years (median). On multivariable logistic regression analysis, FGF21 (P = 0·003), adipocyte fatty acid-binding protein (P = 0·003) and adiponectin (P = 0·035) were independent predictors of incident diabetes. FGF21 had the best change in log likelihood when added to a diabetes prediction model (DP) based on age, family history, smoking, hypertension, BMI, dyslipidaemia and FG. It also improved the area under ROC curve (AUROC) of diabetes prediction (DP) from 0·797 to 0·819 (P = 0·0072), rendering its performance comparable to the 'DP + 2hG' model (AUROC=0·838, P = 0·19). CONCLUSIONS:As a biomarker for diabetes prediction, serum FGF21 appeared to be superior to other adipokines and, on its own, could be considered as an alternative to the OGTT.
Circulating adipokines and risk of obesity related cancers: A systematic review and meta-analysis.
Yoon Yeong Sook,Kwon A Rom,Lee Yoon Kyung,Oh Sang Woo
Obesity research & clinical practice
BACKGROUND:Obesity can influence on carcinogenesis through alterations in adipokines and subsequent inflammatory changes. This meta-analysis was aimed to comprehensively assess the association between circulating adipokines and risk of obesity-related cancers. METHODS:Pubmed and Embase were searched up to October 2017 for observational studies investigating the relationship between adipokines and cancers. Pooled odds ratio and the corresponding 95% confidence interval was estimated through the meta-analysis using a random-effects model. Findings A total of 93 observational studies (adiponectin = 60, high molecular weight adiponectin = 9, leptin = 39, IL-6 = 16, TNF-α = 10, and resistin = 17) were included. Adiponectin was significantly associated with decreased risk of cancer (pooled OR 0.70, 95% CI 0.60-0.80; I = 71.9%; P <0.01). Leptin was significantly associated with increased risk of cancer (1.26, 1.05-1.51; I = 65.7%; P <0.01). For each 5 μg/ml increase in adiponectin and 5 ng/ml increase in leptin, the pooled OR was 0.88 (0.83-0.93; I = 80.2%; P <0.01) and 1.05 (1.01-1.09; I = 67.9%; P<0.01)), respectively. There was nonlinear dose-response association (P for adiponectin = 0.01; P for leptin = 0.003).IL-6 (1.09, 0.94-1.25), TNF- α (1.65, 0.99-2.74), and resistin (1.28, 0.78-2.11) was not associated with risk of cancer. By cancer site and type, highest category of adiponectin was associated with decreased risk of breast (OR 0.74, 0.60-0.91), colorectal (0.74, 0.60-0.91), and endometrial cancer (0.49, 0.34-0.72). Higher leptin was associated with increased risk of endometrial (1.88, 1.24-2.87) and kidney cancer (2.07, 1.51-2.83). CONCLUSION:Our study suggests that adiponectin and leptin may play a role in the etiology of cancer.
Adipokines in Multiple Sclerosis Patients with and without Optic Neuritis as the First Clinical Presentation.
Düzel Berna,Tamam Yusuf,Çoban Arzu,Tüzün Erdem
BACKGROUND:Adipocytokines have been implied to be involved in multiple sclerosis (MS) pathogenesis. MS patients whose first clinical episode is optic neuritis (ON) have been reported to display a milder disease course. In this study, we aimed to show whether this milder disease course is related to reduced adipokine production. METHODS:A total of 55 (24 with ON as the first clinical episode) relapsing-remitting MS (RRMS) patients and 40 healthy individuals were recruited. Concentrations of adipokines were measured in sera by ELISA. RESULTS:The levels of adiponectin, leptin, resistin, monocyte chemoattractant protein-1 (MCP-1) and IL-8 were significantly higher in RRMS patients compared with healthy controls. RRMS cases starting with ON had lower expanded disability status scale scores. Serum adiponectin, leptin, resistin and MCP-1 levels were significantly lower in MS patients, whose first clinical episode was ON. CONCLUSIONS:MS patients with ON as the first manifestation display both lower disability scores and reduced serum adipokine levels implying that adipocytokine production is associated with MS progression. Exact mechanisms of this association in MS patients with first episode ON need to be further studied.
Serum cytokines, adipokines and ferritin for non-invasive assessment of liver fibrosis in chronic liver disease: a systematic review.
Haghgoo Seyyed Mortaza,Sharafi Heidar,Alavian Seyed Moayed
Clinical chemistry and laboratory medicine
Chronic liver disease (CLD) is a major health problem worldwide. Non-alcoholic fatty liver disease (NAFLD), chronic hepatitis C (CHC), chronic hepatitis B (CHB), and alcoholic liver disease (ALD) are the most common etiologies of CLD. Liver biopsy is the gold standard for assessment of liver fibrosis, however, it is an invasive method. This review attempts to evaluate the usefulness of serum adiponectin, serum leptin, serum ferritin, serum transforming growth factor-β1 (TGF-β1), and serum platelet derived growth factor-BB (PDGF-BB) as non-invasive markers in the diagnosis of liver fibrosis/cirrhosis. A systematic search in MEDLINE, Web of Science, Scopus, and local databases was performed to identify articles published in English or Persian as of November 2017. Studies conducted among CLD patients, with biopsy proven fibrosis/cirrhosis, and providing sufficient details of patients' clinicopathological characteristics were included. In the 95 studies included, there were a total of 15,548 CLD patients. More than 83% of studies were carried out in Asia and Europe. The relationship between liver fibrosis/cirrhosis and serum levels of ferritin, adiponectin, leptin, TGF-β1, and PDGF-BB was assessed in 42, 33, 27, nine, and three studies, respectively. Serum levels of the markers, particularly ferritin, could successfully predict liver fibrosis/cirrhosis, however, these data might not be clinically replicated and further studies are needed.
Severe degenerative aortic stenosis with preserved ejection fraction does not change adipokines serum levels.
Mizia-Stec Katarzyna,Bochenek Tomasz,Kusz Błażej,Mizia-Szubryt Magdalena,Sikora-Puz Agnieszka,Gieszczyk-Strózik Klaudia
BACKGROUND:The role of the adipokines in the pathogenesis of aortic stenosis (AS) is not well established. The aim was to evaluate the relationship between adipokines and clinical characteristics as well as echocardiographic indices and noninvasive markers of vascular remodeling in patients with severe AS with preserved ejection fraction (EF). METHODS:Sixty-five patients (F/M: 38/27; age: 68.3 ± 9.0 years; body mass index [BMI]: 29.6 ± 4.3 kg/m2) with severe AS with preserved EF: 33 patients with paradoxical low-flow low-gradient AS (PLFLG AS) and 32 patients with normal flow high-gradient AS (NFHG AS) were prospectively enrolled into the study. Twenty-four subjects (F/M: 14/10; age: 65.4 ± 8.7 years; BMI: 29.6 ± 4.3 kg/m2) who matched as to age, sex, BMI and coronary artery disease (CAD) constituted the control group (CG). Clinical data and markers of vascular remodeling were related to the serum adipokines. RESULTS:There were no differences in the adipokines concentrations in the AS/CG. Patients with AS and coexisting CAD were characterized by decreased serum adiponectin (9.9 ± 5.5 vs. 12.7 ± 5.8 μg/mL, p = 0.040) and leptin (8.3 ± 7.8 vs. 21.6 ± 17.1 ng/mL, p < 0.001) levels compared to subjects without CAD. There were no differences in the serum adipokines concentrations between patients with PLFLG AS and NFHG AS. Systemic hypertension, diabetes, hyperlipidemia or markers of vascular remodeling did not discriminate adipokines concentrations. Multivariate regression analysis indicated that age (F = 3.02; p = 0.015) and E/E' index (F = 0.87, p = 0.032) were independent predictors of the adiponectin level in the AS group. CONCLUSIONS:The presence of AS with preserved EF did not change the adipokine serum profile. Adipokines levels were modified by coexisting atherosclerosis but not the typical cardiovascular risk factors or the hemodynamic type of AS.
Inflammatory processes in obesity: focus on endothelial dysfunction and the role of adipokines as inflammatory mediators.
Singh Manindra,Benencia Fabian
International reviews of immunology
Obesity predisposes the affected individuals to several metabolic, inflammatory, cardiovascular and malignant pathologies and is a top risk factor for premature mortality. It is now well known that inflammation has a major causative role in obesity-associated disease development and that obesity favors the establishment of a pro-inflammatory milieu at the level of adipose microenvironment. These inflammatory signals result in a disruption of normal cellular-crosstalk between adipose and non-adipose components leading to an altered metabolic and immunological status and a dysfunctional phenotype. Abnormal secretion of adipokines - small adipose-derived signaling molecules - can further assist in the inflammatory processes to offset the adipose tissue towards a dysfunctional state. Although adipokines have been recognized as the link between obesity and pathogenesis, studies are needed to fully understand their mechanism of action and underscore their therapeutic value. Here, we have reviewed obesity-induced metabolic and immunological changes at the level of vasculature and emphasize on the importance of adipokines, particularly leptin, vaspin and visfatin, for their therapeutic relevance.
Angiotensin-(1-7), Adipokines and Inflammation.
Lelis Deborah de Farias,Freitas Daniela Fernanda de,Machado Amanda Souto,Crespo Thaísa Soares,Santos Sérgio Henrique Sousa
Metabolism: clinical and experimental
Nowadays the adipose tissue is recognized as one of the most critical endocrine organs releasing many adipokines that regulate metabolism, inflammation and body homeostasis. There are several described adipokines, including the renin-angiotensin system (RAS) components that are especially activated in some diseases with increased production of angiotensin II and several pro-inflammatory hormones. On the other hand, RAS also expresses angiotensin-(1-7), which is now recognized as the main peptide on counteracting Ang II effects. New studies have shown that increased activation of ACE2/Ang-(1-7)/MasR arm can revert and prevent local and systemic dysfunctions improving lipid profile and insulin resistance by modulating insulin actions, and reducing inflammation. In this context, the present review shows the interaction and relevance of Ang-(1-7) effects on regulating adipokines, and as one adipokine itself, modulating body homeostasis, with emphasis on its anti-inflammatory properties, especially in the context of metabolic disorders with focus on obesity and type 2 diabetes mellitus pandemic.
Association of plasma leptin, pro-inflammatory adipokines and cancer-related fatigue in early-stage breast cancer patients: A prospective cohort study.
Toh Yi Long,Tan Chia Jie,Yeo Angie Hui Ling,Shwe Maung,Ho Han Kiat,Gan Yan Xiang,Foo Koon Mian,Chu Pat,Olson Karin,Chan Alexandre
Journal of cellular and molecular medicine
Cancer-related fatigue (CRF) is subjective and has wide inter-individual variability. Given that leptin is commonly associated with fatigue syndrome, its use as a potential biomarker for CRF is being investigated. The primary objective of this study was to evaluate the association between leptin and CRF in early-stage breast cancer patients receiving chemotherapy. In a prospective cohort study, patients completed assessments at baseline (T1), during chemotherapy (T2) and after chemotherapy (T3). Levels of plasma leptin and adipokines were measured using a Luminex bead-immunoassay and CRF was measured using the Multi-Dimensional Fatigue Symptom Inventory-Short Form (MFSI-SF). Data were analysed longitudinally using a generalised estimating equation incorporating clinically relevant parameters and pro-inflammatory adipokines. The analysis included 136 patients (mean age ± SD = 51.5 ± 8.8 years; 69.1% receiving anthracycline-based chemotherapy). More patients experienced CRF at T3 (23.8%) than at T2 (13.8%) compared to baseline. An increase was observed in the median plasma leptin level at T2, followed by a decrease at T3 (T1: 4.07 ng/mL, T2: 4.95 ng/mL and T3: 3.96 ng/mL). In the multivariate model, the change in leptin levels over time was significantly associated with the total MFSI-SF score (β = -0.15, P = 0.003) after adjusting for the tumour necrosis factor-α (TNF-α) level, anxiety, depression, insomnia, age, menopausal status and type of chemotherapy. This is the first study to report leptin as a biomarker that predicts the onset of CRF over time. Future studies are required to validate the findings.
Associations between Adipokines in Arthritic Disease and Implications for Obesity.
MᵃᶜDonald Iona J,Liu Shan-Chi,Huang Chien-Chung,Kuo Shu-Jui,Tsai Chun-Hao,Tang Chih-Hsin
International journal of molecular sciences
Secretion from adipose tissue of adipokines or adipocytokines, comprising of bioactive peptides or proteins, immune molecules and inflammatory mediators, exert critical roles in inflammatory arthritis and obesity. This review considers the evidence generated over the last decade regarding the effects of several adipokines including leptin, adiponectin, visfatin, resistin, chemerin and apelin, in cartilage and bone homeostasis in the pathogenesis of rheumatoid arthritis and osteoarthritis, which has important implications for obesity.
The Role of Adipokines as Circulating Biomarkers in Critical Illness and Sepsis.
Loosen Sven H,Koch Alexander,Tacke Frank,Roderburg Christoph,Luedde Tom
International journal of molecular sciences
Sepsis represents a major global health burden. Early diagnosis of sepsis as well as guiding early therapeutic decisions in septic patients still represent major clinical challenges. In this context, a whole plethora of different clinical and serum-based markers have been tested regarding their potential for early detection of sepsis and their ability to stratify patients according to their probability to survive critical illness and sepsis. Adipokines represent a fast-growing class of proteins that have gained an increasing interest with respect to their potential to modulate immune responses in inflammatory and infectious diseases. We review current knowledge on the role of different adipokines in diagnostic work-up and risk stratification of sepsis as well as critical illness. We discuss recent data from animal models as well as from clinical studies and finally highlight the limitations of these analyses that currently prevent the use of adipokines as biomarkers in daily practice.
Role of Adipokines in the Association between Thyroid Hormone and Components of the Metabolic Syndrome.
Delitala Alessandro P,Scuteri Angelo,Fiorillo Edoardo,Lakatta Edward G,Schlessinger David,Cucca Francesco
Journal of clinical medicine
Metabolic syndrome (MS) increases cardiovascular risk. The role of thyroid hormone on components of MS is unclear. We analyzed a sample of 4733 euthyroid subjects from SardiNIA study. In female thyrotropin (TSH) was significantly and positively associated with triglycerides (Standardized regression coefficients () = 0.081, < 0.001). Free thyroxine (FT4) was positively associated with HDL ( = 0.056, < 0.01), systolic blood pressure (SBP) ( = 0.059, < 0.001), diastolic blood pressure (DBP) ( = 0.044, < 0.01), and fasting glucose ( = 0.046, < 0.01). Conversely, FT4 showed a negative association with waist circumference ( = -0.052, < 0.001). In TSH was positively associated with triglycerides ( = 0.111, = <0.001) and FT4 showed a positive association with DBP ( = 0.51, < 0.01). The addition of leptin and adiponectin to the regression models did not substantially change the impact of thyroid hormones on components of MS. Our data suggest that, even within the euthyroid range, excess of truncal adipose tissue is associated with variations in FT4. Leptin and adiponectin exert an additive effect rather than a causal effect. Additional studies should be performed to determine the clinical significance of this finding.
Circulating microRNAs and adipokines as markers of metabolic syndrome in adolescents with obesity.
Al-Rawaf Hadeel A
Clinical nutrition (Edinburgh, Scotland)
BACKGROUND:Circulating microRNAs (miRNAs) as valuable biomarkers yielded important insights into the pathogenesis of obesity. AIM:This study aimed to describe the circulating miRNA profile for adolescences and its association with the circulating levels leptin and adiponectin according to specific degree of obesity. METHODS:RT-PCR and immunoassy analysis were used to study circulating miRNA profile, adipokines; adiponectin (A), leptin (L), and L/A ratio as well as other factors of metabolic syndrome (MS) in 250 adolescents with severe obesity. RESULTS:In morbidly obese adolescents, we identified at least 10 circulating miRNAs, including increased concentrations of miRNAS; miR-142-3p, miR-140-5p, miR-222 miR-143, miR-130, and decreased concentrations of miR-532-5p, miR-423-5p, miR-520c-3p, miR-146a, and miR-15a, which were strongly linked to measures of BMI, WHtR, adipokines; adiponectin, leptin, L/A ratio, and other MS related biomarkers such as FBS, insulin, HOMA-IR, C-peptide, and circulated plasma lipids such as TG, HDL-C, and LDL-C. CONCLUSION:Circulating miRNAs showed significant association with plasma levels of adipokines; adiponectin, leptin, and L/A ratios in adolescents with severe obesity. The study provides that regulation of miRNAs expression is associated with adipokines, and other related MS metabolic factors. Thus, early detection of any changes in circulating miRNAs profiles may play a promising role in identifying obese children or adolescents who may suffer from severe metabolic syndrome.
Relevance of Leptin and Other Adipokines in Obesity-Associated Cardiovascular Risk.
Landecho Manuel F,Tuero Carlota,Valentí Víctor,Bilbao Idoia,de la Higuera Magdalena,Frühbeck Gema
Obesity, which is a worldwide epidemic, confers increased risk for multiple serious conditions including type 2 diabetes, nonalcoholic fatty liver disease, and cardiovascular diseases. Adipose tissue is considered one of the largest endocrine organs in the body as well as an active tissue for cellular reactions and metabolic homeostasis rather than an inert tissue only for energy storage. The functional pleiotropism of adipose tissue relies on its ability to synthesize and release a large number of hormones, cytokines, extracellular matrix proteins, and growth and vasoactive factors, which are collectively called adipokines known to influence a variety of physiological and pathophysiological processes. In the obese state, excessive visceral fat accumulation causes adipose tissue dysfunctionality that strongly contributes to the onset of obesity-related comorbidities. The mechanisms underlying adipose tissue dysfunction include adipocyte hypertrophy and hyperplasia, increased inflammation, impaired extracellular matrix remodeling, and fibrosis together with an altered secretion of adipokines. This review describes the relevance of specific adipokines in the obesity-associated cardiovascular disease.
Role of Obesity, Mesenteric Adipose Tissue, and Adipokines in Inflammatory Bowel Diseases.
Bilski Jan,Mazur-Bialy Agnieszka,Wojcik Dagmara,Surmiak Marcin,Magierowski Marcin,Sliwowski Zbigniew,Pajdo Robert,Kwiecien Slawomir,Danielak Aleksandra,Ptak-Belowska Agata,Brzozowski Thomas
Inflammatory bowel diseases (IBDs) are a group of disorders which include ulcerative colitis and Crohn's disease. Obesity is becoming increasingly more common among patients with inflammatory bowel disease and plays a role in the development and course of the disease. This is especially true in the case of Crohn's disease. The recent results indicate a special role of visceral adipose tissue and particularly mesenteric adipose tissue, also known as "creeping fat", in pathomechanism, leading to intestinal inflammation. The involvement of altered adipocyte function and the deregulated production of adipokines, such as leptin and adiponectin, has been suggested in pathogenesis of IBD. In this review, we discuss the epidemiology and pathophysiology of obesity in IBD, the influence of a Western diet on the course of Crohn's disease and colitis in IBD patients and animal's models, and the potential role of adipokines in these disorders. Since altered body composition, decrease of skeletal muscle mass, and development of pathologically changed mesenteric white adipose tissue are well-known features of IBD and especially of Crohn's disease, we discuss the possible crosstalk between adipokines and myokines released from skeletal muscle during exercise with moderate or forced intensity. The emerging role of microbiota and the antioxidative and anti-inflammatory enzymes such as intestinal alkaline phosphatase is also discussed, in order to open new avenues for the therapy against intestinal perturbations associated with IBD.
Adipokines: Linking metabolic syndrome, the immune system, and arthritic diseases.
Francisco Vera,Ruiz-Fernández Clara,Pino Jesús,Mera Antonio,González-Gay Miguel A,Gómez Rodolfo,Lago Francisca,Mobasheri Ali,Gualillo Oreste
Metabolic syndrome (MetS) represents a cluster of metabolic and cardiovascular complications, including obesity and visceral adiposity, insulin resistance, dyslipidemia, hyperglycemia and hypertension, which directly increase the risk of cardiovascular diseases (CVD) and diabetes mellitus type 2 (DM2). Patients with arthritic diseases, such as rheumatoid arthritis and osteoarthritis, have a higher incidence of CVD. Although recent advances in the treatment of arthritic diseases, the incidence of CVD remains elevated, and MetS has been identified as a possible link between CVD and arthritic diseases. Chronic low-grade inflammation associated with obesity has been established as a significant contributing factor to the increased prevalence of MetS. Adipokines, which play important physiological roles in metabolic activities contributing to the pathogenesis of MetS, are also involved in the regulation of autoimmune and/or inflammatory processes associated with arthritic diseases. Therefore, MetS and dysregulated secretion of pro-inflammatory adipokines have been recognized as a molecular link between CVD and arthritis diseases. In the present paper, we review recent evidence supporting the role played by adipokines, in particular leptin, adiponectin, and lipocalin-2, in the modulation of the immune system, MetS and arthritic diseases. The underlying cellular and molecular mechanisms are discussed, as well as potential new therapeutic strategies.
The Role of Adipokines in Breast Cancer: Current Evidence and Perspectives.
Christodoulatos Gerasimos Socrates,Spyrou Nikolaos,Kadillari Jona,Psallida Sotiria,Dalamaga Maria
Current obesity reports
PURPOSE:The current review shows evidence for the role of adipokines in breast cancer (BC) pathogenesis summarizing the mechanisms underlying the association between adipokines and breast malignancy. Special emphasis is given also on intriguing insights into the relationship between obesity and BC as well as on the role of novel adipokines in BC development. RECENT FINDINGS:Recent evidence has underscored the role of the triad of obesity, insulin resistance, and adipokines in postmenopausal BC. Adipokines exert independent and joint effects on activation of major intracellular signal networks implicated in BC cell proliferation, growth, survival, invasion, and metastasis, particularly in the context of obesity, considered a systemic endocrine dysfunction characterized by chronic inflammation. To date, more than 10 adipokines have been linked to BC, and this catalog is continuously increasing. The majority of circulating adipokines, such as leptin, resistin, visfatin, apelin, lipocalin 2, osteopontin, and oncostatin M, is elevated in BC, while some adipokines such as adiponectin and irisin (adipo-myokine) are generally decreased in BC and considered protective against breast carcinogenesis. Further evidence from basic and translational research is necessary to delineate the ontological role of adipokines and their interplay in BC pathogenesis. More large-scale clinical and longitudinal studies are awaited to assess their clinical utility in BC prognosis and follow-up. Finally, novel more effective and safer adipokine-centered therapeutic strategies could pave the way for targeted oncotherapy.
The potential of adipokines as biomarkers and therapeutic agents for vascular complications in type 2 diabetes mellitus.
Liang Wei,Ye Dong Dong
Cytokine & growth factor reviews
Over the past decades, there has been a major increase in type 2 diabetes (T2D) prevalence in most regions of the world. Diabetic patients are more prone to cardiovascular complications. Accumulating evidence suggests that adipose tissue is not simply an energy storage tissue but it also functions as a secretory tissue producing a variety of bioactive substances, also referred to as adipokines. The balance between pro-inflammatory adipokines and protective adipokines is disturbed in type 2 diabetes, this can be regarded as adipose tissue dysfunction which partly promote the pathogenesis of diabetes complications. In this review, we not only discuss the favorable adipokines like adiponectin, omentin, C1q tumor necrosis factor-related proteins, but also unfavorable ones like resisitin and visfatin, in the aim of finding potential biomarkers recommended for the clinical use in the diagnosis, prognosis and follow up of patients with T2D at high risk of developing cardiovascular diseases as well as leading to new therapeutic approaches.
Perinatal Whole Blood Zinc Status and Cytokines, Adipokines, and Other Immune Response Proteins.
Kyvsgaard Julie Nyholm,Ellervik Christina,Lindkvist Emilie Bundgaard,Pipper Christian Bressen,Pociot Flemming,Svensson Jannet,Thorsen Steffen Ullitz
(1) Background: Zinc is an essential micronutrient and zinc deficiency is associated with immune dysfunction. The neonatal immune system is immature, and therefore an optimal neonatal zinc status may be important. The aim of this study was to investigate the possible association between neonatal whole blood (WB)-Zinc content and several immune markers. (2) Methods: In total, 398 healthy newborns (199 who later developed type 1 diabetes and 199 controls) from the Danish Newborn Screening Biobank had neonatal dried blood spots (NDBS) analyzed for WB-Zinc content and (i) cytokines: Interleukin (IL)-1β, IL-4, IL-6, IL-8, IL-10, IL-12 (p70), interferon gamma, tumor necrosis factor alpha, and transforming growth factor beta; (ii) adipokines: leptin and adiponectin; (iii) other immune response proteins: C-reactive protein (CRP), and mannose-binding lectin (MBL), and soluble triggering receptors expressed on myeloid cells1 (sTREM-1). WB-Zinc content was determined using laser ablation inductively coupled plasma mass spectrometry. For each analyte, the relative change in mean level was modelled by a robust log-normal model regression. (3) Results: No association was found between WB-Zinc content and all the immune response markers in either the unadjusted or adjusted models overall or when stratifying by case status. (4) Conclusions: In healthy Danish neonates, WB-Zinc content was not associated with cytokines, adipokines, CRP, MBL or sTREM, which does not indicate a strong immunological function of neonatal zinc status.
Adipokines underlie the early origins of obesity and associated metabolic comorbidities in the offspring of women with pregestational obesity.
Arroyo-Jousse V,Jaramillo A,Castaño-Moreno E,Lépez M,Carrasco-Negüe K,Casanello P
Biochimica et biophysica acta. Molecular basis of disease
Maternal pregestational obesity is a well-known risk factor for offspring obesity, metabolic syndrome, cardiovascular disease and type 2 diabetes. The mechanisms by which maternal obesity can induce alterations in fetal and later neonatal metabolism are not fully elucidated due to its complexity and multifactorial causes. Two adipokines, leptin and adiponectin, are involved in fetal and postnatal growth trajectories, and both are altered in women with pregestational obesity. The placenta synthesizes leptin, which goes mainly to the maternal circulation and in lesser amount to the developing fetus. Maternal pregestational obesity and hyperleptinemia are associated with placental dysfunction and changes in nutrient transporters which directly affect fetal growth and development. By the other side, the embryo can produce its own leptin from early in development, which is associated to fetal weight and adiposity. Adiponectin, an insulin-sensitizing adipokine, is downregulated in maternal obesity. High molecular weight (HMW) adiponectin is the most abundant form and with most biological actions. In maternal obesity lower total and HMW adiponectin levels have been described in the mother, paralleled with high levels in the umbilical cord. Several studies have found that cord blood adiponectin levels are related with postnatal growth trajectories, and it has been suggested that low adiponectin levels in women with pregestational obesity enhance placental insulin sensitivity and activation of placental amino acid transport systems, supporting fetal overgrowth. The possible mechanisms by which maternal pregestational obesity, focusing in the actions of leptin and adiponectin, affects the fetal development and postnatal growth trajectories in their offspring are discussed.
Adipokines are associated with pediatric multiple sclerosis risk and course.
Keyhanian Kiandokht,Saxena Shrishti,Gombolay Grace,Healy Brian C,Misra Madhusmita,Chitnis Tanuja
Multiple sclerosis and related disorders
BACKGROUND:Obesity during adolescence confers an increased risk of multiple sclerosis (MS) in both adults and children. However, obesity-mediated inflammatory mechanisms require elucidation. In models of MS, leptin and fatty acid binding protein-4 (FABP-4) have been identified as proinflammatory adipokines, while adiponectin has anti-inflammatory effects. METHODS:Morning serum samples from 32 pediatric MS (POMS) patients (22 females;10 males) and 67 pediatric healthy controls (PHC) (47 females; 20 males) followed at Massachusetts General Hospital were studied. Levels of leptin, FABP-4 and adiponectin were compared between POMS and PHC groups, adjusting for sex, age and vitamin D3 levels. Associations between each marker and the time to next relapse was assessed using a Cox proportional hazards model. The association between each marker and EDSS was assessed using linear regression. RESULTS:Pediatric MS patients had significantly higher levels of leptin and FABP4 and significantly lower adiponectin than healthy controls. Higher levels of adiponectin were associated with a lower hazard of relapse. Similar differences were observed between POMS and PHC males for both leptin and adiponectin, and within females for FABP4. In females with MS, there was a trend for a positive association between higher leptin levels and higher disability scores. In males with MS, paradoxically, higher leptin levels were associated with longer time to next relapse. All these results remained significant after adjusting for Vitamin D. CONCLUSIONS:FABP4 and leptin levels are higher, while adiponectin levels are lower in pediatric MS compared to controls in sex-specific patterns. These adipokines could serve as biomarkers and therapeutic targets of disease risk and course in early forms of MS.
Adipokines as key players in β cell function and failure.
Gómez-Banoy Nicolás,Lo James C
Clinical science (London, England : 1979)
The growing prevalence of obesity and its related metabolic diseases, mainly Type 2 diabetes (T2D), has increased the interest in adipose tissue (AT) and its role as a principal metabolic orchestrator. Two decades of research have now shown that ATs act as an endocrine organ, secreting soluble factors termed adipocytokines or adipokines. These adipokines play crucial roles in whole-body metabolism with different mechanisms of action largely dependent on the tissue or cell type they are acting on. The pancreatic β cell, a key regulator of glucose metabolism due to its ability to produce and secrete insulin, has been identified as a target for several adipokines. This review will focus on how adipokines affect pancreatic β cell function and their impact on pancreatic β cell survival in disease contexts such as diabetes. Initially, the "classic" adipokines will be discussed, followed by novel secreted adipocyte-specific factors that show therapeutic promise in regulating the adipose-pancreatic β cell axis.
Diagnostic Significance of Plasma Levels of Novel Adipokines in Patients With Symptomatic Intra- and Extracranial Atherosclerotic Stenosis.
Yu Fang,Zhou Xiaoqing,Li Zhibin,Feng Xianjing,Liao Di,Liu Zeyu,Huang Qin,Li Xi,Yang Qidong,Xiao Bo,Xia Jian
Frontiers in neurology
Adipokines have been proven to be associated with atherosclerotic diseases such as ischemic stroke and coronary heart disease. The role of novel adipokines in the development of symptomatic intracranial atherosclerotic stenosis (sICAS) and extracranial atherosclerotic stenosis (sECAS) has not yet been investigated. This study aimed to evaluate the plasma levels of novel adipokines in patients with sICAS and sECAS and their associations with the prognosis of sICAS groups. A total of 134 patients with acute ischemic stroke attribute to large-artery atherosclerosis (LAA) and 66 age- and sex-matched controls without atherosclerotic stenosis (NCAS) were included in this study. The LAA group was further sub-classified as sICAS ( = 102) and sECAS ( = 32) according to the location of atherosclerosis. Demographics, clinical parameters, angiographical features and plasma levels of novel adipokines (apelin, visfatin, omentin, RBP-4) were assayed and compared among groups. LAA patients had significantly lower levels of omentin [39.92 (30.74-52.61) ng/ml vs. 54.42 (34.73-79.91) ng/ml, < 0.001] and visfatin [11.32 (7.62-16.44) ng/ml vs. 13.01 (9.46-27.54) ng/ml, < 0.001] than those in the NCAS group. Multiple logistic regression analysis identified that the lowest tertile of omentin was independently associated with LAA (OR, 3.423; 95% CI, 1.267-9.244, when referenced to the third tertile). Levels of omentin, visfatin and RBP-4 showed no significant difference between sICAS and sECAS groups. However, median concentrations of apelin were lower in sECAS [84.94 (46.88-130.41) ng/mL) than in sICAS [118.64 (93.22-145.08) ng/mL, = 0.002] and NCAS [114.38 (80.56-162.93) ng/mL, = 0.004]. Logistic regression analysis showed that the lowermost tertile of apelin was independently associated with sECAS (OR, 5.121; 95% CI, 1.597-16.426) when adjusted for risk factors. As for sICAS patients, spearman coefficient analysis showed no significant correlation between these four adipokines and the severity of sICAS or the number of vessels with intracranial stenoses. Patients with severe stroke had lower levels of apelin ( = 0.005), while the other three adipokines showed no such difference. During follow up, no difference was found between these four novel adipokines and short- and long-term outcome of sICAS. Lower levels of omentin are independent biomarkers of LAA while low apelin plasma levels seem to be risk factors of sECAS.
Adipokines disrupt cardiac differentiation and cardiomyocyte survival.
Pérez Laura M,de Lucas Beatriz,Bernal Aurora,Gálvez Beatriz G
International journal of obesity (2005)
BACKGROUND:The role of adipose tissue in the pathophysiology of cardiovascular disease remains a major subject of research. The objective of the present study was to dissect the molecular mechanisms that regulate the survival and differentiation of cardiac cells in an obese environment. MATERIAL AND METHODS:We isolated murine/human cardiac cells from adult hearts of control and obese mice/subjects and analyzed the communication between cardiac cells and adipocytes in vitro, as well as the effects on their main functions such as survival and differentiation. RESULTS:We found that the presence of visceral or subcutaneous adipocytes in the environment of cardiomyocytes or cardiac precursors provoked apoptosis or blocked differentiation, respectively, and these effects were mediated by secreted adipokines. Remarkably, cardiac precursors changed their fate and differentiated into mature adipocytes, contributing to the overall increase in adipose cell content. Inhibiting the adipokines TNF-α, visfatin, or HMGB1 could block the deleterious effects of adipokines on cardiac cells. CONCLUSIONS:Our findings demonstrate that mouse and human visceral adipose tissue contributes negatively to the homeostasis and regeneration of the heart. Moreover, our results suggest that blocking the action of certain adipokines might enhance cardiac differentiation and survival.
The adipokines and inflammatory status in the era of pediatric obesity.
Mărginean Cristina Oana,Meliţ Lorena Elena,Huțanu Adina,Ghiga Dana Valentina,Săsăran Maria Oana
INTRODUCTION:Obesity is associated with a chronic inflammation due to the deficiency in immune activity related to adipose tissue. A wide-spectrum of pro-inflammatory cytokines secreted by adipocytes play an important role in the assessment of obesity-associated inflammatory status. The aim of this study was to assess the relationship between IL and 1β, IL-6, TNF α, leptin, and inflammatory status in children with overweight/obesity. MATERIAL AND METHODS:We performed a cross-sectional study on 193 children, admitted to a Pediatric Tertiary Hospital in Romania. The children were divided according to BMI into: the study group-91 children with overweight/obesity, and the control group-102 children with normal BMI. Demographic, anthropometric, and laboratory parameters including the serum levels of several adipokines (leptin, IL-1β, IL-6, and TNF α) were assessed in both groups. RESULTS:Our findings revealed significantly higher values of leukocytes, lymphocytes, platelets, AST, and ALT, as well as for the lipid metabolism parameters including cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, and CRP, in children with overweight/obesity. We found significantly higher levels of adipokines in the serum of children with overweight and obesity assessed for leptin, IL6, and TNF α (p = 0.0145/p < 0.0001/p = 0.004/), except for IL-1β serum levels. CONCLUSIONS:Childhood overweight and/or obesity is associated with a systemic inflammatory status demonstrated by increased levels of CBC parameters. Pro-inflammatory adipokines are also an essential factor in obesity-related inflammatory status according to our findings that underlined the importance of increased serum levels of IL-6, TNF α, and leptin in pediatric patients with overweight/obesity. Clinically, CBC parameters along with adipokines might represent useful diagnostic tools for low-grade systemic inflammation in children with overweight or obesity.
A Novel Link Between Adipokines And Lipoprotein (A) To Contemplate Their Diagnostic Role In Patients With Stemi And Nstemi.
Rashid Shazia,Khurshid Rukhshan,Amir Uzma Faryal,Malik Arif,Qazi Sumera
Journal of Ayub Medical College, Abbottabad : JAMC
BACKGROUND:Early detection of cardiac events allow better and cost-effective triage and welltimed management of these patients. Study was conducted to evaluate the prognostic significance of plasma adiponectin, resistin and lipoprotein (a) in a group of patients with ST segment elevation myocardial infarction and non-ST-segment elevation myocardial infarction. These parameters were also compared with other predictors like troponin T, troponin I and CK-MB. METHODS:Present study was based on the 100 patients with AMI of whom 52 had a diagnosis of STEMI, and 48 had NSTEMI. Duration of study was January to June 2015. Patients having chest pain that was indicative of myocardial ischemia within first 12 hours after the onset of symptoms were included in the study. Adiponectin, Lp (a), resistin, troponin T and troponin I were estimated using ELISA method. Level of CK-MB was measured by Auto-analyser using standard kit of Merck. RESULTS:Mean age of patients with STEMI was 52.32 years and with NSTEMI it was 48.17 years. Mean value of BMI of patients with STEMI was 28.33 and with NSTEMI was 25.22 Kg/m2. Duration of chest pain in patients with STEMI was 8.64 and patients with NSTEMI it was 16.52hours with highly significant difference (p<0.001). History of smoking in patients with STEMI was more as compared to the patients with NSTEMI. Level of CPK, adiponectin and lipoprotein (a) was raised in patients with STEMI as compared to patients with NSTEMI but significant difference was only found in levels of CPK (p<0.001) and in adiponectin (p<0.05). Level of serum CK-MB, TnT, TnI and resistin was raised in patients with NSTEMI as compared to patients with STEMI but significant difference (p<0.001) was only observed in serum troponin I concentration. CONCLUSIONS:It is concluded that the incidence of STEMI and NSTEMI is similar in our patients. However, the markers of STEMI are increased level of adiponectin and Lp(a) and the markers of NSTEMI are troponins especially troponin I, resistin and CKMB.
Adiposity Measures and Plasma Adipokines in Females with Rheumatoid and Osteoarthritis.
DeClercq Vanessa,Cui Yunsong,Forbes Cynthia,Grandy Scott A,Keats Melanie,Parker Louise,Sweeney Ellen,Yu Zhijie Michael,Dummer Trevor J B
Mediators of inflammation
The objective of this study was to examine the relationship between adipokines and adiposity in individuals with rheumatoid and osteoarthritis in the Atlantic PATH cohort. Using a nested case-control analysis, participants in the Atlantic PATH cohort with rheumatoid or osteoarthritis were matched for measures of adiposity with participants without a history of arthritis. Both measured and self-reported data were used to examine disease status, adiposity, and lifestyle factors. Immunoassays were used to measure plasma markers. BMI was positively correlated with percentage body fat, fat mass index (FMI), and a change in BMI from 18 years of age in all 3 groups. There were no statistical differences between levels of plasma adipokines; adiponectin levels were 6.6, 7.9, and 8.2 g/ml, leptin levels were 10.3, 13.7, and 11.5 ng/ml, and resistin levels were 10.0, 12.1, and 10.8 ng/ml in participants without arthritis, with rheumatoid arthritis, and with osteoarthritis, respectively. Those with higher levels of adiponectin were more likely to have osteoarthritis (but not rheumatoid arthritis). No association was found between arthritis types and leptin or resistin. This study demonstrates differences in measures of adiposity and adipokines in specific types of arthritis and highlights the need for more research targeting specific adipokines during arthritic disease progression.
Programming of Adiposity in Childhood and Adolescence: Associations With Birth Weight and Cord Blood Adipokines.
Simpson Joy,Smith Andrew D A C,Fraser Abigail,Sattar Naveed,Lindsay Robert S,Ring Susan M,Tilling Kate,Davey Smith George,Lawlor Debbie A,Nelson Scott M
The Journal of clinical endocrinology and metabolism
Context:Exposure to maternal adiposity during pregnancy is associated with higher offspring birth weight and greater adiposity through childhood and adult life. As birth weight reflects the summation of lean and fat mass, the extent to which fat mass at birth tracks into later life is unknown. Objective:To determine whether fat mass at birth is associated with child and adolescent adiposity. Design, Setting, and Participants:UK birth cohort with markers of neonatal fat mass; cord blood leptin, adiponectin, and birth weight and adiposity outcomes at age 9 (n = 2775) and 17 years (n = 2138). Main Outcomes:Offspring body mass index (BMI), waist circumference, dual-energy X-ray absorptiometry-determined fat mass, and obesity at age 9 and 17 years. Results:Higher cord blood leptin was associated with higher z scores of fat mass [difference in mean per 10 pg/mL: 0.03 standard deviation (SD); 95% confidence interval (CI), 0.00 to 0.06], waist circumference (0.04 SD; 95% CI, 0.00 to 0.07), and BMI (0.04 SD; 95% CI, 0.00 to 0.08) at age 9. However, by age 17 the adjusted results were attenuated to the null. Cord blood adiponectin was not associated with measures of adiposity at age 9. At age 17, cord blood adiponectin was positively associated with fat mass (0.02 SD per 10 μg/mL; 95% CI, 0.02 to 0.03) and waist circumference (0.04 SD per 10 μg/mL; 95% CI, 0.03 to 0.05). Birth weight was positively associated with waist circumference (0.03 SD per 100 g; 95% CI, 0.02 to 0.04) and BMI (0.02 SD per 100 g; 95% CI, 0.00 to 0.03), but not fat mass or odds of obesity. Cord blood leptin and adiponectin were not associated with obesity at either age. Conclusions:Increased cord blood leptin and adiponectin, known surrogates of fetal fat mass, were weakly associated with increased fat mass in late childhood and adolescence, respectively.
Adipokines: Potential Therapeutic Targets for Vascular Dysfunction in Type II Diabetes Mellitus and Obesity.
El Husseny Mostafa Wanees Ahmed,Mamdouh Mediana,Shaban Sara,Ibrahim Abushouk Abdelrahman,Zaki Marwa Mostafa Mohamed,Ahmed Osama M,Abdel-Daim Mohamed M
Journal of diabetes research
Adipokines are bioactive molecules that regulate several physiological functions such as energy balance, insulin sensitization, appetite regulation, inflammatory response, and vascular homeostasis. They include proinflammatory cytokines such as adipocyte fatty acid binding protein (A-FABP) and anti-inflammatory cytokines such as adiponectin, as well as vasodilator and vasoconstrictor molecules. In obesity and type II diabetes mellitus (DM), insulin resistance causes impairment of the endocrine function of the perivascular adipose tissue, an imbalance in the secretion of vasoconstrictor and vasodilator molecules, and an increased production of reactive oxygen species. Recent studies have shown that targeting plasma levels of adipokines or the expression of their receptors can increase insulin sensitivity, improve vascular function, and reduce the risk of cardiovascular morbidity and mortality. Several reviews have discussed the potential of adipokines as therapeutic targets for type II DM and obesity; however, this review is the first to focus on their therapeutic potential for vascular dysfunction in type II DM and obesity.
Circulating adipokines in children with nonalcoholic fatty liver disease: possible noninvasive diagnostic markers.
Mohamed Amal Ahmed,Sabry Said,Abdallah Asmaa Mahmoud,Elazeem Naglaa Adly Abd,Refaey Doaa,Algebaly Hebat Allah Fadel,Fath Gamal Abo El,Omar Heba
Annals of gastroenterology
BACKGROUND:The growing obesity pandemic is the leading cause for increasing prevalence of nonalcoholic fatty liver disease (NAFLD) in children. Histopathological evaluation of the liver remains the gold standard for NAFLD diagnosis, but it is an invasive procedure with a low but real risk of morbidity and mortality. The current study evaluated circulating chemerin and adiponectin as possible noninvasive diagnostic markers for NAFLD in obese non-diabetic children. METHODS:A prospective case-control study was conducted, which included 101 obese children with biopsy-proven NAFLD and 57 age- and sex-matched controls. The overall mean age of the children was 10.08±3.12 years. All underwent a full clinical assessment, routine laboratory investigation, and abdominal ultrasound. Homeostatic model assessment-insulin resistance was calculated and circulating chemerin and adiponectin were evaluated using ELISA. RESULTS:Elevated serum chemerin and decreased serum adiponectin were significantly associated with an increased likelihood of exhibiting NAFLD. Receiver operator characteristic curve analysis for differentiation of NAFLD patients from those in the control group demonstrated that chemerin, at a cutoff value of 186.7 ng/mL, yielded a sensitivity and specificity of 56.44% and 87.72% respectively (P<0.001), whereas adiponectin, at a cutoff value of 2.4 µg/mL, had a sensitivity and specificity of 74.26% and 3.51% respectively (P<0.001). Furthermore, body mass index, aspartate transaminase, alanine transaminase, triglycerides, and gamma-glutamyl transferase had significant positive correlations with chemerin and significant negative correlations with adiponectin (P≤0.001). CONCLUSION:Circulating chemerin and adiponectin could serve as simple noninvasive diagnostic markers for NAFLD in non-diabetic obese children.
The association between obesity related adipokines and risk of breast cancer: a meta-analysis.
Gui Yu,Pan Qinwen,Chen Xianchun,Xu Shuman,Luo Xiangdong,Chen Li
The risk of breast cancer is significantly increased among obese women as the deleterious adipokines can be over secreted and beneficial adipokines can be hyposecreted. We aim to evaluate the association between obesity-associated adipokines and breast cancer. We searched PubMed, EMBASE, Web of Science, and Chinese Biomedical Literature (CBM) databases for studies reporting association of obesity related adipokines with breast cancer published before Sept. 15, 2015. Initially, 26783 publications were identified, and later, 119 articles were selected for further meta-analysis. Out of these 119 studies, twenty-six studies had reported adipokine levels among obese and non-obese healthy subjects and ninety-three studies had reported adipokine levels among patients with breast cancer. The subjects with BMI >25 kg/m2 had significantly lower adiponectin levels and higher leptin and tumor necrosis factor-α (TNF-α) levels than those with BMI <25 kg/m2. Decreased concentrations of adiponectin, and increased concentrations of leptin, IL-6, IL-8, TNF-α, resistin and visfatin were significantly associated with risk of breast cancer. Adipokine levels were strongly associated with breast cancer among Asian women as compared to non-Asian women. Our results might explain the relationship of obesity, adipokine levels and risk of breast cancer, especially in Asian women.
Role of Adipokines in Cardiovascular Disease.
Lau Wayne Bond,Ohashi Koji,Wang Yajing,Ogawa Hayato,Murohara Toyoaki,Ma Xin-Liang,Ouchi Noriyuki
Circulation journal : official journal of the Japanese Circulation Society
Cardiovascular disease (CVD) is the greatest cause of death, accounting for nearly one-third of all deaths worldwide. The increase in obesity rates over 3 decades is widespread and threatens the public health in both developed and developing countries. Obesity, the excessive accumulation of visceral fat, causes the clustering of metabolic disorders, such as type 2 diabetes, dyslipidemia, and hypertension, culminating in the development of CVD. Adipose tissue is not only an energy storage organ, but an active endocrine tissue producing various biologically active proteins known as adipokines. Since leptin, a central regulator of food intake and energy expenditure, was demonstrated to be an adipose-specific adipokine, attention has focused on the identification and characterization of unknown adipokines to clarify the mechanisms underlying obesity-related disorders. Numerous adipokines have been identified in the past 2 decades; most adipokines are upregulated in the obese state. Adipokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, and resistin are pro-inflammatory, and exacerbate various metabolic and cardiovascular diseases. However, a small number of adipokines, including adiponectin, are decreased by obesity, and generally exhibit antiinflammatory properties and protective functions against obesity-related diseases. Collectively, an imbalance in the production of pro- and antiinflammatory adipokines in the obese condition results in multiple complications. In this review, we focus on the pathophysiologic roles of adipokines with cardiovascular protective properties.
Adipokines in Liver Cirrhosis.
Buechler Christa,Haberl Elisabeth M,Rein-Fischboeck Lisa,Aslanidis Charalampos
International journal of molecular sciences
Liver fibrosis can progress to cirrhosis, which is considered a serious disease. The Child-Pugh score and the model of end-stage liver disease score have been established to assess residual liver function in patients with liver cirrhosis. The development of portal hypertension contributes to ascites, variceal bleeding and further complications in these patients. A transjugular intrahepatic portosystemic shunt (TIPS) is used to lower portal pressure, which represents a major improvement in the treatment of patients. Adipokines are proteins released from adipose tissue and modulate hepatic fibrogenesis. These proteins affect various biological processes that are involved in liver function, including angiogenesis, vasodilation, inflammation and deposition of extracellular matrix proteins. The best studied adipokines are adiponectin and leptin. Adiponectin protects against hepatic inflammation and fibrogenesis, and leptin functions as a profibrogenic factor. These and other adipokines are supposed to modulate disease severity in patients with liver cirrhosis. Consequently, circulating levels of these proteins have been analyzed to identify associations with parameters of hepatic function, portal hypertension and its associated complications in patients with liver cirrhosis. This review article briefly addresses the role of adipokines in hepatitis and liver fibrosis. Here, studies having analyzed these proteins in systemic blood in cirrhotic patients are listed to identify adipokines that are comparably changed in the different cohorts of patients with liver cirrhosis. Some studies measured these proteins in systemic, hepatic and portal vein blood or after TIPS to specify the tissues contributing to circulating levels of these proteins and the effect of portal hypertension, respectively.
Investigation of the prognostic value of adipokines in multiple sclerosis.
Çoban Arzu,Düzel Berna,Tüzün Erdem,Tamam Yusuf
Multiple sclerosis and related disorders
BACKGROUND:Adipokines may be involved in multiple sclerosis (MS) as well as other inflammatory diseases. This study aimed to analyze the value of serum adipokine levels as biomarkers in determining the clinical progression of MS. METHODS:A total of 90 subjects including 40 healthy individuals and 50 MS patients [24 with classical clinical course of MS (C-MS), 26 with benign MS (B-MS)] were recruited for this study. The levels of serum adipokines and inflammatory mediators were measured using immunoassay methods. RESULTS:The levels of adiponectin, MCP-1, TNF-α and IL-6 were significantly higher in C-MS patients compared with B-MS patients and healthy controls. Only adiponectin and MCP-1 levels remained significantly high after Bonferroni correction. Adiponectin, MCP-1 and TNF-α levels showed a modest correlation with expanded disability status scale (EDSS) scores, which disappeared after Bonferroni correction. CONCLUSIONS:Our findings suggest the potential role of adipokines in pathogenesis and clinical progression of MS. Adiponectin and MCP-1 might potentially serve as prognostic biomarkers in MS.
The association between polycystic ovary syndrome, obesity, and the serum concentration of adipokines.
Behboudi-Gandevani S,Ramezani Tehrani F,Bidhendi Yarandi R,Noroozzadeh M,Hedayati M,Azizi F
Journal of endocrinological investigation
PURPOSE:This study aimed to investigate the interactive effect of polycystic ovary syndrome (PCOS) status and obesity status on the serum levels of adipokines. METHODS:In this comparative case-control cross-sectional study, 58 women with PCOS and 104 eumenorrheic non-hirsute women as the control group were recruited. They were further divided into two subgroups of overweight/obese and normal weight. The interactive effect of the PCOS status and obesity status on the circulating levels of adipokines was assessed using general linear model with the adjustment of age. RESULTS:A statistically significant negative interaction was reported between obesity status and PCOS status in the determination of serum adiponectin and resistin concentrations (effect size = -0.14, interaction P = 0.001, effect size = -0.15, P = 0.016). It indicated that adiponectin and resistin were significantly decreased in overweight/obese patients with PCOS compared with other subgroups. Statistically significant positive interactive effects were found between PCOS status obesity status and leptin (effect size = 0.321, interaction P = 0.036), indicating that the overweight/obese women with PCOS had the higher levels of leptin compared with the control group. Also, no interaction was reported between PCOS status and obesity status with regard to the serum levels of other adipokines. CONCLUSIONS:While no sufficient evidence is available with regard to the causal association between adipokines and PCOS, they may contribute to the development of PCOS and regarded as the novel biomarkers of PCOS.
Adipokines may mediate the relationship between resting metabolic rates and bone mineral densities in obese women.
Moradi S,Mirzaei K,Abdurahman A A,Keshavarz S A
Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA
The researchers sought to test the possible link between resting metabolic rate and bone mineral density through four adipokines. Participants with lower resting metabolic rate (RMR) per kilogram demonstrated higher total bone mineral density (BMD), total T-score, and total Z-score. Omentin-1 had a mediatory effect on the relationship between RMR/kg of body weight and bone parameters. INTRODUCTION:The previous results of studies regarding the links between obesity and bone health are controversial. For this reason, the researchers sought to test the possible link between RMR and BMD through the following four adipokines: vaspin, retinol binding protein 4, angiopoietin-like 6 (ANGPL6), and omentin-1. METHODS:We enrolled 312 obese Iranian women (30 ≤ body mass index <40) in this cross-sectional study. In order to examine the association of serum adipokine levels with RMR and BMD, the participants were grouped based on RMR per body weight. Body composition, dietary intake, bone mineral density, and resting metabolic rate were assessed in all participants. Serum adipokine levels were quantified by the enzyme-linked immunosorbent assay (ELISA) method. RESULTS:Low levels of RMR/kg were strongly associated with higher weight, body mass index, fat mass, and visceral fat levels. In fact, participants with an RMR/kg of body weight <20 kcal/24 h/kg were more obese (p < 0.05). Another noteworthy finding was that participants with lower RMR/kg demonstrated higher total BMD, total T-score, and total Z-score. Our results showed that omentin-1 had a mediatory effect on the relationship between RMR per kilogram of body weight and bone parameters (p < 0.05). Nevertheless, other adipokines such as vaspin, retinol-binding protein 4 (RBP4), and ANGPL6 did not affect the relationship between RMR and BMD (p > 0.05). CONCLUSIONS:The inhibitory effect of omentin-1 on TNF-alpha seems to be able to reduce the amount of circulating leptin as adipokine, affecting energy expenditure and improving bone loss induced by estrogen deficiency and controlled effect of RMR on BMD.
Association between adipokines and critical illness outcomes.
Hajri Tahar,Gharib Mohamed,Kaul Sanjeev,Karpeh Martin S
The journal of trauma and acute care surgery
BACKGROUND:Adipose tissue is an endocrine organ that plays a critical role in immunity and metabolism by virtue of a large number of hormones and cytokines, collectively termed adipokines. Dysregulation of adipokines has been linked to the pathogenesis of multiple diseases, but some questions have arisen concerning the value of adipokines in critical illness setting. The objective of this review was to evaluate the associations between blood adipokines and critical illness outcomes. METHODS:PubMed, CINAHL, Scopus, and the Cochrane Library databases were searched from inception through July 2016 without language restriction. Studies reporting the associations of adipokines, leptin, adiponectin, resistin, and/or visfatin with critical illness outcomes mortality, organ dysfunction, and/or inflammation were included. RESULTS:A total of 38 articles were selected according to the inclusion/exclusion criteria of the study. Significant alterations of circulating adipokines have been reported in critically ill patients, some of which were indicative of patient outcomes. The associations of leptin and adiponectin with critical illness outcomes were not conclusive in that blood levels of both adipokines did not always correlate with the illness severity scores or risks of organ failure and mortality. By contrast, studies consistently reported striking increase of blood resistin and visfatin, independently of the critical illness etiology. More interestingly, increased levels of these adipokines were systematically associated with severe inflammation, and high incidence of organ failure and mortality. CONCLUSIONS:There is strong evidence to indicate that increased levels of blood resistin and visfatin are associated with poor outcomes of critically ill patients, including higher inflammation, and greater risk of organ dysfunction and mortality. LEVEL OF EVIDENCE:Systematic review, level III.
Novel adipokines: methodological utility in human obesity research.
Eichelmann F,Rudovich N,Pfeiffer A F,Schulze M B,Giuseppe R D,Boeing H,Aleksandrova K
International journal of obesity (2005)
BACKGROUND:Adipokines could pose a link between adiposity, systemic inflammation and metabolic disease risk. However, it is unclear whether representative biomarkers are methodologically suitable for use in human obesity research. METHODS:We assessed the intra-individual reproducibility of selected adipokines in a sample of 207, apparently healthy, participants with available biosample collections over a 4-month period. Concentrations of the following adipokines were measured at each sampling time point: fatty-acid binding protein-4 (FABP-4), lipocalin-2, monocyte chemoattractant protein 1 (MCP-1), procalcitonin, progranulin, vaspin and visfatin/Nampt. We calculated intraclass correlation coefficients (ICC) and examined Bland-Altman plots. RESULTS:The analyses suggested an overall good to excellent biomarker reproducibility over 4 months: FABP-4: ICC=0.73 (95% confidence interval: 0.65, 0.78), lipocalin-2: 0.64 (0.55, 0.71), MCP-1: 0.85 (0.81; 0.89), procalcitonin: 0.78 (0.72, 0.83), progranulin: 0.59 (0.50, 0.68) and vaspin: 0.86 (0.82, 0.89). A good agreement of the repeated measurements was further supported by the Bland-Altman plots. No substantial differences in biomarker performance according to adiposity status could be observed. Reliability of visfatin/Nampt could not be assessed due to a high number of measurements below the lower limit of detection. CONCLUSION:Results suggest that single measurements of the evaluated adipokines could be used in population-based studies aimed to assess links between obesity, inflammation and metabolic diseases.
Adipokines as atherothrombotic risk factors in obese subjects: Associations with haemostatic markers and common carotid wall thickness.
Csongrádi É,Káplár M,Nagy B,Koch C A,Juhász A,Bajnok L,Varga Z,Seres I,Karányi Z,Magyar M T,Oláh L,Facskó A,Kappelmayer J,Paragh G
Nutrition, metabolism, and cardiovascular diseases : NMCD
BACKGROUND AND AIMS:Some crucial associations between obesity-related altered adipokine levels and the main factors of atherosclerotic, atherothrombotic processes are not fully known. We analysed the relationships of classic adipokines, namely leptin, resistin, adiponectin, tumour necrosis factor-alpha (TNF-α), interleukin 6 (IL-6) with the markers of platelet activation, including mean platelet volume (MPV), platelet surface/soluble P-selectin, platelet-derived microparticles (PMPs), the parameters of coagulation abnormalities and common carotid intima-media thickness (IMT) in obese patients with or without atherosclerotic comorbidities in comparison to age- and sex-matched controls. METHODS AND RESULTS:We enrolled 154 obese individuals, including 98 suffering from atherosclerotic concomitant conditions, 56 free of atherosclerotic comorbidities and 62 healthy controls. Plasma levels of leptin, resistin, adiponectin, TNF-α, IL-6, soluble P-selectin, and plasminogen activator inhibitor-1 antigen (PAI-1 ag) were analysed by ELISA. Platelet surface P-selectin and PMPs were measured by flow cytometry. IMT was detected by ultrasonography. Adipokines were closely associated with markers of platelet hyperactivity, hypercoagulability, hypofibrinolysis and IMT. Significant independent associations were found between leptin and platelet count (p < 0.0001), MPV (p = 0.019), PMPs (p < 0.0001), fibrinogen (p = 0.001), factor VIII (FVIII) activity (p = 0.035); adiponectin and PAI-1 ag (p = 0.035); resistin and soluble P-selectin (p = 0.002); TNF-α and PAI-1 ag (p < 0.0001); and IL-6 and fibrinogen (p = 0.011). Finally, leptin (p = 0.0005), adiponectin (p = 0.019), IL-6 (p = 0.001), MPV (p = 0.0003), PMP (p = 0.008), and FVIII activity (p = 0.043) were independent predictors of IMT. CONCLUSION:Overall, we suggest that in obese subjects altered adipokine levels play a key role in common carotid atherosclerosis both directly and through haemostatic parameters.
Association Between Peripheral Adipokines and Inflammation Markers: A Systematic Review and Meta-Analysis.
Graßmann Sophie,Wirsching Jan,Eichelmann Fabian,Aleksandrova Krasimira
Obesity (Silver Spring, Md.)
OBJECTIVE:Obesity-induced inflammation potentially promotes a variety of chronic conditions. This study aimed to summarize cross-sectional associations between adipose tissue-derived hormones (leptin and adiponectin) and inflammatory biomarkers (C-reactive protein [CRP], interleukin [IL]-6, and tumor necrosis factor [TNF]-α) by means of meta-analysis. METHODS:A systematic search of the databases EMBASE and MEDLINE (PubMed) up to January 2017 was conducted. Data were independently extracted and evaluated by two reviewers. Pooled effect sizes and 95% confidence intervals were calculated using random-effects models. RESULTS:After the initial search, 5,907 publications were retrieved; of these, an overall 60 studies with 45,210 participants were deemed eligible for inclusion in the meta-analysis. Positive correlations with inflammatory biomarkers were observed for leptin (pooled R = 0.35, 0.20, and 0.20 for CRP, IL-6, and TNF-α, respectively), whereas the respective correlations with adiponectin were negative (pooled R = -0.18, -0.14, and -0.12 for CRP, IL-6, and TNF-α, respectively). Stratification by age showed that the observed correlations tended to be weaker with the increasing age of participants. No apparent differences were observed by sex and adiposity status. CONCLUSIONS:This is the first quantitative synthesis of human studies on the association between circulating adipokines and inflammation biomarkers. Potential influence of age on these associations requires further evaluation.
Effect of ezetimibe on plasma adipokines: a systematic review and meta-analysis.
Dolezelova Eva,Stein Evan,Derosa Giuseppe,Maffioli Pamela,Nachtigal Petr,Sahebkar Amirhossein
British journal of clinical pharmacology
AIMS:Statins are known to influence the status of adipokines, which play a key role in the pathophysiology of cardiometabolic diseases. As the effect of ezetimibe as an add-on to statin therapy on the impact of statins on plasma adipokines levels is currently unclear, the aim of the present study was to investigate this through a meta-analysis of controlled trials. METHODS:A systematic review was performed, followed by a bibliographic search in PubMed, Medline, SCOPUS, Web of Science and Google Scholar databases. Quantitative data synthesis was performed using a fixed- or random-effects model (based on the level of interstudy heterogeneity) and the generic inverse variance weighting method. Effect sizes were expressed as standardized mean difference (SMD) and 95% confidence interval (CI). RESULTS:Meta-analysis of 23 controlled trials did not suggest any significant effect of adding ezetimibe on top of statin therapy on plasma concentrations of adiponectin (SMD 0.34, 95% CI -0.28, 0.96; P = 0.288), leptin (SMD -0.75, 95% CI: -2.35, 0.85; P = 0.360), plasminogen activator inhibitor 1 (SMD -1.06, 95% CI: -2.81, 0.69; P = 0.236) and interleukin 6 (SMD 0.30, 95% CI: -0.08, 0.67; P = 0.124). However, significantly greater reductions in plasma concentrations of tumour necrosis factor α (TNF-α) (SMD -0.48, 95% CI -0.87, -0.08; P = 0.018) were achieved with ezetimibe/statin combination therapy. CONCLUSIONS:The results suggested that ezetimibe add-on to statin therapy is associated with an enhanced TNF-α-lowering effect compared with statin monotherapy. Owing to the emerging role of TNF-α in the pathogenesis of metabolic disorders, further investigations are required to unveil the translational relevance of this TNF-α-lowering effect.
Prospective Relation of Circulating Adipokines to Incident Metabolic Syndrome: The Framingham Heart Study.
Zachariah Justin P,Quiroz Rene,Nelson Kerrie P,Teng Zhaoyang,Keaney John F,Sullivan Lisa M,Vasan Ramachandran S
Journal of the American Heart Association
BACKGROUND:Adipokines are elaborated by adipose tissue and are associated with glycemic, lipid, and vascular traits. We hypothesized that in a cross-sectional analysis circulating adipokines are altered among subsets of obesity stratified by presence versus absence of metabolic syndrome (MetS) and prospectively predict the incidence of MetS. METHODS AND RESULTS:Participants in the community-based Framingham Third Generation Cohort who attended examination cycle 1 were included in the study (2002-2005; N=3777, mean age, 40 years; 59% women). Circulating adiponectin, leptin, leptin receptor, fetuin-A, fatty acid-binding protein 4, and retinol binding protein 4 were assayed and related to incident MetS in follow-up (mean 6 years). The adipokines were compared among individuals with excess body weight (body mass index ≥25 kg/m) and prevalent MetS, excess body weight without MetS (metabolically healthy obese), and normal-weight with MetS (metabolically obese, normal-weight) with normal-weight participants without MetS as a referent. Metabolically healthy obese individuals (n=1467) had higher circulating levels of fetuin-A and fatty acid-binding protein 4 but lower levels of leptin, leptin receptor, and adiponectin (<0.001 for all). The adipokine panel was associated with incident MetS (263 new-onset cases; =0.002). Higher circulating concentrations of retinol-binding protein 4 and fetuin-A were associated with incidence of MetS (odds ratio per 1-SD increment log marker, 1.21; 95% CI, 1.03-1.41 [=0.02] and 1.17; 95% CI, 1.01-1.34 [=0.03], respectively). CONCLUSIONS:In our community-based sample of young to middle-aged adults, metabolically healthy obese individuals demonstrated an adverse adipokine profile. Higher circulating levels of retinol-binding protein 4 and fetuin-A marked future cardiometabolic risk.
Adipokines and Non-Alcoholic Fatty Liver Disease: Multiple Interactions.
Adolph Timon E,Grander Christoph,Grabherr Felix,Tilg Herbert
International journal of molecular sciences
Accumulating evidence links obesity with low-grade inflammation which may originate from adipose tissue that secretes a plethora of pro- and anti-inflammatory cytokines termed adipokines. Adiponectin and leptin have evolved as crucial signals in many obesity-related pathologies including non-alcoholic fatty liver disease (NAFLD). Whereas adiponectin deficiency might be critically involved in the pro-inflammatory state associated with obesity and related disorders, overproduction of leptin, a rather pro-inflammatory mediator, is considered of equal relevance. An imbalanced adipokine profile in obesity consecutively contributes to metabolic inflammation in NAFLD, which is associated with a substantial risk for developing hepatocellular carcinoma (HCC) also in the non-cirrhotic stage of disease. Both adiponectin and leptin have been related to liver tumorigenesis especially in preclinical models. This review covers recent advances in our understanding of some adipokines in NAFLD and associated HCC.
Epigenetic Regulation of Adipokines.
Pham Tho X,Lee Ji-Young
International journal of molecular sciences
Adipose tissue expansion in obesity leads to changes in the expression of adipokines, adipocyte-specific hormones that can regulate whole body energy metabolism. Epigenetic regulation of gene expression is a mechanism by which cells can alter gene expression through the modifications of DNA and histones. Epigenetic mechanisms, such as DNA methylation and histone modifications, are intimately tied to energy metabolism due to their dependence on metabolic intermediates such as S-adenosylmethionine and acetyl-CoA. Altered expression of adipokines in obesity may be due to epigenetic changes. The goal of this review is to highlight current knowledge of epigenetic regulation of adipokines.
Variations of Adipokines and Insulin Resistance in Primary Hypothyroidism.
Kar Kaushik,Sinha Satwika
Journal of clinical and diagnostic research : JCDR
INTRODUCTION:Hypothyroidism is a common concern in endocrinology practice, which plays a significant role in metabolic and development processes. Obesity, hyperlipidaemia and hypertension may complicate hypothyroidism. Recent studies have shown that cytokines like leptin and adiponectin, secreted by adipose tissue and exert their endocrinal functions by modulating appetite, obesity and insulin sensitivity in conjunction with thyroid hormones. Interrelation between thyroid hormone, insulin resistance and adipokines are not yet clear. AIM:To estimate serum leptin, adiponectin and insulin resistance in patients with hypothyroidism and to compare with control subjects and measure the relation between the mean value of one variable with others. MATERIALS AND METHODS:Forty primary hypothyroidism patients and forty age and sex matched controls were selected for the study with informed consent. Fasting serum Thyroid Stimulating Hormone (TSH), leptin, adiponectin, glucose and insulin were estimated. Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) was evaluated from fasting plasma glucose and serum insulin levels. Statistical analysis was carried out using SPSS version 17.0. Unpaired t-test and regression analysis were used to compare and determine the dependence, p<0.05 was considered significant. RESULTS:Serum TSH, leptin, adiponectin HOMA-IR were significantly higher (p<0.05) in patients with hypothyroidism (10.37±4.10, 10.97±0.60, 31.09±4.07, 3.64±0.40) than controls (2.41±2.09, 10.37±0.12, 33.32±1.44, 2.36±0.35). Regression analysis showed that leptin was significantly (p=0.054) dependent on adiponectin but not on others. CONCLUSION:Increased oxidative stress by hypothyroid mediated leptin secretion and increased insulin resistance can down-regulate the adiponectin secretion and future complications. Serum estimation and correction of imbalance of adipokines in hypothyroidism can prevent severe consequences.
Adipokines and Myokines: A Pivotal Role in Metabolic and Cardiovascular Disorders.
Chung Hye Soo,Choi Kyung Mook
Current medicinal chemistry
Obesity induces an imbalance in the expression and secretion of several cytokines, which contributes to the development of metabolic and cardiovascular disorders. On the contrary, skeletal muscle is known to have a role in reversing the detrimental impact of obesity. It has been established that adipose tissue acts as an endocrine organ that secretes proinflammatory and anti-inflammatory adipokines. Similarly, skeletal muscle produces secretory molecules, called myokines, from contracting muscle fibers. Myokines were recently recognized as beneficial modulators of obesity, metabolic syndrome, and type 2 diabetes. Furthermore, adipokines and myokines play a crucial role in the communication between adipose tissue, skeletal muscle and other organs. It could be beneficial to find novel adipokines and myokines, and to explore their signaling pathways to identify targets for the treatment and prevention of cardiometabolic disorders. In this review, we summarize recent studies on cross-talk between skeletal muscle and adipose tissue. In particular, we concentrate on the major action mechanisms of adipokines and myokines, such as adiponectin, adipocyte fatty acid binding protein, C1q/TNF-related proteins, interleukin- 6, irisin, and fibroblast growth factor 21.
Relationship between Proinflammatory Cytokines/Chemokines and Adipokines in Serum of Young Adults with Obesity.
Borges Maraisa D,Franca Eduardo L,Fujimori Mahmi,Silva Silvia M C,de Marchi Patricia G F,Deluque Alessandra L,Honorio-Franca Adenilda C,de Abreu Luiz C
Endocrine, metabolic & immune disorders drug targets
BACKGROUND AND OBJECTIVE:The adipose tissue has been recognized as an important endocrine organ, which is metabolically active and expresses and secretes various inflammatory cytokines. Inflammation is involved in obesity-related complications. As such, the present study investigated the correlation between biochemical parameters, serum proinflammatory cytokines and adipokines in individuals with obesity. METHODS:Based on the body mass index (BMI), 30 subjects were divided into 3 groups: eutrophic (GC, n = 10), overweight (GOW, n = 10) and obese (GOB, n = 10). Serum glucose, cholesterol (total-C, HDLC and LDL-C), triglycerides, total proteins, uric acid and insulin were determined, as well as cytokines IL-8, TNF-α, IL-1β, and IL-6, leptin and adiponectin. RESULTS:GOB showed the highest glucose, total and LDL-C, triglycerides, uric acid, insulin, leptin, IL- 8, IL-1β, IL-6, TNF-α and lowest adiponectin levels. In general, adiponectin exhibited an inverse correlation with BMI, abdominal circumference, LDL-C, IL-6, TNF-α, leptin and leptin-adiponectin ratio (LAR) and a positive correlation with HDL-C. Leptin was positively correlated with BMI, abdominal circumference, insulin, IL-6, TNF-α and LAR and negatively correlated with HDL-C and adiponectin. The LAR was positively correlated with BMI, waist circumference, insulin, TNF-α and negatively associated with HDL-C. CONCLUSION:The results confirm that obesity changes the lipid and glycemic profiles of individuals, increases the proinflammatory adipokine levels and reduces those of anti-inflammatory adipokines, promoting a state of chronic inflammation.
The role of adipokines in cardiovascular disease.
Shibata Rei,Ouchi Noriyuki,Ohashi Koji,Murohara Toyoaki
Journal of cardiology
Obesity leads to the development of cardiovascular diseases. Adipose tissue produces various bioactive molecules, also known as adipokines, and imbalanced production of adipokines contributes to the pathogenesis of obesity-linked metabolic and cardiovascular complications. Some adipokines such as adiponectin exert salutary actions on cardiovascular and metabolic disorders. Recent research has been conducted to identify poorly-characterized adipokines involved in cardiovascular regulation. In this review, we focus on the protective role of novel adipokines that are of current interest in the field of cardiology.
Research on the correlation of diabetes mellitus complicated with osteoporosis with lipid metabolism, adipokines and inflammatory factors and its regression analysis.
Chen Z,Zhao G-H,Zhang Y-K,Shen G-S,Xu Y-J,Xu N-W
European review for medical and pharmacological sciences
OBJECTIVE:To investigate the correlation of type 2 diabetes mellitus (DM) complicated with osteoporosis with lipid metabolism, adipokines and inflammatory factors, and to define the risk factors via the multivariate regression analysis. PATIENTS AND METHODS:A total of 80 patients with DM admitted into our hospital from November 2015 to November 2016 were enrolled, including 40 patients complicated with osteoporosis and 40 patients not complicated with osteoporosis. The levels of blood lipid, adipokines and inflammatory factors were compared; the correlations between bone mineral density (BMD) and total cholesterol (TC), adiponectin and tumor necrosis factor-α (TNF-α) were analyzed; and multivariate Logistic regression analysis was performed for osteoporosis, hyperlipidemia, abnormal adipokine levels and body's inflammatory response. RESULTS:The levels of serum lipid indexes, total cholesterol (TC), triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C), in patients without complicating osteoporosis were significantly lower than those in patients complicated with osteoporosis. The level of high-density lipoprotein cholesterol (HDL-C) was significantly higher than that in patients complicated with osteoporosis. The levels of adipokines, adiponectin and visfatin, in patients without complicating osteoporosis were significantly lower than those in patients complicated with osteoporosis. The levels of inflammatory factors, TNF-α, interleukin-6 (IL-6) and C-reactive protein (CRP), in patients without complicating osteoporosis were significantly lower than those in patients complicated with osteoporosis. There were negative correlations between BMD and TC, adiponectin and TNF-α. Abnormal blood lipid, abnormal adipokine levels and elevated inflammatory factor levels were independent risk factors for osteoporosis. CONCLUSIONS:Enhanced inflammatory response, abnormal blood lipid metabolism and abnormal changes in adipokines may increase the risk of osteoporosis in patients with diabetes mellitus.
Association Between Adipokines Levels with Inflammatory Bowel Disease (IBD): Systematic Reviews.
Morshedzadeh Nava,Rahimlou Mehran,Asadzadeh Aghdaei Hamid,Shahrokh Shabnam,Reza Zali Mohammad,Mirmiran Parvin
Digestive diseases and sciences
BACKGROUND:A combination of genetic and environmental factors is involved in the etiology of inflammatory bowel disease (IBD). Recent studies have shown that adipocytes play a crucial role, by actively participating in systemic immune responses in IBD patients. But findings remain controversial. To the best of our knowledge, no systematic review has evaluated the roles of adipokines in IBD, considering which this systematic review was undertaken to summarize the effects of these adipokines in IBD pathogenesis. METHODS:For this review, articles published between 1980 and 2016 were identified from the PubMed, EMBASE, Scopus, and Cochrane and Google scholar databases. Thirteen articles were ultimately selected for inclusion in this systematic review. RESULTS:Findings of the present study indicate that some of the adipokines such as leptin, adiponectin and resistin are associated with disease severity, body composition and glucose hemostasis in IBD patients, although some of these associations are stronger than others. CONCLUSIONS:Overall findings indicate that some adipokines may play a crucial role in IBD severity or other IBD related outcomes. Further studies are recommended to confirm the results.
Serum concentrations of adipokines in men with prostate cancer and benign prostate hyperplasia.
Siemińska Lucyna,Borowski Artur,Marek Bogdan,Nowak Mariusz,Kajdaniuk Dariusz,Warakomski Jakub,Kos-Kudła Beata
INTRODUCTION:Obesity and prostate cancer are related, but the causal relationship remains unknown. The aim of the study was to compare concentrations of leptin, adiponectin and chemerin in patients with prostate cancer and benign prostate hyperplasia and to examine associations of the adipokines with the grade of prostate cancer, interleukin-6 (IL-6), insulin resistance and anthropometric and metabolic variables. MATERIAL AND METHODS:The study group consisted of 140 men divided into two groups: I- prostate cancer (n=74) and II- with benign hyperplasia (n=66). Serum leptin, adiponectin, chemerin, IL-6 and metabolic profile were measured. Considering histological differentiation prostate cancer patients were divided into 3 subgroups: well differentiated (Gleason score ≤ 6), moderately differentiated subgroup (Gleason 7), and poorly differentiated (Gleason ≥8). RESULTS:There were no differences between groups in BMI, waist circumference, HOMA-I, serum levels of total cholesterol, glucose, triglycerides, adiponectin, leptin and chemerin. However, the concentrations of PSA, leptin-to-adiponectin ratio and IL-6 were significantly higher in cancer group compared with benign hyperplasia group. In the poorly differentiated cancer subgroup, subjects had higher PSA, leptin, chemerin, IL-6 and triglycerides concentrations. Overweight and obese men with prostate cancer were more likely to have moderately or poorly differentiated cancer than those with normal BMI. In the all men serum adiponectin was significantly correlated with HOMA-I, BMI, glucose, triglycerides, cHDL. There were significant correlations between leptin and BMI, HOMA-I, waist, glucose, triglycerides and cHDL. Among all the participants we observed associations between chemerin and waist as well as triglycerides. In prostate cancer patients chemerin correlated with IL-6 and leptin. We measured significant positive correlations between Gleason score and chemerin and leptin concentrations. There was a positive correlation between adiponectin and PSA levels in all men, as well as in cancer group. CONCLUSION:Leptin-to-adiponectin ratio and IL-6 were elevated in men with prostate cancer. Leptin, chemerin and IL-6 were associated with Gleason score. The relationships between leptin, chemerin and IL-6 were dependent on each other. Overweight and obese men had a higher Gleason score.
Adipokines and inflammation: is it a question of weight?
Francisco Vera,Pino Jesus,Gonzalez-Gay Miguel Angel,Mera Antonio,Lago Francisca,Gómez Rodolfo,Mobasheri Ali,Gualillo Oreste
British journal of pharmacology
Obesity has reached epidemic proportions in the Western society and is increasing in the developing world. It is considered as one of the major contributors to the global burden of disability and chronic diseases, including autoimmune, inflammatory and degenerative diseases. Research conducted on obesity and its complications over the last two decades has transformed the outdated concept of white adipose tissue (WAT) merely serving as an energy depot. WAT is now recognized as an active and inflammatory organ capable of producing a wide variety of factors known as adipokines. These molecules participate through endocrine, paracrine, autocrine or juxtacrine crosstalk mechanisms in a great variety of physiological or pathophysiological processes, regulating food intake, insulin sensitivity, immunity and inflammation. Although initially restricted to metabolic activities (regulation of glucose and lipid metabolism), adipokines currently represent a new family of proteins that can be considered key players in the complex network of soluble mediators involved in the pathophysiology of immune/inflammatory diseases. However, the complexity of the adipokine network in the pathogenesis and progression of inflammatory diseases has posed, since the beginning, the important question of whether it may be possible to target the mechanism(s) by which adipokines contribute to disease selectively without suppressing their physiological functions. Here, we explore in depth the most recent findings concerning the involvement of adipokines in inflammation and immune responses, in particular in rheumatic, inflammatory and degenerative diseases. We also highlight several possible strategies for therapeutic development and propose that adipokines and their signalling pathways may represent innovative therapeutic strategies for inflammatory disorders.
Adipokines and inflammatory markers in elderly subjects with high risk of type 2 diabetes and cardiovascular disease.
Saukkonen Tuula,Mutt Shivaprakash Jagalur,Jokelainen Jari,Saukkonen Anna-Maria,Raza Ghulam Shere,Karhu Toni,Härkönen Pirjo,Eckel Jürgen,Herzig Karl-Heinz,Rajala Ulla,Keinänen-Kiukaanniemi Sirkka
Inflammation plays a significant role in pathogenesis of diabetes and atherosclerosis. Increased adiposity with an upregulation of cytokines in prediabetes has been associated with vascular inflammation and considered a leading causal factor for type 2 diabetes (T2D). Information on adipokines and inflammatory markers in prediabetes, defined by hemoglobin A1C (HbA1c) 5.7-6.4% in addition to impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), are sparse. We conducted a population-based cross-sectional study (part of a follow-up study) of inhabitants of Oulu, Finland, born in 1935. Inflammatory markers and traditional risk markers of 367 subjects were measured. The glucose status was determined by an oral glucose tolerance test (OGTT) and HbA1c. Inflammatory markers and glycemic levels were analysed using analysis of covariance (ANCOVA). Of the participants, 193 were normoglycemic, 82 had prediabetes and 40 T2D. Inflammatory cytokines were significantly higher in subjects with prediabetes as compared to normoglycemic subjects: IL-4 (14.9 vs 5.9 pg/ml, p = 0.041), IP-10 (251 vs 209 pg/ml, p = 0.05), TNF-α (10.4 vs 6.9 pg/ml, p = 0.027), RANTES (43.3 vs 33.1 pg/ml, p = 0.009), CD40L (3708 vs 1671 pg/ml, p = 0.010) and VEGF (269 vs 174 pg/ml, p = 0.013). These inflammatory cytokines remained significant even after adjustment for waist circumference. The differences in inflammatory markers in prediabetic and T2D subjects were not statistically significant. Prediabetes was associated with low-grade inflammation with increased inflammatory cytokine levels, while the levels in prediabetic subjects were comparable to those in T2D subjects. The associations were independent of visceral adiposity.
Relationship of Selected Adipokines with Markers of Vascular Damage in Patients with Type 2 Diabetes.
Spurná Jaromíra,Karásek David,Kubíčková Veronika,Goldmannová Dominika,Krystyník Ondřej,Schovánek Jan,Zadražil Josef
Metabolic syndrome and related disorders
BACKGROUND:In this study we compared levels of selected adipokines between patients with type 2 diabetes (T2D) and healthy individuals and we determined their relationship with early vascular damage markers. METHODS:Seventy-seven subjects: 56 patients with T2D (34 men and 22 women) and 21 healthy controls (8 men and 13 women) were examined in this cross-sectional study. Selected adipokines [adiponectin, adipocyte fatty acid-binding protein (A-FABP), fibroblast growth factor 21 (FGF-21), C1q/TNF-related protein 9 (CTRP-9), and allograft inflammatory factor-1 (AIF-1)] with possible cardiovascular impact were measured in all participants. To identify markers of vascular damage von Willebrand factor (vWF), plasminogen activator inhibitor-1 (PAI-1) and arterial stiffness parameters were examined in all the subjects. RESULTS:When compared with healthy controls, T2D had significantly higher levels of A-FABP [50.0 (38.1-68.6) vs. 28.6 (23.6-32.9) ng/mL, P < 0.0001] and lower levels of adiponectin [5.9 (4.3-9.0) vs. 11.3 (8.7-14.8) μg/mL, P < 0.0001]. Differences in other adipokines were not statistically significant. Adiponectin level correlated negatively with vWF levels (ρ = -0.29, P < 0.05) and PAI-1 (ρ = -0.36, P < 0.05) and A-FABP positively with vWF (ρ = 0.61, P < 0.05) and PAI-1 (ρ = 0.47, P < 0.05) and augmentation index (ρ = 0.26, P < 0.05). Multivariate regression analysis showed independent association between A-FABP and vWF (b = 0.24, P < 0.05). CONCLUSIONS:Patients with T2D have significantly higher levels of A-FABP and lower levels of adiponectin. These adipokines correlate with indicators of vascular damage and could contribute to cardiovascular risk in patients with T2D. A-FABP may participate in direct endothelium damage.
Usefulness of the Adipokines as Biomarkers of Ischemic Cardiac Dysfunction.
Mocan Hognogi Larisa-Diana,Goidescu Cerasela-Mihaela,Farcaş Anca-Daniela
Cardiovascular disease is the leading cause of death among both women and men, but there is still a great percentage of misdiagnosis and lack of clearly defined criteria. Advances in biomolecular science have proven the crucial role of inflammation and, more importantly, the role of adipokines in mediating all stages of coronary artery disease. It has also been suggested that regional fat deposits, more precisely from thoracic region, have a major influence on the development of coronary artery disease by creating a local proatherogenic environment. The immune system closely interacts with metabolic risk factors to initiate, promote, and further aggravate the atherosclerotic lesions on the arterial wall all with the "help" of adipokines. So nowadays, research extensively focuses on uncovering biomarkers that would provide an increased chance of detecting subclinical cardiac distress and also add a consistent value to current guideline-imposed risk criteria.
Autophagy induction: a critical event for the modulation of cell death/survival and inflammatory responses by adipokines.
Archives of pharmacal research
Adipose tissue acts as a dynamic endocrine organ playing critical roles in many metabolic and immune responses. Endocrine functions by adipose tissue are achieved by secretion of diverse cytokines and hormones, collectively called adipokines. Adiponectin and leptin the most abundantly expressed adipokines within adipose tissue have an impact on various physiological responses. While both adiponectin and leptin are secreted from the same location, their physiological functions are not identical. Adiponectin possesses potent anti-inflammatory properties and anti-tumor activities, whereas leptin acts as a pro-inflammatory hormone and generates tumor-promoting effects. Autophagy, a highly conserved intracellular self-digestive process, is implicated in the maintenance of diverse physiological responses. In particular, autophagy plays dual roles in the regulation of cell death/survival (e.g., inducing cell death and cytoprotection) and is associated with anti-inflammatory actions. Increasing recent evidence has indicated that autophagy is implicated in various biological responses by adipokines. Therefore, autophagy would be a promising target for the management of inflammation and tumor growth by adipokines. In this review, we summarize the effects of adiponectin and leptin on autophagy induction and highlight their implications in modulating inflammatory responses and tumor growth.
Role of adipokines FGF21, leptin and adiponectin in self-concept of youths with obesity.
Li Ge,Feng Dan,Qu Xiaoxue,Fu Junling,Wang Yonghui,Li Lianxia,Li Lujiao,Han Lanwen,Esangbedo Issy C,Li Mingyao,Li Ming,Gao Shan
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology
The mechanisms by which obesity increases the risk of psychosocial disorders remain unclear. We aimed at exploring the association between obesity and self-concept in Chinese youths and the role of adipokines. Data for 559 participants (aged 14-28 years) were analyzed. Self-concept was assessed by utilizing the Self-Description Questionnaire II (SDQ-II). Subjects with obesity had higher leptin, FGF21 and lower adiponectin levels (all p < 0.001). They also had lower SDQ-II scores especially in the domains of general school, physical abilities, physical appearance and opposite-sex relations (all p < 0.001). Both elevated FGF21 and leptin were correlated with lower scores in math (p < 0.01), physical abilities (p < 0.01), and opposite-sex relations (p < 0.05), meanwhile FGF21 negatively correlated with the scores in general school and honesty/trustworthiness, and leptin negatively correlated with physical appearance (p < 0.01) but positively with verbal (p < 0.01). In contrast, decreased adiponectin was correlated with poorer physical abilities (p < 0.05), physical appearance (p < 0.05), and parent relations (p < 0.01). Moreover, these associations of leptin, FGF21 and adiponectin with certain domains remained significant after adjustment for BMI and other metabolic confounders. In conclusion, youths with obesity experienced poorly on self-concept, and these associations may be explained in part by adipokines leptin, FGF21 and adiponectin.
Influence of weight loss on pulmonary function and levels of adipokines among asthmatic individuals with obesity: One-year follow-up.
Baltieri Letícia,Cazzo Everton,de Souza Aglecio Luiz,Alegre Sarah Monte,de Paula Vieira Rodolfo,Antunes Edson,de Mello Glaucia Coelho,Claudio Martins Luiz,Chaim Elinton Adami
BACKGROUND:Individuals with obesity are more likely to develop asthma, but the exact mechanism is still uncertain and several hypotheses have been raised, such as the release of inflammatory mediators secreted by adipose tissue. OBJECTIVE:To assess the effects of weight loss in patients submitted to bariatric surgery on pulmonary and systemic inflammation. METHOD:The study evaluated patients undergoing bariatric surgery (Roux-en-Y gastric bypass) with the diagnosis of asthma, except smokers. The patients were evaluated at the time of entry into a preoperative weight loss group (T1), just before bariatric surgery (T2), six months after surgery (T3), and 12 months after surgery (T4). The following were measured: anthropometric data, dosage of systemic inflammatory markers by means of blood collection, pulmonary inflammatory markers obtained by induced sputum collection, pulmonary function parameters, and asthma activity assessed by a Asthma Control Test (ACT) questionnaire. RESULTS:Nineteen patients participated in the study. There were significant reductions in the systemic levels of interleukin (IL)-8 (p = 0.002), C-reactive protein (CRP) (p = 0.003), leptin (p = 0.001) and tumor necrosis factor (TNF)-α (p = 0.007), and significant increase in the systemic levels of IL-6 (p = 0.004) over time and adiponectin in T2 (p = 0.025). In regards to pulmonary inflammation, there were significant reductions in the sputum levels of TNF-α (p < 0.001). There was no significant improvement of the pulmonary function parameters (p > 0.05) and significant improvement in asthma activity scores (p < 0.0001). CONCLUSION:Weight loss was associated with significant changes in the systemic and pulmonary inflammatory profiles of individuals with asthma, leading to a better asthma control as a result of an increase in some anti-inflammatory mediators and a reduction of pro-inflammatory mediators.
The relation between body fat distribution, plasma concentrations of adipokines and the metabolic syndrome in patients with clinically manifest vascular disease.
Schrover Ilse M,van der Graaf Yolanda,Spiering Wilko,Visseren Frank Lj,
European journal of preventive cardiology
Introduction We evaluated the relationship between adipokine plasma concentrations and body fat distribution and the metabolic syndrome. Methods In a cohort of 1215 patients with clinically manifest vascular disease the relation between subcutaneous adipose tissue, visceral adipose tissue, waist circumference, body mass index and plasma concentrations of adipsin, chemerin, monocyte chemoattractant protein-1, migration inhibitory factor, nerve growth factor, resistin, plasma amyloid A1, adiponectin, leptin, plasminogen activator inhibitor-1 and hepatic growth factor were cross-sectionally assessed with linear regression and adjusted for age and gender. The relation between adipokines and the metabolic syndrome was cross-sectionally evaluated using logistic regression. An adipokine profile was developed to measure the effect of combined rather than single adipokines. Results Adiposity was related to higher nerve growth factor, hepatic growth factor, migration inhibitory factor, leptin and adipsin and with lower chemerin, plasminogen activator inhibitor-1, resistin, plasma amyloid A1 and adiponectin. The strongest positive relations were between body mass index and adipsin (β 0.247; 95% CI 0.137-0.356) and leptin (β 0.266; 95% CI 0.207-0.324); the strongest negative relations were between body mass index and plasma amyloid A1 (β -0.266; 95% CI -0.386 to -0.146) and visceral adipose tissue and adiponectin (β -0.168; 95% CI -0.226 to -0.111). There was no relation between subcutaneous adipose tissue and adipokines. Odds for the metabolic syndrome were higher with each 1 SD higher hepatic growth factor (OR 1.21; 95% CI 1.06-1.38) and leptin (OR 1.26; 95% CI 1.10-1.45) and lower with each 1 SD higher adiponectin (OR 0.73; 95% CI 0.64-0.83) and resistin (OR 0.85; 95% CI 0.74-0.97). The adipokine profile was related to the metabolic syndrome (OR 1.03; 95% CI 1.00-1.06). Conclusion Plasma concentrations of adipokines are related to obesity and body fat distribution. The relation between adipokine concentrations and the metabolic syndrome is independent of visceral adipose tissue.
Adipokines and Their Role in Intestinal Inflammation.
Weidinger Carl,Ziegler Jörn F,Letizia Marilena,Schmidt Franziska,Siegmund Britta
Frontiers in immunology
Fat tissue was initially described for its endocrine and metabolic function. Over the last two decades increasing evidence indicated a close interaction with the immune system. Partly responsible for this immune modulatory function are soluble factors released by the fat tissue, most prominently the so-called adipokines. These discoveries led to the question how adipokines influence inflammatory diseases. Linking inflammation and adipose tissue, Crohn's disease, a chronic inflammatory bowel disease, is of particular interest for studying the immune modulatory properties of adipokines since it is characterized by a hyperplasia of the mesenteric fat that subsequently is creeping around the inflamed segments of the small intestine. Thus, the role of several adipokines in the creeping fat as well as in intestinal inflammation was recently explored. The present review selected the four adipokines adiponectin, apelin, chemerin, and leptin and provides a working model based on the available literature how these factors participate in the maintenance of intestinal immune homeostasis.
Depressive symptoms and adipokines in women: Study of women's health across the nation.
Everson-Rose Susan A,Clark Cari J,Wang Qi,Guo Hongfei,Mancuso Peter,Kravitz Howard M,Bromberger Joyce T
Small clinical studies suggest depression is associated with alterations in adiponectin and leptin, adipocyte-derived secretory proteins involved in metabolic regulation; however, longitudinal data on these association are lacking. This study examined cross-sectional and longitudinal associations of depressive symptoms and major depressive disorder (MDD) with adiponectin and leptin in healthy middle-aged women (mean (SD) age, 45.6 (2.5) years). Cross-sectional analyses included 575 women with baseline adipokine data; longitudinal analyses included 262 women with 2-4 adipokine measurements over 5 years. The 20-item Center for Epidemiologic Studies Depression scale (CES-D) was used to assess depressive symptoms; history of MDD was determined by the Structured Clinical Interview for DSM-IV. Adipokines were assayed from stored serum specimens; values were log-transformed for analyses. Linear and repeated measure random effects regression models evaluated associations of baseline CES-D scores with baseline adipokine concentrations and changes over time, respectively. Secondary analyses evaluated the relation of MDD history with adipokine concentrations. Mean (SD) baseline concentrations of adiponectin and leptin were 9.90 (4.92) μg/mL and 27.02 (20.06) ng/mL; both increased over time (p < .0001). CES-D scores were associated with lower adiponectin at baseline (per 1-SD: estimate=-0.04, SE=.02, p=.03) and over time (per 1-SD: estimate=-0.055, SE = .024, p=.02). Associations were unchanged in risk factor-adjusted models. Women with elevated CES-D scores (≥16) had 6.9% (95% CI: -1.1%, 14.3%; p = .089) lower median adiponectin at baseline and 11.5% (95% CI: 1.5%, 20.4%, p = .025) lower median adiponectin over time in adjusted models, compared to women with CES-D<16. Rate of change in adipokines did not vary by baseline depressive symptoms or MDD history. Depressive symptoms and MDD history were unrelated to leptin. In women at midlife, depressive symptoms are associated with lower adiponectin, a critical anti-inflammatory biomarker involved in metabolic and cardiovascular conditions.
Adipokines in neurovascular diseases.
Opatrilova Radka,Caprnda Martin,Kubatka Peter,Valentova Vanda,Uramova Sona,Nosal Vladimir,Gaspar Ludovit,Zachar Lukas,Mozos Ioana,Petrovic Daniel,Dragasek Jozef,Filipova Slavomira,Büsselberg Dietrich,Zulli Anthony,Rodrigo Luis,Kruzliak Peter,Krasnik Vladimir
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
Adipose tissue is now described as an endocrine organ secreting a number of adipokines contributing to the development of inflammation and metabolic imbalance, but also endothelial dysfunction, vascular remodeling, atherosclerosis, and ischemic stroke. Leptin, adiponectin, and resistin are the most studied adipokines which play important roles in the regulation of cardiovascular homeostasis. Leptin and adiponectin mediate both proatherogenic and antiatherogenic responses. Leptin and adiponectin have been linked to the development of coronary heart disease and may be involved in the underlying biological mechanism of ischemic stroke. Resistin, a pro-inflammatory cytokine, is predictive of atherosclerosis and poor clinical outcomes in patients with coronary artery disease and ischemic stroke. The changes in serum levels of novel adipokines apelin, visfatin are also associated with acute ischemic stroke. These adipokines have been proposed as potential prognostic biomarkers of cardiovascular mortality/morbidity and therapeutic targets in patients with cardiometabolic diseases. In this article, we summarize the biologic role of the adipokines and discuss the link between dysfunctional adipose tissue and metabolic/inflammation imbalance, consequently endothelial damage, progression of atherosclerotic disease, and the occurrence of ischemic stroke.