Adiponectin: Anti-inflammatory and cardioprotective effects

Adipose tissue is an endocrine organ that plays an essential role in regulating several metabolic functions through the secretion of biological mediators called "adipokines". Dysregulation of adipokines plays a crucial role in obesity-related diseases. Adiponectin (APN) is the most abundant adipokine accounting for the 0.01% of total serum protein, and is involved in a wide variety of physiological processes including energy metabolism, inflammation, and vascular physiology. APN plasma levels are reduced in individuals with obesity, type 2 diabetes and coronary artery disease, all traits with low-grade chronic inflammation. It is has been suggested that the absence of APN anti-inflammatory effects may be a contributing factor to this inflammation. APN inhibits the expression of tumor necrosis factor-α-induced endothelial adhesion molecules, macrophage-to-foam cell transformation, tumor necrosis factor-α expression in macrophages and adipose tissue, and smooth muscle cell proliferation. It also has anti-apoptotic and anti-oxidant effects, which play a role in its cardioprotective action. This review will focus on APN as an anti-inflammatory, anti-atherogenic and cardioprotective plasma protein.     

Adiponectin expression in human epicardial adipose tissue in vivo is lower in patients with coronary artery disease

BACKGROUND: Intra-peritoneal adipose tissue is recognized as a predictor of metabolic syndrome and may contribute to the risk for cardiovascular disease by the production of adipocytokines, including adiponectin. Nevertheless, there is no knowledge on whether other visceral depots of adipose tissue, including the epicardial fat, have any metabolically active role, including production of adiponectin. AIM OF THE STUDY: We sought to evaluate adiponectin protein expression in epicardial adipose tissue in vivo both in patients with severe coronary artery disease (CAD) and in subjects without CAD. METHODS: Twenty-two patients were enrolled for the study. We selected 16 patients who underwent elective coronary artery bypass graft surgery for critical CAD, 5 who underwent surgery for valve replacement and 1 for correction of an interatrial defect. Epicardial adipose tissue biopsy samples were obtained before the initiation of cardiopulmonary bypass. Adiponectin protein level in epicardial adipose tissue was evaluated by Western blotting. RESULTS: Adiponectin protein value, expressed as adiponectin/actin ratio, in epicardial adipose tissue was significantly lower in patients with severe CAD than in those without CAD (1.42 +/- 0.77 vs 2.36 +/- 0.84 p = 0.02, 95% CI 0.64-1.74). CONCLUSIONS: This study showed for the first time that human epicardial adipose tissue expresses adiponectin. Adiponectin expression is significantly lower in epicardial fat isolated from patients with CAD.     

The potential of adiponectin in driving arthritis

Articular adipose tissue is a ubiquitous component of human joints, but its local functions are largely unknown. Because recent studies revealed several links between adipose tissue, adipocytokines, and arthritis, we investigated the expression of the adipocytokine adiponectin and its functional role in articular adipose tissue and synovium of patients with different arthritides. In contrast to its protective role in endocrinological and vascular diseases, adiponectin was found to be involved in key pathways of inflammation and matrix degradation in the human joint. The effects of adiponectin in human synovial fibroblasts appear to be highly selective by inducing only two of the main mediators of rheumatoid arthritis pathophysiology, IL-6 and matrix metalloproteinase-1, via the p38 MAPK pathway. Owing to the observation that these effects could be inhibited by different TNF-alpha inhibitors, adipocytokines such as adiponectin may also be key targets for therapeutic strategies in inflammatory joint diseases. In summary, articular adipose tissue and adipocytokines cannot be regarded as innocent bystanders any more in chronic inflammatory diseases such as arthritis.     

Adiponectin Promotes Macrophage Polarization toward an Anti-inflammatory Phenotype

It is established that the adipocyte-derived cytokine adiponectin protects against cardiovascular and metabolic diseases, but the effect of this adipokine on macrophage polarization, an important mediator of disease progression, has never been assessed. We hypothesized that adiponectin modulates macrophage polarization from that resembling a classically activated M1 phenotype to that resembling alternatively-activated M2 cells. Peritoneal macrophages and the stromal vascular fraction (SVF) cells of adipose tissue isolated from adiponectin knock-out mice displayed increased M1 markers, including tumor necrosis factor-α, interleukin-6, and monocyte chemoattractant protein-1 and decreased M2 markers, including arginase-1, macrophage galactose N-acetyl-galactosamine specific lectin-1, and interleukin-10. The systemic delivery of adenovirus expressing adiponectin significantly augmented arginase-1 expression in peritoneal macrophages and SVF cells in both wild-type and adiponectin knock-out mice. In culture, the treatment of macrophages with recombinant adiponectin protein led to an increase in the levels of M2 markers and a reduction of reactive oxygen species and reactive oxygen species-related gene expression. Adiponectin also stimulated the expression of M2 markers and attenuated the expression of M1 markers in human monocyte-derived macrophages and SVF cells isolated from human adipose tissue. These data show that adiponectin functions as a regulator of macrophage polarization, and they indicate that conditions of high adiponectin expression may deter metabolic and cardiovascular disease progression by favoring an anti-inflammatory phenotype in macrophages.     

The metabolic syndrome and adipocytokines

Visceral fat accumulation has been shown to play crucial roles in the development of cardiovascular disease as well as the development of obesity-related disorders such as diabetes mellitus, hyperlipidemia and hypertension and the so-called metabolic syndrome. Given these clinical findings, adipocytes functions have been intensively investigated in the past 10 years, and have been revealed to act as endocrine cells that have been termed adipocytokines, which secrete various bioactive substances. Among adipocytokines, tumor necrosis factor-alpha, plasminogen activator inhibitor type 1 and heparin binding epidermal growth factor-like growth factor are produced in adipocytes as well as other organs, and may contribute to the development of vascular diseases. Visfatin has been identified as a visceral-fat-specific protein that might be involved in the development of obesity-related diseases, such as diabetes mellitus and cardiovascular disease. On the contrary to these adipocytokines, adiponectin, an adipose-tissue-specific, collagen-like protein, has been noted as an important antiatherogenic and antidiabetic protein, or as an anti-inflammatory protein. The functions of adipocytokine secretion might be regulated dynamically by nutritional state. Visceral fat accumulation causes dysregulation of adipocyte functions, including oversecretion of tumor necrosis factor-alpha, plasminogen activator inhibitor type 1 and heparin binding epidermal growth factor-like growth and hyposecretion of adiponectin, which results in the development of a variety of metabolic and circulatory diseases. In this review, the importance of adipocytokines, especially focusing on adiponectin is discussed with respect to cardiovascular diseases.     

Anti-inflammatory and anti-atherogenic properties of adiponectin

Obesity-related disorders, such as insulin resistance, hypertension and atherosclerosis, are associated with chronic inflammation. Adiponectin is an adipocyte-derived secreted factor that is down-regulated in obese states. Adiponectin exerts the protective actions on obesity-linked diseases, such as insulin resistance and atherosclerosis by attenuating chronic inflammation in its target organs. Adiponectin also exerts the salutary effects on vascular disorders by directly acting on vascular component cells including endothelial cells, smooth muscle cells and macrophages. This review will focus on the role of adiponectin in control of inflammatory responses and atherogenic processes.     

Adiponectin is a negative regulator of NK cell cytotoxicity

NK cells are a key component of innate immune systems, and their activity is regulated by cytokines and hormones. Adiponectin, which is secreted from white adipose tissues, plays important roles in various diseases, including hypertension, cardiovascular diseases, inflammatory disorders, and cancer. In this study the effect of adiponectin on NK cell activity was investigated. Adiponectin was found to suppress the IL-2-enhanced cytotoxic activity of NK cells without affecting basal NK cell cytotoxicity and to inhibit IL-2-induced NF-kappaB activation via activation of the AMP-activated protein kinase, indicating that it suppresses IL-2-enhanced NK cell cytotoxicity through the AMP-activated protein kinase-mediated inhibition of NF-kappaB activation. IFN-gamma enhances NK cell cytotoxicity by causing an increase in the levels of expression of TRAIL and Fas ligand. The production of IFN-gamma, one of the NF-kappaB target genes in NK cells, was also found to be suppressed by adiponectin, accompanied by the subsequent down-regulation of IFN-gamma-inducible TRAIL and Fas ligand expression. These results clearly demonstrate that adiponectin is a potent negative regulator of IL-2-induced NK cell activation and thus may act as an in vivo regulator of anti-inflammatory functions.     

Adiponectin, an adipocyte-derived protein

Adipose tissue is a hormonally active tissue, producing adipocytokines which may influence activity of other tissues. Adiponectin, abundantly present in the plasma increases insulin sensitivity by stimulating fatty acid oxidation, decreases plasma triglycerides and improves glucose metabolism. Adiponectin levels are inversely related to the degree of adiposity. Anorexia nervosa and type 1 diabetes are associated with increased plasma adiponectin levels and higher insulin sensitivity. Decreased plasma adiponectin levels were reported in insulin-resistant states, such as obesity and type 2 diabetes and in patients with coronary artery disease. Activity of adiponectin is associated with leptin, resistin and with steroid and thyroid hormones, glucocorticoids, NO and others. Adiponectin suppresses expression of extracellular matrix adhesive proteins in endothelial cells and atherosclerosis potentiating cytokines. Anti-atherogenic and anti-inflammatory properties of adiponectin and the ability to stimulate insulin sensitivity have made adiponectin an important object for physiological and pathophysiological studies with the aim of potential therapeutic applications.     

Adiponectin: a biomarker of obesity-induced insulin resistance in adipose tissue and beyond

Adiponectin is one of the most thoroughly studied adipocytokines. Low plasma levels of adiponectin are found to associate with obesity, metabolic syndrome, diabetes and many other human diseases. From animal experiments and human studies, adiponectin has been shown to be a key regulator of insulin sensitivity. In this article, we review the evidence and propose that hypo-adiponectinemia is not a major cause of obesity. Instead, it is the result of obesity-induced insulin resistance in the adipose tissue. Hypo-adiponectinemia then mediates the metabolic effects of obesity on the other peripheral tissues, such as liver and skeletal muscle and may also exert some direct effects on end-organ damage. We propose that deciphering the molecular details governing the adiponectin gene expression and protein secretion will lead us to more comprehensive understanding of the mechanisms of insulin resistance in the adipose tissue and provide us new avenues for the therapeutic intervention of obesity and insulin resistance-related human disorders     

APPL1: role in adiponectin signaling and beyond

Adiponectin, an adipokine secreted by the white adipose tissue, plays an important role in regulating glucose and lipid metabolism and controlling energy homeostasis in insulin-sensitive tissues. A decrease in the circulating level of adiponectin has been linked to insulin resistance, type 2 diabetes, atherosclerosis, and metabolic syndrome. Adiponectin exerts its effects through two membrane receptors, AdipoR1 and AdipoR2. APPL1 is the first identified protein that interacts directly with adiponectin receptors. APPL1 is an adaptor protein with multiple functional domains, the Bin1/amphiphysin/rvs167, pleckstrin homology, and phosphotyrosine binding domains. The PTB domain of APPL1 interacts directly with the intracellular region of adiponectin receptors. Through this interaction, APPL1 mediates adiponectin signaling and its effects on metabolism. APPL1 also functions in insulin-signaling pathway and is an important mediator of adiponectin-dependent insulin sensitization in skeletal muscle. Adiponectin signaling through APPL1 is necessary to exert its anti-inflammatory and cytoprotective effects on endothelial cells. APPL1 also acts as a mediator of other signaling pathways by interacting directly with membrane receptors or signaling proteins, thereby playing critical roles in cell proliferation, apoptosis, cell survival, endosomal trafficking, and chromatin remodeling. This review focuses mainly on our current understanding of adiponectin signaling in various tissues, the role of APPL1 in mediating adiponectin signaling, and also its role in the cross-talk between adiponectin/insulin-signaling pathways.     

Genetic admixture, adipocytokines, and adiposity in Black Americans: the Health, Aging, and Body Composition study

Adipocytokines are a subset of cytokines produced by adipose tissue and are associated with risk of type II diabetes and atherosclerosis. Levels of adipocytokines differ between Black and White Americans, even after adjustment for differences in adiposity, diseases associated with adipocytokines including type 2 diabetes and cardiovascular disease, and general socioeconomic status indicators such as income. We used a series of ancestry informative markers to estimate genetic ancestry in a population-based study of older Black Americans, and examined the association between genetic ancestry and adipocytokines and soluble receptors to help determine which of these may be most amenable to admixture mapping. We typed 35 ancestry informative markers in 1,241 self-reported Black Americans with available DNA from the Health, Aging, and Body Composition (Health ABC) study with available DNA and used a maximum likelihood approach to estimate percent European ancestry. We used linear regression models to determine the association between these adipocytokines and percent ancestry, and staged models to examine whether adiposity or other measures affected the associations of genetic ancestry and adipocytokines. Mean European ancestry was 22.3 ± 15.9%. In multivariate adjusted models, the strongest associations observed were between higher European ancestry and interleukin-6 soluble receptor (IL-6 SR), C-reactive protein (CRP), and adiponectin levels, with interleukin-2 soluble receptor (IL-2 SR) and soluble tumor necrosis factor receptor II (TNF-α SR II) also showing more modest but significant associations. The association with adiponectin became stronger after adjustment for adiposity. These novel findings suggest that admixture mapping may identify genetic factors influencing the levels of IL-6 SR, CRP, IL-2 SR, and adiponectin. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Adiponectin--its role in metabolism and beyond.

Adiponectin is a recently identified adipose tissue-derived protein (adipocytokine) with important metabolic effects. It is exclusively expressed in adipose tissue and released into the circulation. Adiponectin expression and/or secretion is increased by insulin like growth factor-1 and ionomycin, and decreased by tumor necrosis factor-alpha, glucocorticoids, beta-adrenergic agonists and cAMP. Data for insulin are somewhat inconclusive. Moreover, adiponectin expression and secretion are increased by activators of peroxisome proliferator-activated receptor (PPAR)-gamma. Besides inhibiting inflammatory pathways, recombinant adiponectin increases insulin sensitivity and improves glucose tolerance in various animal models. This insulin-sensitizing effect appears to be mostly attributable to enhanced suppression of glucose production, but beneficial effects on muscle cannot be excluded. In humans, plasma adiponectin concentrations exceed those of any other hormone by a thousand times; they decrease with obesity and are positively associated with whole-body insulin sensitivity. Therefore, low adiponectin may contribute to the decrease in whole-body insulin sensitivity that accompanies obesity. Furthermore, there is increasing evidence that genetic variants in the adiponectin gene itself and/or in genes encoding adiponectin-regulatory proteins--such as PPAR-gamma--may be associated with hypoadiponectinemia, insulin resistance and type 2 diabetes. This suggests that adiponectin may reflect PPAR-gamma activity in vivo. Finally, reversal or alleviation of hypoadiponectinemia may represent a target for development of drugs improving insulin sensitivity and glucose tolerance.     

Increased adiponectin is negatively linked to the local inflammatory process in patients with rheumatoid arthritis

Adiponectin has been shown to exert insulin-sensitizing, anti-atherogenic, and anti-inflammatory properties in metabolic diseases. It has been suggested that adiponectin may play a role in rheumatoid arthritis (RA). To assess adiponectin in serum and synovial fluid from patients with RA and osteoarthritis (OA), and in serum from healthy controls. Adiponectin and CRP levels were analyzed by ELISA. The clinical activity of RA patients was assessed according to the 28 joint count Disease Activity Score. Synovial fluid adiponectin was significantly higher in RA than in OA patients (p<0.001). Adiponectin was negatively associated with the leukocyte count in RA synovial fluid (r=-0.45, p<0.05). Serum adiponectin was higher in RA compared to healthy controls (p<0.02), however comparable to OA patients. Serum adiponectin was higher than in synovial fluid in both diseases (p<0.001). In general, women had higher adiponectin levels than men. Adiponectin was not related to age, disease duration, body mass index, or disease activity of RA patients. Adiponectin is decreased in synovial fluid compared to serum indicating that peripheral fat stores are major producers of adiponectin into the blood stream. However, increased synovial fluid adiponectin in RA patients may counterpart the local inflammatory process.     

Functional Effects of Adiponectin on Endothelial Progenitor Cells

Adiponectin is an adipokine whose plasma levels are inversely correlated to metabolic syndrome components. Adiponectin protects against atherosclerosis and decreases risks in myocardial infarction. Endothelial progenitor cells (EPCs) are a heterogeneous population of circulating cells involved in vascular repair and neovascularization. EPCs number is reduced in patients with cardiovascular disease. We hypothesize that the positive effects of adiponectin against atherosclerosis are explained in part by its interactions with EPCs. Cells were obtained from healthy volunteers' blood by mononuclear cell isolation and plating on collagen‐coated dishes. Three sub‐populations of EPCs were identified and characterized using flow cytometry. EPCs' expression of adiponectin receptors, AdipoR1, and AdipoR2 was evaluated by quantitative PCR. The effects of recombinant adiponectin on EPCs' susceptibility to apoptosis were assessed. Finally, expression of neutrophil elastase by EPCs and activity of this enzyme on adiponectin processing were assessed. Quantitative PCR analysis of EPCs mRNAs showed that AdipoR1 mRNA is expressed at higher levels than AdipoR2. Expression of AdipoR1 protein was confirmed by western blot. Adiponectin significantly increased survival of two sub‐populations of EPCs in conditions of serum deprivation. Such effect could not be demonstrated in the third EPCs sub‐population. We also demonstrated that EPCs, particularly one sub‐population, express neutrophil elastase. Neutrophil elastase activity was confirmed in EPCs' conditioned media. Adiponectin protects some EPCs sub‐populations against apoptosis and therefore could modulate EPCs ability to induce repair of vascular damage. Neutrophil elastase activity of EPCs could locally modulate adiponectin activity by its involvement in the generation of the globular form of adiponectin.     

Adiponectin protects against myocardial ischemia-reperfusion injury through AMPK- and COX-2-dependent mechanisms

Obesity-related disorders are associated with the development of ischemic heart disease. Adiponectin is a circulating adipose-derived cytokine that is downregulated in obese individuals and after myocardial infarction. Here, we examine the role of adiponectin in myocardial remodeling in response to acute injury. Ischemia-reperfusion in adiponectin-deficient (APN-KO) mice resulted in increased myocardial infarct size, myocardial apoptosis and tumor necrosis factor (TNF)-alpha expression compared with wild-type mice. Administration of adiponectin diminished infarct size, apoptosis and TNF-alpha production in both APN-KO and wild-type mice. In cultured cardiac cells, adiponectin inhibited apoptosis and TNF-alpha production. Dominant negative AMP-activated protein kinase (AMPK) reversed the inhibitory effects of adiponectin on apoptosis but had no effect on the suppressive effect of adiponectin on TNF-alpha production. Adiponectin induced cyclooxygenase (COX)-2-dependent synthesis of prostaglandin E(2) in cardiac cells, and COX-2 inhibition reversed the inhibitory effects of adiponectin on TNF-alpha production and infarct size. These data suggest that adiponectin protects the heart from ischemia-reperfusion injury through both AMPK- and COX-2-dependent mechanisms.     

Adiponectin and the metabolic syndrome: mechanisms mediating risk for metabolic and cardiovascular disease

PURPOSE OF REVIEW: Adiponectin is secreted exclusively by adipocytes, aggregates in multimeric forms, and circulates at high concentrations in blood. This review summarizes recent studies highlighting cellular effects of adiponectin and its role in human lipid metabolism and atherosclerosis. RECENT FINDINGS: Adiponectin is an important autocrine/paracrine factor in adipose tissue that modulates differentiation of preadipocytes and favors formation of mature adipocytes. It also functions as an endocrine factor, influencing whole-body metabolism via effects on target organs. Adiponectin multimers exert differential biologic effects, with the high-molecular-weight multimer associated with favorable metabolic effects (i.e. greater insulin sensitivity, reduced visceral adipose mass, reduced plasma triglycerides, and increased HDL-cholesterol). Adiponectin influences plasma lipoprotein levels by altering the levels and activity of key enzymes (lipoprotein lipase and hepatic lipase) responsible for the catabolism of triglyceride-rich lipoproteins and HDL. It thus influences atherosclerosis by affecting the balance of atherogenic and antiatherogenic lipoproteins in plasma, and by modulating cellular processes involved in foam cell formation. SUMMARY: Recent studies emphasize the role played by adiponectin in the homeostasis of adipose tissue and in the pathogenesis of the metabolic syndrome, type 2 diabetes, and atherosclerosis. These pleiotropic effects make it an attractive therapeutic target for obesity-related conditions.     

Adiponectin ameliorates angiotensin II-induced vascular endothelial damage

Adiponectin is an adipocyte-specific adipocytokine that possesses anti-atherogenic and anti-diabetic properties. It has been shown to have a beneficial effect on the cardiovascular system, but it remains to be elucidated whether adiponectin has a therapeutic effect on vascular damage induced by the potential vasoactive substance angiotensin II (Ang II). In this study, the effects of adiponectin on Ang II-induced vascular endothelial damage were investigated. In cultured human umbilical vein endothelium cells, Ang II stimulation increased generation of ROS and 4-hydroxy-2-nonenal, both of which were clearly restored by administration of adiponectin. In addition, administration of adiponectin was found to increase cell viability and prevent apoptosis. Our results also demonstrate that the protective effects of adiponectin against Ang II-induced vascular endothelial damage are dependent on the binding of adiponectin to its cell surface receptor 1. Importantly, we found that adiponectin treatment modulates the apoptotic pathway by reducing the expression of LOX-1, up-regulating both cIAP-1 and the ratio of Bcl-2/Bax. Finally, our data displayed that the protective effects of adiponectin against Ang II cytotoxicity depend on AMPK activation mediated by the endosomal adaptor protein, adaptor protein with phosphotyrosine binding, pleckstrin homology domains, and leucine zipper motif.     

Adipocytokines - novel link between inflammation and vascular function?

Obesity and obesity related diseases are a major public health problem. Recent studies have shown that fat tissue is not a simple energy storage organ, but exerts important endocrine and immune functions. These are achieved predominantly through release of adipocytokines, which include several novel and highly active molecules released abundantly by adipocytes like leptin, resistin, adiponectin or visfatin, as well as some more classical cytokines released possibly by inflammatory cells infiltrating fat, like TNF-alpha, IL-6, MCP-1 (CCL-2), IL-1. All of those molecules may act on immune cells leading to local and generalized inflammation and may also affect vascular (endothelial) function by modulating vascular nitric oxide and superoxide release and mediating obesity related vascular disorders (including hypertension, diabetes, atherosclerosis, and insulin resistance) but also cancer or non-alcoholic fatty liver diseases. Present review, in a concise form, focuses on the effects of major adipocytokines, characteristic for adipose tissue like leptin, adiponectin, resistin and visfatin on the immune system, particularly innate and adaptive immunity as well as on blood vessels. Macrophages and T cells are populating adipose tissue which develops into almost an organized immune organ. Activated T cells further migrate to blood vessels, kidney, brain and other organs surrounded by infiltrated fat leading to their damage, thus providing a link between metabolic syndrome, inflammation and cardiovascular and other associated disorders. Ceretain treatments may lead to significant changes in adipocytokine levels. For example include beta-2 adrenoreceptor agonists, thiazolidinediones as well as androgens lead to decrease of plasma leptin levels. Moreover future treatments of metabolic system associated disorders should focus on the regulation of adipocytokines and their modes of action.     

脂联素的研究进展

脂联素（adiponectin）是一种由脂肪细胞特异性高分泌,具有多种生物学功能的特殊蛋白质它直接作用于肝脏、骨骼肌和血管,能提高胰岛素敏感性,增强脂肪酸β氧化,抵制血管炎症反应,最新研究还发现脂联素和骨生成密切相关。与其它脂肪因子不同的是,循环中脂联素的浓度与人体脂肪含量成反比,会因TNF-α的作用而上调,会被噻唑烷二酮类药物所抑制,还受到胰岛素抵抗和炎症反应的影响脂联素受体有2类,分别为AdipoR1和AdipoR2,AdipoR1主要分布在骨骼肌上,AdipoR2则高表达于肝脏组织。本文主要综述了脂联素及其受体的结构、生物学功能和研究进展。