Adipokines and the cardiovascular system: mechanisms mediating health and disease

This review focuses on the role of adipokines in the maintenance of a healthy cardiovascular system, and the mechanisms by which these factors mediate the development of cardiovascular disease in obesity. Adipocytes are the major cell type comprising the adipose tissue. These cells secrete numerous factors, termed adipokines, into the blood, including adiponectin, leptin, resistin, chemerin, omentin, vaspin, and visfatin. Adipose tissue is a highly vascularised endocrine organ, and different adipose depots have distinct adipokine secretion profiles, which are altered with obesity. The ability of many adipokines to stimulate angiogenesis is crucial for adipose tissue expansion; however, excessive blood vessel growth is deleterious. As well, some adipokines induce inflammation, which promotes cardiovascular disease progression. We discuss how these 7 aforementioned adipokines act upon the various cardiovascular cell types (endothelial progenitor cells, endothelial cells, vascular smooth muscle cells, pericytes, cardiomyocytes, and cardiac fibroblasts), the direct effects of these actions, and their overall impact on the cardiovascular system. These were chosen, as these adipokines are secreted predominantly from adipocytes and have known effects on cardiovascular cells.     

Adipose tissue secretory function: implication in metabolic and cardiovascular complications of obesity

The adipose tissue exerts a double function that is crucial for energy homeostasis. On the one hand, it is the only organ suited to stock triglycerides in highly specialized cells, the adipocytes. On the other hand, the adipose tissue produces biologically active molecules, collectively named "adipokines", which have been implicated in energy balance and glucose and lipid metabolism. Both adipocytes and cells of the stromal fraction participate in this function of secretion. The adipokines acts locally, in an autocrine or paracrine manner, and distantly (endocrine), on various targets, including muscles, the liver and the hypothalamus. Some adipokines, as TNFalpha and IL6, promote insulin resistance and inflammation, whereas others, as leptin and adiponectin, are required for energy and glucose homeostasis. In obesity, adipose cell hypertrophy and the recruitment of macrophages alter the secretory function and induce an inflammatory profile in the adipose tissue. Analyses of gene expression suggest that hypoxia is one of the factors favoring the attraction of the macrophages. The local and systemic consequences of interactions between macrophages and adipocytes are currently actively studied, to understand their potential implication in the metabolic and cardiovascular complications associated with obesity.     

The double role of epicardial adipose tissue as pro- and anti-inflammatory organ.

Obesity is associated with low grade inflammation. Whether this is just an adaptive response to excess adiposity to maintain a normal oxygen supply or a chronic activation of the innate immune system is still unknown. Recent research has focused on the origin of the inflammatory markers in obesity and the extent to which adipose tissue has a direct effect. The production of adipokines by visceral adipose tissue is of particular interest since their local secretion by visceral fat depots may provide a novel mechanistic link between obesity and the associated vascular complications. Growing evidences suggest that the epicardial adipose tissue, the visceral fat depot located around the heart, may locally interact with myocardium and coronary arteries. Epicardial fat is a source of adiponectin and adrenomedullin, adipokines with anti-inflammatory properties, and several proinflammatory cytokines as well as Tumor Necrosis Factor-alpha (TNF-alpha), Interleukin 1 (IL1), IL-1 h, Interleukin (IL6), Monocyte Chemoattractive Protein-1 (MCP-1), Nerve Growth Factor (NGF), resistin, Plasminogen Activator Inhibitor-1 (PAI-1), and free fatty acids. Epicardial adipose tissue could locally modulate the heart and vasculature, through paracrine secretion of pro- and anti-inflammatory cytokines, thereby playing a possible role in the adiposity-related inflammation and atherosclerosis. On the other hand, epicardial fat could exert a protective effect through adiponectin and adrenomedullin secretion as response to local or systemic metabolic or mechanical insults. Future studies will continue to provide new and fascinating insights into the double role of epicardial adipose tissue in the development of cardiovascular pathology and/or in protecting the heart and arteries.     

脂肪细胞因子对代谢的调节

脂肪组织可将多余能量以甘油三酯(triglycerides,TG)形式储存,在饥饿状态下可分解TG产生游离脂肪酸(free fatty acids,FFAs)为机体供能。此外,脂肪组织还具有体温调节和器官保护功能,并且越来越多的证据表明,脂肪组织也是一种重要的内分泌组织。脂肪组织分泌的蛋白质物质被称为脂肪细胞因子(adipokine),可通过自分泌、旁分泌和内分泌方式发挥多种生物学功能,例如调节能量摄入和能量消耗,调节糖脂代谢,抗炎和促炎反应。对整体而言,脂肪细胞因子可调节大脑、肝、肌肉、血管系统、心、胰腺和免疫系统等不同靶器官的生物反应。其中,脂肪细胞因子在糖脂代谢中发挥特定的作用,包括:葡萄糖代谢[瘦素(leptin)、脂联素(adiponectin)、抵抗素(resistin)];胰岛素敏感性 [瘦素、脂联素、锌-α2-糖蛋白(zinc-α2-glycoprotein,ZAG)];脂肪形成[骨形成蛋白4(bone morphogenetic protein 4,BMP4)]等生物反应过程。但目前对脂肪组织功能障碍与代谢之间机制的理解尚不完善。脂肪组织功能发生紊乱时,脂肪细胞因子的分泌会发生改变,并可能导致一系列与肥胖相关的代谢性疾病的发生。临床前和临床研究表明,激活或抑制特定脂肪细胞因子的信号转导可能是一种适合干预代谢疾病的方法。本文就部分脂肪细胞因子对代谢的调控作用做出综述,以增强对脂肪细胞因子功能的理解。     

Resveratrol inhibits TNF-alpha-induced changes of adipokines in 3T3-L1 adipocytes

Tumor necrosis factor-α (TNF-α) is chronically elevated in adipose tissues of obese rodents and humans. Increased levels of TNF-α are implicated in the induction of atherogenic adipokines, such as plasminogen activator inhibitor -1 (PAI-1) and IL-6, and the inhibition of the anti-atherogenic adipokine, adiponectin. In this study, we investigated the effects of resveratrol on TNF-α-induced atherogenic changes of the adipokines in 3T3-L1 cells. Exposure to TNF-α for 24 h increased PAI-1 and IL-6 secretion and decreased adiponectin secretion. The mRNA expression of adipokines changed in parallel with mRNA expression. Resveratrol effectively reversed the secretion and mRNA expression of the atherogenic adipokines, PAI-1 and IL-6, induced by TNF-α. Decreased secretion levels and mRNA expression of adiponectin by TNF-α were also recovered by resveratrol treatment. Our results suggest that resveratrol may improve obesity-induced cardiovascular disease, particularly atherosclerosis, by attenuating the TNF-α-induced changes of adipokines.     

The role of epicardial and perivascular adipose tissue in the pathophysiology of cardiovascular disease

Obesity, insulin resistance and the metabolic syndrome, are characterized by expansion and inflammation of adipose tissue, including the depots surrounding the heart and the blood vessels. Epicardial adipose tissue (EAT) is a visceral thoracic fat depot located along the large coronary arteries and on the surface of the ventricles and the apex of the heart, whereas perivascular adipose tissue (PVAT) surrounds the arteries. Both fat depots are not separated by a fascia from the underlying tissue. Therefore, factors secreted from epicardial and PVAT, like free fatty acids and adipokines, can directly affect the function of the heart and blood vessels. In this review, we describe the alterations found in EAT and PVAT in pathological states like obesity, type 2 diabetes, the metabolic syndrome and coronary artery disease. Furthermore, we discuss how changes in adipokine expression and secretion associated with these pathological states could contribute to the pathogenesis of cardiac contractile and vascular dysfunction.     

Adiponectin: A biomarker for rheumatoid arthritis?

Recent achievements in the biology and the function of adipose tissue have regarded white adipose tissue (WAT) as an important endocrine and secretory organ. Releasing a series of multiple-function mediators, WAT is involved in a wide spectrum of diseases, including not only cardiovascular and metabolic complications, such as atherosclerosis and type 2 diabetes, but also inflammatory- and immune-related disorders, such as rheumatoid arthritis (RA) and osteoarthritis (OA). A large number of these mediators, called adipokines, such as tumor necrosis factor alpha (TNF-α), leptin, adiponectin, resistin, chemerin, interleukin-6 (IL-6), visfatin, and so on have been identified and studied widely. Important advances related to these proteins shed new insights into the pathophysiological mechanisms of many complicated diseases, although details of which remain unclear. Adiponectin, one of the most widely investigated adipokine, has been shown to possess both anti- and pro-inflammatory effects. RA is a chronic systemic inflammatory-related autoimmune disease. Accumulated evidence has demonstrated that cytokines and adipokines play an important role in the pathogenesis of RA. In this review, we have summarized the most recent advances in adiponectin research in the context of RA, focusing primarily on its effect on RA-related cells, its regulation on pro-inflammatory cytokines, as well as its validation as a biomarker for RA.     

Adiponectin and cardiovascular disease: state of the art?

The cardiometabolic syndrome, associated with increased cardiovascular disease risk in the industrialized world, is estimated to affect one in four adults. Although the mechanisms linking obesity and cardiovascular disease remain unclear, research continues to unravel the molecular pathways behind this pandemic. Adipose tissue has emerged as a metabolically active participant in mediating vascular complications, serving as an active endocrine and paracrine organ secreting adipokines, which participate in diverse metabolic processes. Among these adipokines is adiponectin, which seems to possess antiatherogenic and anti-inflammatory effects and may be protective against cardiovascular disease development. The current review describes the pathophysiology of adiponectin in atherosclerotic disease.     

The potential of adipokines as therapeutic agents for cardiovascular disease

Adipose tissue functions as an endocrine organ by producing bioactive secretory proteins, also known as adipokines, that can directly act on nearby or remote organs. Most of the adipokines are upregulated by obese conditions, and typically promote obese complications. In contrast, some adipokines, such as adiponectin, CTRP9 and omentin, are downregulated in obese states. These factors exert salutary actions on obesity-linked cardiovascular disorders. In this review, we focus on the significance of adiponectin, CTRP9 and omentin as therapeutic agents for cardiovascular disease.     

Adipokines underlie the early origins of obesity and associated metabolic comorbidities in the offspring of women with pregestational obesity

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.     

Central role of the adipocyte in the insulin-sensitising and cardiovascular risk modifying actions of the thiazolidinediones

Insulin resistance is a key metabolic defect in type 2 diabetes that is exacerbated by obesity, especially if the excess adiposity is located intra-abdominally/centrally. Insulin resistance underpins many metabolic abnormalities-collectively known as the insulin resistance syndrome-that accelerate the development of cardiovascular disease. Thiazolidinedione anti-diabetic agents improve glycaemic control by activating the nuclear receptor peroxisome proliferator activated receptor-gamma (PPARgamma). This receptor is highly expressed in adipose tissues. In insulin resistant fat depots, thiazolidinediones increase pre-adipocyte differentiation and oppose the actions of pro-inflammatory cytokines such as tumour necrosis factor-alpha. The metabolic consequences are enhanced insulin signalling, resulting in increased glucose uptake and lipid storage coupled with reduced release of free fatty acids (FFA) into the circulation. Metabolic effects of PPARgamma activation are depot specific-in people with type 2 diabetes central fat mass is reduced and subcutaneous depots are increased. Thiazolidinediones increase insulin sensitivity in liver and skeletal muscle as well as in fat, but they do not express high levels of PPARgamma, suggesting that improvement in insulin action is indirect. Reduced FFA availability from adipose tissues to liver and skeletal muscle is a pivotal component of the insulin-sensitising mechanism in these latter two tissues. Adipocytes secrete multiple proteins that may both regulate insulin signalling and impact on abnormalities of the insulin resistance syndrome--this may explain the link between central obesity and cardiovascular disease. Of these proteins, low plasma adiponectin is associated with insulin resistance and atherosclerosis--thiazolidinediones increase adipocyte adiponectin production. Like FFA, adiponectin is probably an important signalling molecule regulating insulin sensitivity in muscle and liver. Adipocyte production of plasminogen activator inhibitor-1 (PAI-1), an inhibitor of fibrinolysis, and angiotensin II secretion are partially corrected by PPARgamma activation. The favourable modification of adipocyte-derived cardiovascular risk factors by thiazolidinediones suggests that these agents may reduce cardiovascular disease as well as provide durable glycaemic control in type 2 diabetes.     

c-Jun N-terminal kinase is involved in the suppression of adiponectin expression by TNF-alpha in 3T3-L1 adipocytes

Adiponectin, one of adipokines that is secreted from adipocytes, plays an important role in the regulation of glucose and lipid metabolism. Paradoxically, serum concentrations of adiponectin are decreased in obese and type 2 diabetic patients, although it is produced in adipose tissue. On the other hand, plasma TNF-alpha levels are increased in such subjects. In the present study, the mechanism by which adiponectin is regulated by TNF-alpha was investigated. The decreased adiponectin mRNA levels by TNF-alpha were partially recovered by treatment with a c-Jun N-terminal kinase (JNK) inhibitor or the PPAR-gamma agonist rosiglitazone in 3T3-L1 adipocytes. Interestingly, however, cotreatment with the JNK inhibitor and rosiglitazone led to a recovery of TNF-alpha-mediated adiponectin suppression to the control level. The JNK inhibitor regulated the expression of adiponectin by the increase of PPAR-gamma DNA binding activity and the recovery of its mRNA expression while rosiglitazone acted via a PPAR-gamma independent pathway which remains to be elucidated. These findings suggest that the JNK signaling pathway, activated by TNF-alpha, is involved in the regulation of adiponectin expression.     

脂肪因子与代谢综合征关系的研究进展

代谢综合症是一系列代谢和心血管功能失调的临床特征,包括中心性肥胖、高血压、血脂异常、高血糖及胰岛素抵抗等,其发病机制及如何预防及控制代谢综合症正日益成为目前的学术热点。目前已经公认,脂肪不仅是能量存储器官,也是一个重要的内分泌器官。脂肪组织分泌的生物活性分子被称为脂肪因子。近年来的研究表明,脂肪因子广泛参与肥胖、2型糖尿病、高血压病及心血管疾病等一系列代谢相关性疾病的病理生理过程。脂肪因子能通过介导一系列的信号转导通路,并广泛参与机体复杂的代谢平衡网络的调节。脂肪因子的失衡能导致机体发生对胰岛素敏感性改变等一系列的生物学反应,从而在肥胖和代谢综合症的病理过程中发挥重要的作用。本文综述了脂肪因子与代谢综合征的关系的研究进展。     

The potential of adipokines as biomarkers and therapeutic agents for vascular complications in type 2 diabetes mellitus

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.     

The emerging role of adipokines in osteoarthritis: a narrative review

Osteoarthritis (OA) is a most common multifactorial degenerative joint disease in elderly individuals. OA is affecting severely the quality of life of patients, while the causes of OA are not completely understood. Age, obesity, the female sex, and previous injury are considered as significant risk factors. Recently, increased levels of adipokines which are mainly produced by adipocytes have been detected in patients with osteoarthritis. Moreover, studies on different adipokines all reveal that they have played proinflammatory and catabolic/anabolic roles during the pathophysiology of OA. In the present review, we summarize current data on the effect of the adipose tissue-derived hormones leptin, adiponectin, resistin and visfatin on initiation and progression of OA.     

Inflammation and metabolic dysfunction: links to cardiovascular diseases

Abdominal obesity is a major risk factor for cardiovascular disease, and recent studies highlight a key role of adipose tissue dysfunction, inflammation, and aberrant adipokine release in this process. An increased demand for lipid storage results in both hyperplasia and hypertrophy, finally leading to chronic inflammation, hypoxia, and a phenotypic change of the cellular components of adipose tissue, collectively leading to a substantially altered secretory output of adipose tissue. In this review we have assessed the adipo-vascular axis, and an overview of adipokines associated with cardiovascular disease is provided. This resulted in a first list of more than 30 adipokines. A deeper analysis only considered adipokines that have been reported to impact on inflammation and NF-κB activation in the vasculature. Out of these, the most prominent link to cardiovascular disease was found for leptin, TNF-α, adipocyte fatty acid-binding protein, interleukins, and several novel adipokines such as lipocalin-2 and pigment epithelium-derived factor. Future work will need to address the potential role of these molecules as biomarkers and/or drug targets.     

Hypoxia and the endocrine and signalling role of white adipose tissue

White adipose tissue is a major endocrine and signalling organ. It secretes multiple protein hormones and factors, termed adipokines (such as adiponectin, leptin, IL-6, MCP-1, TNFalpha) which engage in extensive cross-talk within adipose tissue and with other tissues. Many adipokines are linked to inflammation and immunity and these include cytokines, chemokines and acute phase proteins. In obesity, adipose tissue exhibits a major inflammatory response with increased production of inflammation-related adipokines. It has been proposed that hypoxia may underlie the inflammatory response in adipose tissue and evidence that the tissue is hypoxic in obesity has been obtained in animal models. Cell culture studies have demonstrated that the expression and secretion of key adipokines, including leptin, IL-6 and VEGF, are stimulated by hypoxia, while adiponectin (with an anti-inflammatory action) production falls. Hypoxia also stimulates glucose transport by adipocytes and may have a pervasive effect on cell function within adipose tissue.     

Cytokines and male infertility

Many male infertility cases have no apparent cause, being characterized as idiopathic. Both inflammation and obesity have long been associated with infertility. On one hand, inflammation, such as orchitis and male accessory gland infections (MAGIs), are regulated by inflammatory cytokines. The latter are also produced in the testis by Leydig and Sertoli cells, being associated with gap junctional communication at the blood–testis barrier. Furthermore, they regulate spermatogenesis through cell interaction, Toll-like receptors and production of reactive oxygen species. Additionally, they affect testosterone production, acting at many levels of the pituitary - gonadal axis. Any imbalance in their production may result in infertility. On the other hand, obesity has also been associated with infertility. Adipokines, cytokines produced by white adipose tissue, regulate the lipid and glucose metabolism and the inflammatory system. Recent data on leptin show that it regulates reproduction by adjusting hypothalamus - pituitary - gonadal axis at both the central and peripheral levels. In this regard, resistin, visfatin and the GH secretagogue peptic hormone ghrelin affect spermatogenesis, whereas data on adiponectin are rather scarce. In conclusion, inflammatory cytokines and adipokines seem to have a pivotal role in the regulation of spermatogenesis; any imbalance in this stable environment may lead to infertility. Nevertheless, further studies are needed to clarify their exact role.