Adiponectin and adipocyte fatty acid binding protein in the pathogenesis of cardiovascular disease

The heart and blood vessels are surrounded by epicardial and perivascular adipose tissues, respectively, which play important roles in maintaining cardiovascular homeostasis by secreting a number of biologically active molecules, termed "adipokines." Many of these adipokines function as an important component of the 'adipo-cardiovascular axis' mediating the cross talk between adipose tissues, the heart, and the vasculature. On the one hand, most adipokines [including tumor necrosis factor-α, resistin, adipocyte fatty acid binding protein (A-FABP), and lipocalin-2] are proinflammatory and causally associated with endothelial and cardiac dysfunction by their endocrine/paracrine actions. On the other hand, adiponectin is one of the few adipokines that possesses multiple salutary effects on the prevention of cardiovascular disease, because of its pleiotropic actions on the heart and the blood vessels. The discordant production of adipokines in dysfunctional adipose tissue is a key contributor to obesity-related cardiovascular disease. This review provides an update in understanding the roles of adipokines in the pathogenesis of cardiovascular disorders associated with obesity and diabetes and focuses on the two most abundant adipokines, adiponectin and A-FABP. Indeed, data from both animal studies and clinical investigations imply that these two adipokines are prognostic biomarkers for cardiovascular disease and even promising therapeutic targets for its treatment.     

Adipokines and coronary vasomotor dysfunction

Research in the last 10-15 years has shown that fat cells (adipocytes) produce and release proteins with specific biologic activities. These proteins, termed adipokines, include the hormones leptin, adiponectin, and resistin. Adipose tissue is now recognized as an active endocrine organ. With the obesity pandemic swelling in the Western world, ongoing research is aimed at determining the biologic links between obesity and cardiovascular disease. This review presents basic historical background information on the major adipokines, introduces findings from clinical studies associating adipokines with cardiovascular disease, and summarizes results from recent basic science research studies of mechanisms of adipokine-induced cardiovascular dysfunction. Particular emphasis is placed on the action of adipokines in the coronary circulation-especially effects of adipokines on endothelial function, as endothelial damage is likely a critical event initiating atherosclerotic coronary artery disease.     

Type 2 diabetes and cardiovascular disease: getting to the fat of the matter

The increasing national prevalence of obesity is a major public health concern and a substantial burden on the health care resources of Canada. In addition to the direct health impact of obesity, this condition is a well-established risk factor for the development of various prevalent comorbidities including type 2 diabetes, hypertension, and cardiovascular disease. Historically, adipose tissue has been regarded primarily as an organ for energy storage. However, the discovery of leptin in the mid 1990's revolutionized our understanding of this tissue and has focused attention on the endocrine function of adipose tissue as a source of secreted bioactive peptides. These compounds, collectively termed adipokines, regulate a number of biological functions including appetite and energy balance, insulin sensitivity, lipid metabolism, blood pressure, and inflammation. The physiological importance of adipokines has led to the hypothesis that changes in the synthesis and secretion of these compounds in the obese are a causative factor contributing to the development of obesity and obesity-related diseases in these individuals. Following from this it has been proposed that pharmacologic manipulation of adipokine levels may provide novel effective therapeutic strategies to treat and prevent obesity, type 2 diabetes, and cardiovascular disease.     

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.     

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.     

Endothelial dysfunction and diabetes: roles of hyperglycemia,impaired insulin signaling and obesity

Endothelial dysfunction comprises a number of functional alterations in the vascular endothelium that are associated with diabetes and cardiovascular disease, including changes in vasoregulation, enhanced generation of reactive oxygen intermediates, inflammatory activation, and altered barrier function. Hyperglycemia is a characteristic feature of type 1 and type 2 diabetes and plays a pivotal role in diabetes-associated microvascular complications. Although hyperglycemia also contributes to the occurrence and progression of macrovascular disease (the major cause of death in type 2 diabetes), other factors such as dyslipidemia, hyperinsulinemia, and adipose-tissue-derived factors play a more dominant role. A mutual interaction between these factors and endothelial dysfunction occurs during the progression of the disease. We pay special attention to the possible involvement of endoplasmic reticulum stress (ER stress) and the role of obesity and adipose-derived adipokines as contributors to endothelial dysfunction in type 2 diabetes. The close interaction of adipocytes of perivascular adipose tissue with arteries and arterioles facilitates the exposure of their endothelial cells to adipokines, particularly if inflammation activates the adipose tissue and thus affects vasoregulation and capillary recruitment in skeletal muscle. Hence, an initial dysfunction of endothelial cells underlies metabolic and vascular alterations that contribute to the development of type 2 diabetes. E.C. Eringa is supported by the Dutch Diabetes Foundation (grant 2003.00.030), the Dutch Kidney foundation (grant C03.2046), and the Dutch organization for scientific research (grant 916.76.179). V.W.M. van Hinsbergh is supported by the European Vascular Genomics Network (grant LSHM-CT-2003–503254).     

Adipose tissue-derived progenitor cells and cancer

Recruitment of stem cells and partially differentiated progenitor cells is a process which accompanies and facilitates the progression of cancer. One of the factors complicating the clinical course of cancer is obesity, a progressively widespread medical condition resulting from overgrowth of white adipose tissue (WAT), commonly known as white fat. The mechanisms by which obesity influences cancer risk and progression are not completely understood. Cells of WAT secret soluble molecules (adipokines) that could stimulate tumor growth, although there is no consensus on which cell populations and which adipokines are important. Recent reports suggest that WAT-derived mesenchymal stem (stromal) cells, termed adipose stem cells (ASC), may represent a cell population linking obesity and cancer. Studies in animal models demonstrate that adipokines secreted by ASC can promote tumor growth by assisting in formation of new blood vessels, a process necessary for expansion of tumor mass. Importantly, migration of ASC from WAT to tumors has been demonstrated, indicating that the tumor microenvironment in cancer may be modulated by ASC-derived trophic factors in a paracrine rather than in an endocrine manner. Here, we review possible positive and adverse implications of progenitor cell recruitment into the diseased sites with a particular emphasis on the role in cancer progression of progenitors that are expanded in obesity.     

Adipokines oversecreted by omental adipose tissue in human obesity

Central-omental obesity plays a causative role in the pathogenesis of the metabolic syndrome. Adipokines are involved in the pathogenesis of this syndrome. However, adipokines secreted by omental adipose tissue (OAT) are still poorly characterized in human obesity. Therefore, we searched for novel adipokines abnormally secreted by OAT in obesity and examined their relationships with some features of metabolic syndrome and the respective contribution of adipocytes vs. stromal-vascular cells. OAT from obese and nonobese men was fractionated into adipocytes and SV cells, which were then cultured. Medium was screened by medium-scale protein arrays and ELISAs. Adipokine mRNA levels were measured by real-time RT-qPCR. We detected 16 cytokines secreted by each cellular fraction of lean and obese subjects. Of the 16 cytokines, six adipokines were newly identified as secretory products of OAT, which were dysregulated in obesity: three chemokines (growth-related oncogen factor, RANTES, macrophage inflammatory protein-1beta), one interleukin (IL-7), one tissue inhibitor of metalloproteinases (TIMP-1), and one growth factor (thrombopoietin). Their secretion and expression were enhanced in obesity, with a relatively similar contribution of the two fractions. The higher proportion of macrophages and endothelial cells in obesity may contribute to this enhanced production as well as changes in intrinsic properties of hypertrophied adipocytes. Accordingly, mRNA concentrations of most of these adipokines increased during adipocyte differentiation. Eventually, expression of the investigated adipokines did correlate with several features of the metabolic syndrome. In conclusion, six adipokines were newly identified as oversecreted by OAT in obesity. These adipokines may link obesity to its cardiovascular or metabolic comorbidities.     

Angiogenesis,adipokines and breast cancer

The prevalence of overweight and obesity is rapidly increasing world wide. Numerous epidemiological studies have shown that obesity is a risk factor for postmenopausal breast cancer and relapse. However, the biological factors that drive the growth and progression of these tumors and how obesity contributes to the tumor microenvironment are poorly understood. Tumor development and metastasis are dependent on the process of angiogenesis or the formation of new blood vessels. More importantly, a ready supply of adipose tissue-derived angiogenic adipokines, notably VEGF and leptin, and the production of inflammatory cytokines by infiltrating macrophages that occurs in adipose tissues with obesity, promotes the paracrine stimulation of vascular endothelial cell growth needed for adipogenesis, while maintaining a microenvironment that is favorable for breast tumorigenesis.     

The interrelationship between physical activity and metabolic regulation of breast cancer progression in obesity via cytokine control

Regular physical activity is known to protect against the development of breast cancer and mediate direct anti-inflammatory effects on adipose tissue. While direct relationships between muscle activity, adipose tissue and breast tissue have been highlighted in recent years, few studies have focused on the effects of obesity and physical activity during the development of breast cancer, particularly at the level of cell signaling. Skeletal muscle and adipose tissue modulate the cell metabolism by secreting myokines and adipokines. These secreted cytokines belong to a crosstalk network via cell signaling pathway modulation. The understanding of the tissue crosstalk is fundamental to the management of physical activity in the care of obese breast cancer patients. Therefore, this review focuses on the effects of obesity and physical activity during the development of breast cancer, particularly at the level of cell signaling. We focuse on the main mediators, secreted by both adipose and muscle tissue, which are implicated in breast cancer development. We presente the variation of these mediators in the physiopathological context of their secreted tissue. Then, we open the discussion on the crosstalk of these tissues in breast carcinogenesis.     

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。     

Obesity and weight loss could alter the properties of adipose stem cells?

The discovery that adipose tissue represents an interesting source of multipotent stem cells has led to many studies exploring the clinical potential of these cells in cell-based therapies. Recent advances in understanding the secretory capacity of adipose tissue and the role of adipokines in the development of obesity and associated disorders have added a new dimension to the study of adipose tissue biology in normal and diseased states. Subcutaneous adipose tissue forms the interface between the clinical application of regenerative medicine and the establishment of the pathological condition of obesity. These two facets of adipose tissue should be understood as potentially related phenomena. Because of the functional characteristics of adipose stem cells, these cells represent a fundamental tool for understanding how these two facets are interconnected and could be important for therapeutic applications. In fact, adipose tissue stem cells have multiple functions in obesity related to adipogenic, angiogenic and secretory capacities. In addition, we have also previously described a predominance of larger blood vessels and an adipogenic memory in the subcutaneous adipose tissue after massive weight loss subsequent to bariatric surgery(ex-obese patients). Understanding the reversibility of the behavior of adipose stem cells in obeses and in weight loss is relevant to both physiological studies and the potential use of these cells in regenerative medicine.     

Hemodynamic and metabolic correlates in adipose tissue: pathophysiologic considerations

Research efforts investigating the pathophysiology of adipose tissue have often focused separately on either the metabolic or cardiovascular components of an expanding fat mass. However, the growth and development of the fat cells and their vasculature are closely interrelated, a fact that has been established through more than a century of diverse studies of adipose tissue. Recently, the prevalence of obesity in the United States has stimulated investigations into the cardiovascular and metabolic correlates occurring with excessive lipid deposition and subsequent adipose tissue expansion. These investigations have resulted in conclusive evidence that, from a cardiovascular perspective, obesity results in an elevated blood volume and cardiac output, accompanied by an expansion of adipose water space, whereas from a metabolic aspect, the disease is characterized by adipocyte enlargement and associated alterations in metabolic pathways and hormonal responsiveness. Because these separate areas of research have independently shown interdepot differences in perfusion requirements and metabolic adaptations during the transition from the lean to obese state, adipocyte expansion may be partially dependent on the pattern of vascularity. This hypothesis is discussed by examining the integral relationship between the cardiovascular system and adipocyte metabolism, hopefully providing new insight into control of the pathophysiological processes of an expanding adipose organ.     

Identification and validation of novel adipokines released from primary human adipocytes

Adipose tissue is a major endocrine organ, releasing signaling and mediator proteins, termed adipokines, via which adipose tissue communicates with other organs. Expansion of adipose tissue in obesity alters adipokine secretion, which may contribute to the development of metabolic diseases. Although recent profiling studies have identified numerous adipokines, the amount of overlap from these studies indicates that the adipokinome is still incompletely characterized. Therefore, we conducted a complementary protein profiling on concentrated conditioned medium derived from primary human adipocytes. SDS-PAGE/liquid chromatography-electrospray ionization tandem MS and two-dimensional SDS-PAGE/matrix-assisted laser desorption ionization/time of flight MS identified 347 proteins, 263 of which were predicted to be secreted. Fourty-four proteins were identified as novel adipokines. Furthermore, we validated the regulation and release of selected adipokines in primary human adipocytes and in serum and adipose tissue biopsies from morbidly obese patients and normal-weight controls. Validation experiments conducted for complement factor H, αB-crystallin, cartilage intermediate-layer protein, and heme oxygenase-1 show that the release and expression of these factors in adipocytes is regulated by differentiation and stimuli, which affect insulin sensitivity, as well as by obesity. Heme oxygenase-1 especially reveals to be a novel adipokine of interest. In vivo, circulating levels and adipose tissue expression of heme oxygenase-1 are significantly increased in obese subjects compared with lean controls. Collectively, our profiling study of the human adipokinome expands the list of adipokines and further highlights the pivotal role of adipokines in the regulation of multiple biological processes within adipose tissue and their potential dysregulation in obesity.     

Adipokines in inflammation and metabolic disease

The worldwide epidemic of obesity has brought considerable attention to research aimed at understanding the biology of adipocytes (fat cells) and the events occurring in adipose tissue (fat) and in the bodies of obese individuals. Accumulating evidence indicates that obesity causes chronic low-grade inflammation and that this contributes to systemic metabolic dysfunction that is associated with obesity-linked disorders. Adipose tissue functions as a key endocrine organ by releasing multiple bioactive substances, known as adipose-derived secreted factors or adipokines, that have pro-inflammatory or anti-inflammatory activities. Dysregulated production or secretion of these adipokines owing to adipose tissue dysfunction can contribute to the pathogenesis of obesity-linked complications. In this Review, we focus on the role of adipokines in inflammatory responses and discuss their potential as regulators of metabolic function.     

Adipokines: molecular links between obesity and atheroslcerosis

Atherosclerotic disease remains the leading cause of death in industrialized nations despite major advances in its diagnosis, treatment, and prevention. The increasing epidemic of obesity, insulin resistance, and diabetes will likely add to this burden. Increasingly, it is becoming apparent that adipose tissue is an active endocrine and paracrine organ that releases several bioactive mediators that influence not only body weight homeostasis but also inflammation, coagulation, fibrinolysis, insulin resistance, diabetes, and atherosclerosis. The cellular mechanisms linking obesity and atherosclerosis are complex and have not been fully elucidated. This review summarizes the experimental and clinical evidence on how excess body fat influences cardiovascular health through multiple yet converging pathways. The role of adipose tissue in the development of obesity-linked insulin resistance, metabolic syndrome, and diabetes will be reviewed, including an examination of the molecular links between obesity and atherosclerosis, namely, the effects of fat-derived adipokines. Finally, we will discuss how these new insights may provide us with innovative therapeutic strategies to improve cardiovascular health.     

Do novel adipokines play a causative or only modulating role in the pathogenesis of obesity and metabolic disorders?

Adipose tissue is an endocrine and paracrine organ that releases a large number of bioactive mediators. Approximately 100 adipokines have been identified including cytokines, chemokines, growth factors and enzymes. The use of adipoproteomic analyses resulted in new findings and, in consequence, the number of new adipokines is rising rapidly. Novel adipokines such as visfatin, vaspin and omentin were discovered about five years ago. Visfatin and vaspin production and secretion take place in adipocytes, but omentin comes from the stromal cells of adipose tissue. Several differences are noticeable between these adipokines especially in correlation with obesity as visfatin and vaspin serum levels increase in obese subjects while omentin serum levels decrease. It has been suggested that these adipokines act as insulin-sensitizers/insulin-mimetics. Increasing number of publications reporting the role of new adipokines does not allow to assess clearly the influence of those adipokines on the pathogenesis of obesity.     

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.