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.     

The renin–angiotensin system in adipose tissue and its metabolic consequences during obesity

Obesity is a worldwide disease that is accompanied by several metabolic abnormalities such as hypertension, hyperglycemia and dyslipidemia. The accelerated adipose tissue growth and fat cell hypertrophy during the onset of obesity precedes adipocyte dysfunction. One of the features of adipocyte dysfunction is dysregulated adipokine secretion, which leads to an imbalance of pro-inflammatory, pro-atherogenic versus anti-inflammatory, insulin-sensitizing adipokines. The production of renin–angiotensin system (RAS) components by adipocytes is exacerbated during obesity, contributing to the systemic RAS and its consequences. Increased adipose tissue RAS has been described in various models of diet-induced obesity (DIO) including fructose and high-fat feeding. Up-regulation of the adipose RAS by DIO promotes inflammation, lipogenesis and reactive oxygen species generation and impairs insulin signaling, all of which worsen the adipose environment. Consequently, the increase of circulating RAS, for which adipose tissue is partially responsible, represents a link between hypertension, insulin resistance in diabetes and inflammation during obesity. However, other nutrients and food components such as soy protein attenuate adipose RAS, decrease adiposity, and improve adipocyte functionality. Here, we review the molecular mechanisms by which adipose RAS modulates systemic RAS and how it is enhanced in obesity, which will explain the simultaneous development of metabolic syndrome alterations. Finally, dietary interventions that prevent obesity and adipocyte dysfunction will maintain normal RAS concentrations and effects, thus preventing metabolic diseases that are associated with RAS enhancement.     

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.     

Role of adipokines in the obesity-inflammation relationship: the effect of fat removal

During the past 10 years, there has been a dramatic increase in the prevalence of obesity in the United States and other developed nations. Recent studies indicate that adipose tissue is an endocrine organ producing numerous proteins, collectively referred to as adipokines, with broad biological activity, that play an important autocrine role in obesity-associated complications. Adipose tissue in general and visceral fat in particular are thought to be key regulators of inflammation. Inflammation is heavily involved in the onset and development of atherothrombotic disease. Moreover, chronic inflammation may also represent a triggering factor in the origin of the metabolic syndrome and type 2 diabetes mellitus. According to a hypothesis, stimuli such as overnutrition, physical inactivity, and aging would result in cytokine hypersecretion and eventually lead to insulin resistance and diabetes in genetically or metabolically predisposed individuals. This article discusses the current understanding of important adipokines thought to be involved in the metabolic and cardiovascular risk associated with obesity. Available evidence linking fat removal by liposuction to modification of cardiovascular risk and vascular inflammatory markers in the obese patient is also presented. Most studies have shown that liposuction produces beneficial effects on insulin resistance and vascular inflammation in the obese patient, reducing its cardiovascular risk. Besides having a significant role in body contouring of the obese patient at the end of the lengthy process of bariatric surgery and massive weight loss, plastic surgery should be incorporated into a multifaceted program of lifestyle changes that allows the obese patient to obtain weight loss and, more importantly, to maintain the reduced weight in the long term.     

Adipose tissue dysfunction in cancer cachexia

Cancer cachexia is a complex disorder that is driven by inflammation and metabolic imbalances, resulting in extreme weight loss. Adipose tissue, a main player in cancer cachexia, is an essential metabolic and secretory organ consisting of both white adipose tissue (WAT) and brown adipose tissue. Its secretory products, including adipokines and cytokines, affect a wide variety of central and peripheral organs, such as the skeletal muscle, brain, pancreas, and liver. Therefore, a combination of metabolic alterations, and systemic inflammation dysregulation of both anti-inflammatory and proinflammatory modulators contribute toward adipose tissue wasting in cancer cachexia. Growing evidence suggests that, during cancer cachexia, WAT undergoes a browning process, resulting in increased lipid mobilization and energy expenditure. In this review, we have summarized the characteristics of cancer cachexia and WAT browning. Furthermore, this review describes how adipose tissue becomes inflamed in cancer, shedding light on the combinatorial action of multiple secreted macromolecules, cytokines, hormones, and tumor mediators on adipose tissue dysfunction. We also highlight the inflammatory responses, energy utilization defects, and molecular mechanisms underlying the WAT dysfunction and browning in cancer cachexia. Further, the actual mechanisms behind the loss of adipose tissue are unknown, but have been attributed to increased adipocyte lipolysis, systemic inflammation, and apoptosis or reduced lipogenesis. The understanding of adipose tissue dysfunction in cancer cachexia will hopefully promote the development of new therapeutic approaches to prevent or treat this wasting syndrome.     

Relationship between obesity, inflammation and insulin resistance: new concepts

White adipose tissue is the main site of energy storage, but it is now recognized as an active participant in regulating physiologic and pathologic processes including immunity and inflammation. It has an endocrine function by secreting at least two main hormones, leptin and adiponectin. It can secrete other products, named adipokines, including cytokines and chemokines, involved in inflammation process. The release of adipokines by either adipocytes or adipose tissue infiltrated macrophages lead to a chronic sub-inflammatory state that could play a central role in cardiovascular complications linked to obesity and insulin resistance, a risk factor to develop type-2 diabetes.     

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.     

Differential adipose tissue inflammatory state in obese nondiabetic Zucker fatty rats compared to obese diabetic zucker diabetic fatty rats

Adipose tissue (AT) inflammation is linked to the pathogenesis of diabetes in obesity. Here, we compare the AT inflammatory state of 2 animal models of obesity and obesity plus diabetes, respectively. Obese nondiabetic ZF rats exhibited a trend towards increased proportions of CD11b positive cells in the adipose tissue stroma vascular fraction suggesting a state of increased AT inflammation compared to their lean littermates, but no alterations in systemic inflammatory parameters. In contrast, obese diabetic ZDF rats exhibited systemic as well as local AT inflammation with elevated levels of circulating Regulated upon Activation, Normal T-cell Expressed and Secreted Protein (Rantes), interleukin 1β (IL-1β) and monocyte chemotactic protein 1 (MCP-1), and an increased infiltration of adipose tissue CD11b positive cells. Our data provide a novel phenotypic characterisation of 2 common metabolic animal models and suggest an association of obesity with local inflammation in adipose tissue, and an association of diabetes with local inflammation in adipose tissue plus systemic inflammation. AT inflammation in obesity might therefore initiate a process that above a certain limits finally results in systemic inflammation and diabetes.     

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.     

Lymphocytes and macrophages in adipose tissue in obesity: markers or makers of subclinical inflammation?

Obesity is accompanied by the development of chronic low-grade inflammation in adipose tissue. The presence of chronic inflammatory response along with metabolically harmful factors released by adipose tissue into the circulation is associated with several metabolic complications of obesity such as type 2 diabetes mellitus or accelerated atherosclerosis. The present review is focused on macrophages and lymphocytes and their possible role in low-grade inflammation in fat. Both macrophages and lymphocytes respond to obesity-induced adipocyte hypertrophy by their migration into adipose tissue. After activation and differentiation, they contribute to the development of local inflammatory response and modulation of endocrine function of adipose tissue. Despite intensive research, the exact role of lymphocytes and macrophages within adipose tissue is only partially clarified and various data obtained by different approaches bring ambiguous information with respect to their polarization and cytokine production. Compared to immunocompetent cells, the role of adipocytes in the obesity-related adipose tissue inflammation is often underestimated despite their abundant production of factors with immunomodulatory actions such as cytokines or adipokines such as leptin, adiponektin, and others. In summary, conflicting evidence together with only partial correlation of in vitro findings with true in vivo situation due to great heterogeneity and molecular complexity of tissue environment calls for intensive research in this rapidly evolving and important area.     

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.     

Friend or foe: Multiple roles of adipose tissue in cancer formation and progression

Obesity is well-known as the second factor for tumorigenesis after smoking and is bound up with the malignant progression of several kinds of cancers, including esophageal cancer, liver cancer, colorectal cancer, kidney cancer, and ovarian cancer. The increased morbidity and mortality of obesity-related cancer are mostly attributed to dysfunctional adipose tissue. The possible mechanisms connecting dysfunctional adipose tissue to high cancer risk mainly focus on chronic inflammation, obesity-related microenvironment, adipokine secretion disorder, and browning of adipose tissue, and so forth. The stromal vascular cells in adipose tissue trigger chronic inflammation through secreting inflammatory factors and promote cancer cell proliferation. Hypertrophic adipose tissues lead to metabolic disorders of adipocytes, such as abnormal levels of adipokines that mediate cancer progression and metastasis. Cancer patients often show adipose tissue browning and cancerous cachexia in an advanced stage, which lead to unsatisfied chemotherapy effect and poor prognosis. However, increasing evidence has shown that adipose tissue may display quite opposite effects in cancer development. Therefore, the interaction between cancers and adipose tissue exert a vital role in mediates adipose tissue dysfunction and further leads to cancer progression. In conclusion, targeting the dysfunction of adipose tissue provides a promising strategy for cancer prevention and therapy.     

Crosstalk between Adipocytes and Immune Cells in Adipose Tissue Inflammation and Metabolic Dysregulation in Obesity

Recent findings, notably on adipokines and adipose tissue inflammation, have revised the concept of adipose tissues being a mere storage depot for body energy. Instead, adipose tissues are emerging as endocrine and immunologically active organs with multiple effects on the regulation of systemic energy homeostasis. Notably, compared with other metabolic organs such as liver and muscle, various inflammatory responses are dynamically regulated in adipose tissues and most of the immune cells in adipose tissues are involved in obesity-mediated metabolic complications, including insulin resistance. Here, we summarize recent findings on the key roles of innate (neutrophils, macrophages, mast cells, eosinophils) and adaptive (regulatory T cells, type 1 helper T cells, CD8 T cells, B cells) immune cells in adipose tissue inflammation and metabolic dysregulation in obesity. In particular, the roles of natural killer T cells, one type of innate lymphocyte, in adipose tissue inflammation will be discussed. Finally, a new role of adipocytes as antigen presenting cells to modulate T cell activity and subsequent adipose tissue inflammation will be proposed.     

Adipose tissue-derived factors as potential biomarkers in cachectic cancer patients

Cachexia, a paraneoplastic syndrome markedly associated with worsened prognosis in cancer patients, provokes profound wasting of both lean and adipose mass in an association with a state of metabolic “chaos”. The white adipose tissue responds to cachexia with marked local inflammation and may be thus a relevant contributor to systemic inflammation. To address this hypothesis we examined the correlation between tissue expression of adipokines and plasma concentration in cachectic and stable weight patients with or without cancer. Adiponectin and liver-derived CRP concentration were significantly higher in the cachectic groups when compared with stable weight patients (P < 0.01). The concentration of plasma IL-6 was higher (11.4-fold) in the cancer cachectic group when compared with weight-stable controls, and presented a significant correlation with the presence of cancer (P < 0.001). A marked increase (5-fold) in IL-6 as a result of the interaction between the presence of cachexia and the presence of tumour was observed in the subcutaneous tissue of the patients, yet not in the visceral depot. Plasma adiponectin levels were higher in cachectic cancer patients, compared with stable weight cancer patients individually matched by age, sex, and BMI, and the subcutaneous depot was found to be the main contributing tissue, rather than the visceral pad. Based on the results we concluded that the subcutaneous adipose tissue is associated with plasma changes that may function as markers of cachexia.     

心外膜脂肪组织与心血管疾病的研究进展

心外膜脂肪组织(epicardial adipose tissue,EAT)是一种特殊的具有局部和全身效应的多功能脂肪组织,其解剖位置特殊,代谢和组织学特征明显区别于其他脂肪组织.在生理条件下,EAT具有产热和保护心脏的作用;而在病理状态下,EAT通过分泌多种促炎细胞因子/脂肪因子,参与心血管疾病(cardiovascular disease,CVD)的发生发展.EAT的厚度/体积及其引发的慢性炎症反应与CVD的严重程度呈显著正相关,运动、减轻体重和药物等均可恢复EAT对心血管的保护作用,提示其有望成为CVD诊断、治疗和预后评价的指标.本文通过对EAT的特征、功能、调节机制以及在血管损伤后重构、动脉粥样硬化、高血压病、心律失常、心功能不全等CVD中的作用做一综述,以期为CVD的防治提供新靶点.     

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.     

Regulation of adipose tissue inflammation and systemic metabolism in murine obesity by polymer implants loaded with lentiviral vectors encoding human interleukin-4

Dysfunctional adipose tissue plays a central role in the pathogenesis of the obesity-related metabolic disease, including type 2 diabetes. Targeting adipose tissue using biopolymer implants is a novel therapeutic approach for metabolic disease. We transplanted porous poly(lactide-co-glycolide) (PLG) implants coated with human interleukin-4 (hIL-4)-expressing lentivirus into epididymal white adipose tissue (eWAT) of mice fed a high-fat diet. Tissue and systemic inflammation and metabolism were studied with flow cytometry, immunohistochemistry, quantitative real-time polymerase chain reaction, adipose tissue histology, and in vivo glucose tolerance testing at 2 and 10 weeks of a high-fat diet. PLG implants carrying hIL-4-expressing lentivirus implanted into epididymal white adipose tissue of mice-regulated adipose tissue inflammation, including increased CD3⁺CD4⁺ T-cell frequency, increased eWAT adipocyte hypertrophy, and decreased FASN and ATGL expression, along with reduced fasting blood glucose levels. These effects were observed in early obesity but were not maintained in established obesity. Local delivery of bioimplants loaded with cytokine-expressing lentivirus vectors to adipose tissue influences tissue inflammation and systemic metabolism in early obesity. Further study will be required to show more durable metabolic effects. These data demonstrate that polymer biomaterials implanted into adipose tissue have the potential to modulate local tissue and systemic inflammation and metabolism.     

人脂联素蛋白与血管功能调控

当前,越来越多的研究聚焦于由脂肪组织分泌产生的血浆蛋白,即脂肪细胞因子对血管的直接作用,其中最引人注目的是脂联素表现出显著的抗炎症和抗动脉粥样硬化的功效。本综述主要总结了脂联素对血管功能影响的研究进展,并从几方面,诸如对血管结构、内皮细胞炎症反应、一氧化氮(NO)产生及血管生成的影响进行详细阐述。     

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.     

Type 2 diabetes – An autoinflammatory disease driven by metabolic stress

Type 2 diabetes has traditionally been viewed as a metabolic disorder characterised by chronic high glucose levels, insulin resistance, and declining insulin secretion from the pancreas. Modern lifestyle, with abundant nutrient supply and reduced physical activity, has resulted in dramatic increases in the rates of obesity-associated disease conditions, including diabetes. The associated excess of nutrients induces a state of systemic low-grade chronic inflammation that results from production and secretion of inflammatory mediators from the expanded pool of activated adipocytes. Here, we review the mechanisms by which obesity induces adipose tissue dysregulation, detailing the roles of adipose tissue secreted factors and their action upon other cells and tissues central to glucose homeostasis and type 2 diabetes. Furthermore, given the emerging importance of adipokines, cytokines and chemokines in disease progression, we suggest that type 2 diabetes should now be viewed as an autoinflammatory disease, albeit one that is driven by metabolic dysregulation.