Introduction

The prevalence of obesity has reached epidemic proportions globally and is still increasing markedly, especially in developed countries. The World Health Organization estimated that, in 2008, 9.8% of adult men and 13.8% of adult women were obese worldwide.1 Obesity is a major public health concern because it is an important risk factor for mortality and morbidity from cardiovascular diseases, diabetes and cancers. Obesity is characterized primarily by an increased fat mass. Rather than simply serving as a passive reservoir for energy storage, adipose tissue is now recognized as the largest endocrine organ. In an average adult human, adipose tissue weighs approximately 15 kg.2 In normal-weight adult humans, white adipose tissue accounts for 10%–29% of bodyweight, making fat the largest organ in the body.3 Moreover, it is a highly active endocrine organ that can produce and secrete many substances, such as various proteins/peptides termed adipokines, free fatty acids, steroid hormones, gaseous mediators and reactive oxygen species.4 Accumulating evidence indicates that the link between obesity and disease is adipose dysfunction, in which an imbalance between beneficial and harmful adipokines plays an important role.4 Although the first adipose-derived protein identified was not leptin, it was the discovery of leptin in 19945 that centred many studies on the secretory function of adipose tissue, thus defining a new field of study called adipobiology. Adipobiology is the study of the molecular and cellular biology of normal and dysfunctional adipose tissue and the diseases that arise from its dysfunction. In the literature, biologically active proteins/peptides secreted from adipose tissue are designated adipocytokines (first mentioned in 1998)6 or adipokines (first mentioned in 2001).7 The term ‘adipokines’ is more accurate because both adipocytes and non-adipocytes in adipose tissue are the source of adipose cytokines. The term ‘adipocytokines’ is more suitable for adipocyte-derived cytokines (i.e. adipokines secreted specifically from adipocytes). Adipokines are proteins involved in the regulation of multiple physiological functions, including metabolism, insulin sensitivity, cardiocerebrovascular function, immunity and inflammation.4 Adipokine research attracts more and more attention. A search in the PubMed database from 1993 until 31 July 2011 retrieved 21 229 papers related to adipokines. The number of publications increased dramatically between 1995 and 2008 and has thereafter remained relatively steady (Fig. 1a). There are 1811 papers related to both adipokines and cardiovascular diseases, such as heart diseases, hypertension, atherosclerosis, cerebrovascular disorders, diabetic angiopathies and thrombosis (Fig. 1b). These provide new insights into the link between obesity and cardiovascular disease. To understand the complex actions of adipokines, as well as to promote further studies on the specific issues in the field, the series of six reviews in this issue of the Journal highlights recent advances in our understanding of the interplay between adipokines and cardiovascular disease. Publications (1993–2011) related to (a) adipokines or (b) both adipokines and cardiovascular disease. Publication data were retrieved from PubMed (http://www.ncbi.nlm.nih.gov/pubmed/, accessed 31 July 2011). Adipokine publications were retrieved by using the search terms ‘adipokine’, ‘adipokines’, ‘adipocytokine’ or ‘adipocytokines’. Cardiovascular disease publications were retrieved by using the corresponding MeSH terms. The search date is 31 July 2011 and thus the publication data for 2011 are incomplete. Leptin is the only adipokine that has been shown to cause an obese phenotype in both animals and humans when deleted.8 It is an intensively studied adipokine that not only acts as a satiety signal to regulate energy balance, but also has multiple other effects. The review by Hou and Luo9 summarizes the huge body of data regarding the effects of leptin on the cardiovascular system and the receptor signalling pathways involved. Leptin has various beneficial actions under physiological conditions. The authors pay close attention to the role of leptin in obesity-related cardiovascular disease because of leptin resistance in states of morbid obesity,9 as identified in their own studies.10,11 Adiponectin is an adipocyte-specific adipokine that has also been studied extensively. Most of the information available indicates that adiponectin is a beneficial adipokine that has antidiabetic, anti-inflammatory and anti-atherogenic effects.4 Studies have further demonstrated that adiponectin is cardioprotective against ischaemic damage through mechanisms that involve the amelioration of oxidative/nitrative stress.12,13 In the present series, Su et al.14 review recent discoveries regarding the regulation of adiponectin biosynthesis under physiological and pathological conditions and discuss the role of hypoadiponectinaemia in insulin resistance, Type 2 diabetes and related cardiovascular disease. In addition to the endocrine action of adipokines, they can also act in a paracrine fashion. For example, the effect of perivascular adipose tissue (PVAT) on vascular function has received considerable attention in recent years.2,4,15 Sacks and Fain16 review our current understanding of the function of epicardial fat, a specific kind of PVAT surrounding coronary arteries. They summarize the physiology and pathophysiology of human epicardial fat, especially its role in coronary artery disease. They also point to the critical gaps in our understanding of this issue, so leading the way to further clinical and experimental studies to elucidate the definitive role of epicardial fat in health and disease. Adipose tissue represents an abundant and accessible source of adult stem cells with the ability to differentiate along multiple lineage pathways.17 Ye and Gimble18 discuss the phenomenon of adipose tissue inflammation in obesity and its impact on adipose stem cell differentiation. The seminal studies from Ye’s group support the proposition that adipose tissue hypoxia provides a common pathway to adipose dysfunction in obesity.19 Ye and Gimble18 present a new concept that inflammation mediates the competition between adipocytes and endothelial cells for the limited source of adipose-derived stem cells in obesity. Thrombosis is a critical component of both venous and arterial disease because platelet aggregation, along with the activation of the coagulation cascade, occurs at all stages of venous thromboembolism and atherosclerotic lesion development.20–23 Schäfer and Konstantinides,24 the authors of the first original article in the field of adipokines and thrombosis,25 summarize the existing clinical and experimental data regarding the direct effect of adipokines on platelet function and the coagulation cascade to help us understand why obesity is prothrombotic. Inflammation and insulin resistance are common characteristics of morbid obesity. Adipokines may modulate inflammation and insulin sensitivity. Our studies have shown that visfatin is associated with metabolic abnormalities in hypertensive rats with increased bodyweight.26 However, it acts as a novel neuroprotector against metabolic and energy stress in stroke.27,28 Furthermore, we have revealed that leptin signalling-mediated downregulation of brain fat mass- and obesity-associated (FTO) mRNA or protein is a new pathway involved in diet restriction-induced beneficial effects, such as bodyweight control and insulin sensitization.29 We review the role of adipokines in inflammation and insulin resistance as well as their contribution to obesity-related cardiovascular disease.30 Adipobiology is a new and exciting field. We hope this series of papers will create greater interest in the basic and applied sciences pertaining to the roles of adipokines in cardiovascular health and disease. There are a number of specific issues that require further investigation: (i) a renewed effort should be made towards the discovery of novel adipokines, because it is likely that far more exist than have currently been identified; (ii) because many adipokines have enzymatic activity (e.g. visfatin, adipsin, lipase), there is a need for us to increase our understanding of the pleiotropic nature of adipokine actions through receptors and/or enzymatic cascades; (iii) most previous research has considered insulin resistance at the whole-body level or with regard to classical insulin targets, such as the liver, skeletal muscle and adipose tissue, so we therefore require a greater understanding of the direct effect of adipokines on insulin sensitivity in the heart, brain and blood vessels; (iv) definitive evidence of the usefulness of adipokines as drug targets is required from studies using in vivo models of cell-specific gene over- and underexpression, as well as systemic gene over- and underexpression; and (v) more translational studies are required to investigate the therapeutic usefulness of recombinant proteins, antibodies and chemicals targeting adipokines. The author sincerely thanks Dr Roger Evans (Monash University, Melbourne, Victoria, Australia) for his critical comments and suggestions. The author’s work reported herein was supported by grants from the National Natural Science Foundation of China Key Project (81130061), the National Basic Research Program of China (2009CB521902), the Program of Shanghai Subject Chief Scientist (10XD1405300) and the Shanghai ‘Shu Guang’ Project (10GG19).