Adipokines and Metabolic Syndrome: Pluripotent Markers for a Complex Relationship?

In recent decades, adipose tissue has been recognized as more than a place to store lipids and triglycerides, gaining the status of an endocrine organ. Adipocytes secrete multiple bioactive factors named adipokines, which act as hormones, growth and angiogenic factors, and cytokines. Adipokines are involved in multiple regulatory functions throughout the body, including but not limited to the regulation of food intake, glucose homeostasis, inflammation, fatty acid oxidation, and formation of reactive oxygen and nitrogen species. Notably, some of these molecules also directly affect cardiovascular biology, including the vascular tone. Indeed, since leptin was described as a secreted product from fat tissue and further associated with obesity,1 a growing number of substances have been found in the human adipose proteome,2 and most of them are putatively involved in the development of cardiovascular diseases. The focus of the study of Professor Fardella and coworkers3 was the relationship between adipokines and clinical parameters associated with metabolic syndrome. Several recent studies link altered levels of adipokines with metabolic diseases such as type-2 diabetes, obesity, and atherosclerosis. The list includes adipsin, adiponectin, resistin, lipocalin 2, cartonectin, and others, not to mention monocyte-derived cytokines.4,5 Among these, adiponectin has drawn attention for its various physiological actions and association with cardiometabolic disorders. Although nonfat cells also express low adiponectin levels, it is mainly produced and released from white adipose tissue. Adiponectin has been identified in human plasma as globular adiponectin and different homomeric complexes, forming the low-molecular-weight trimer, the medium-molecular-weight hexamer, and the high-molecular-weight oligomer.6 However, the plasma levels of adiponectin in humans have been generally described in the range of µg/ml, often without distinction among the different forms. The effects of adiponectin are associated mainly with 2 membrane receptors, named adiponectin receptors 1 and 2 (AdipoR1 and AdipoR2, respectively).7 These receptors present different sensitivity to globular and high-molecular-weight adiponectin, and despite their 7 transmembrane domains, are structurally and functionally distant from G-protein-coupled receptors.8 Although initial studies have suggested a differential distribution of adiponectin receptors among organs, AdipoR1 and AdipoR2 have been found in both endothelial and vascular smooth muscle cells, and were associated with vascular disease.9 Selective sensitivity of adiponectin receptors for adiponectin forms might explain at least part of the multiple actions of adiponectin. Indeed, T-cadherin, a calcium-sensitive adhesion molecule widely expressed in the central nervous system, and previously associated with vascular cell function,10 was also described as a receptor to medium- and high-molecular-weight adiponectin,11 with a significant role in skeletal muscle revascularization12 and protection against vascular damage in experimental atherosclerosis.13 Although the intracellular mechanisms by which adiponectin-mediated T-cadherin activity influences vascular function remains poorly understood, the intracellular signaling associated with AdipoR1 and AdipoR2 receptors in vessels has been detailed over the years.14,15 Not surprisingly, obesity causes a huge unbalance of the nature of adipocyte-released mediators, leading to a more inflammatory environment and contributing to its close relationship with several comorbidities. Interestingly, adipocytes have also been described as a source of plasminogen activator inhibitor-1 (PAI-1), a primarily endothelium-derived inhibitor of tissue- and urokinase-type plasminogen activator, which are physiologically responsible for plasmin generation and fibrin degradation. Thus, augmented levels of PAI-1 can render the vascular system to a state of reduced fibrinolysis and dysregulated homeostasis. Additionally, PAI-1 is directly or indirectly involved in maintaining endothelial permeability,16 cell adhesion, migration, and proliferation,17 among others. Metabolic syndrome has been defined as a group of conditions comprising obesity, insulin resistance, hypertension, augmented low-density lipoproteins with high triglycerides levels, and reduced high-density lipoproteins, which increase the risk of diabetes and severe cardiovascular diseases, such as stroke and acute coronary syndrome, with high cardiovascular mortality rates.18 Thus, the characterization of markers, predictions, and mediators associated with metabolic syndrome may lead to prevention or early treatment of metabolic and cardiovascular diseases, reducing morbidity and mortality rates. In this scenario, Vecchiola et al.3 addressed the levels of adipokines, metalloproteinases (MMP-2 and MMP-9), and high-sensitivity C-reactive protein (hsCRP) in 202 subjects, 60 of them classified with metabolic syndrome. As previously described in several clinical studies,19,20 this study reinforced that adipokines are altered in the plasma from those with metabolic syndrome, including reduced adiponectin and augmented PAI-1 levels. The authors further explored the relationship between adiponectin and PAI-1 and the main characteristics of metabolic syndrome. Indeed, although the sample size limits the conclusions, the strength of this study is the demonstration, through receiver operating characteristic analysis, that PAI-1 and adiponectin values can be both sensitive and specific enough to identify the development of the metabolic syndrome. The consequences of such altered profile of adipokines on vascular function are summarized in Figure 1. Despite the previous efforts, how alterations in adipokines profile in subjects with metabolic syndrome can be used as predictors, biomarkers, or even pharmacological targets are still poorly understood. Thus, studies such as the work developed by Vecchiola et al. are essential to further our understanding of the role of adipokines in contributing to cardiometabolic diseases. In the meantime, we must keep in mind the strategies to maintain a healthy homeostatic balance of adipocyte production of adipokines. Impaired adipokines and their contribution to vascular dysfunction in subjects with metabolic syndrome. In healthy subjects, adipocytes release balanced amounts of several mediators, some of them with well-known regulatory effects in the cardiovascular system, as included in the left box. In those with metabolic syndrome (left-side sequence), adipocyte-released mediators are defective, a phenomenon that has been implicated in cardiometabolic diseases, including metabolic syndrome. In this study, Vecchiola et al.3 demonstrated that the changes in adiponectin and plasminogen activator inhibitor-1 (PAI-1) are closely correlated with components of metabolic syndrome. Indeed, considering the physiological roles of these adipokines, their reduced and augmented levels (* indicates data found in this study) can contribute to several disturbances commonly found in cardiovascular diseases (i.e., see the right-side box). This illustration was created with an academic subscription of Biorender.com. The authors declared no conflict of interest.