SERGAS, Santiago University Clinical Hospital, Institute of Medical Research, Santiago de Compostela, Spain
Santiago University Clinical Hospital, Research Laboratory 9 (Laboratory of Neuro Endocrine Interactions in Rheumatology and Inflammatory Diseases), Building C, Level −2, Calle Choupana s/n, 15706 Santiago de Compostela, Spain
Patients with rheumatic diseases are at an increased risk of mortality and fatal cardiovascular events. Several rheumatic diseases (rheumatoid arthritis [RA], osteoarthritis [OA], ankylosing spondylitis [AS], and systemic lupus erythematosus [SLE]) have been associated with an increase in the prevalence of cardiovascular diseases (CVDs). Visceral fat accumulation and incompletely clarified genetic determinants have been suggested to play an essential role in the development of the coexistent disorders in the metabolic syndrome, such as hyperglycemia, hypertension, hyperlipidemia, and proinflammatory states, which will determine an increased risk of developing CVD. The predisposition to coexist for these risk factors suggests a single etiologic basis. However, although traditional cardiovascular risk factors (sex, smoking, dyslipidemia, age, and hypertension) have been involved in the pathogenesis of CVDs in patients with rheumatic diseases, such features do not clearly and fully account for the enhanced cardiovascular risk in this population. Metabolic syndrome and obesity or, much more correctly, pathologic alteration of fat mass, is likely the link between CVDs and rheumatic diseases. Indeed, the incidence of CVDs is increased when obesity (and associated clinical metabolic manifestations such as hyperlipidemia, diabetes mellitus, hypertension, and forced sedentary style) is present in patients with rheumatic disorders. Although it has been recently evidenced that dysfunctional adipose tissue secretes inflammatory mediators that are able to influence relevant tissue for rheumatic diseases such as cartilage and synovium, this review summarizes recent evidence on the central role of adipokines, specifically leptin and adiponectin, produced by fat tissue in the modulation of CVDs in the general population, but also analyzes the role of adipokine in a special environment that is represented by rheumatic diseases (Figure 1).
Obesity, cardiovascular risk, and rheumatic diseases
Treatments in patients with rheumatic disorders principally involve the management of joint disease, but also target serious associated illnesses such as infections and malignancies, and mainly CVDs. Such comorbidities have a great impact on patient quality of life, chronic disability, life expectancy, and mortality. For instance, CVDs are responsible for almost 50% excess of mortality in patients with RA (1, 2).
Classic risk factors, such as hypertension, dyslipidemia, insulin resistance, and obesity (metabolic syndrome), appear to cluster in patients with RA and are highly prevalent (3). Actually, RA is characterized by hyperproduction of proinflammatory cytokines and adipokines that create a specific milieu that contributes to the worst patient conditions by also establishing a complex metabolic state called rheumatoid cachexia. This latter state is characterized by loss of muscle mass with progressively increased fat mass. Paradoxically, as a result, a patient with RA may have a higher percentage of body fat when compared to a healthy control with the same body mass index; this increased body fat may contribute further to the development of CVD (4, 5).
However, it is noteworthy to mention that Escalante et al (6) described a paradoxical effect of body mass on mortality in patients with RA. Actually, in this cohort, a higher body mass index (BMI) seems to diminish the death risk. Nevertheless, some cautions, i.e., some unmeasured confounders, in the interpretation of these findings are warranted.
The increase of fat mass is also related to the occurrence of OA and to the plethora of cardiovascular comorbidities. The relationship between obesity and OA is an important public health issue. Actually, the increase of disability associated with the increase of a dysfunctional fat mass in these patients enhances the severity of clinical conditions and is perhaps also responsible for disease promotion and progression (7). Regarding the influence of fat mass on OA, it is evident that biomechanical aspects are of weight in the pathogenesis of diseases. However, OA is more common in women and exists in non–weight-bearing joints, indicating that a metabolic component is present.
A link between SLE and metabolic syndrome also exists (reviewed by Pereira et al ). Most of these reports showed a major prevalence of experiencing metabolic syndrome in lupus patients than in healthy controls. Moreover, a higher risk of experiencing CVDs in lupus patients with a concomitant metabolic syndrome is also reported in some of these studies.
The link between metabolic syndrome and rheumatic diseases is also at play in AS. It has been reported to be a considerably higher risk of experiencing metabolic syndrome and CVDs in AS patients than in healthy controls (46% versus 11%), even after receiving anti–tumor necrosis factor (anti-TNF) therapy (9–11). Moreover, in these patients, the metabolic syndrome was associated with higher disease activity.
Several features of metabolic syndrome, such as dyslipidemia and diabetes mellitus, have also been reported, with a higher prevalence in Sjögren's syndrome. It is noteworthy that hypertriglyceridemia and diabetes mellitus were found to be associated with an increased risk of extraglandular findings (12).
Adipokines and cardiovascular risk
During the past 15 years, after the discovery of the first adipokines leptin and adiponectin, it became evident that cells from adipose tissue express a plethora of factors called “adipocytokines” or “adipokines” that prevalently contribute to increased levels of inflammatory markers in the circulation of obese individuals. These adipokines follow the canonical definition of a cytokine having pleiotropic effects according to the site of production, the site of action, the environmental context, and the concentration. Although initially confined to metabolic activities, adipokines represent a new family of compounds that can be currently considered as key players in the complex network of soluble mediators involved in the pathophysiology of rheumatic diseases. Actually, research aimed to study the complex interactions between metabolism and rheumatic disorders soon identified leptin and adiponectin as relevant adipokines involved in these pathologies, particularly in OA and RA. Nevertheless, new adipokines have emerged as potential players in rheumatic diseases. For instance, other adipokines are resistin and visfatin/nicotinamide phosphoribosyltransferase (NAmPRTase). Resistin is elevated after traumatic joint injuries and induces production of inflammatory cytokines and loss of proteoglycans in cartilage. The injection of resistin into mice joints induces arthritis-like conditions. NAmPRTase seems to have a proinflammatory effect on chondrocytes and synovial fibroblasts (13).
In the majority of obese patients, a dysfunctional adipose tissue mechanistically links obesity to other manifestations such as CVDs, fatty liver, and type 2 diabetes mellitus. This dysfunction is caused by a complex disequilibrium between genetic and environmental factors, which is characterized by adipocyte hypertrophy, hypoxia, and inflammation. The direct consequence of this dysfunction is that adipokine secretion is shifted to an atherogenic, diabetogenic, and proinflammatory secretion pattern.
According to the recent literature, all known adipokines are markedly dysregulated when an abnormal abdominal fat accumulation is present, thereby promoting metabolic and cardiovascular complications.
Adipokines, such as leptin, also contribute significantly to the promotion of proinflammatory and prothrombotic states in cardiovascular complications of rheumatic diseases. Indeed, the main mechanisms of CVDs, particularly those related to the atherogenic process (atherosclerosis, inflammation, thrombosis), are deeply influenced by adipokines. Notably, visceral fat accumulation associated with adipokine dysregulation affects both atherosclerotic plaque development and, more importantly, plaque disruption. Clearly, when the advanced plaque becomes unstable, ruptures can occur, establishing an acute coronary syndrome that is aggravated by the adipokine-induced prothrombotic and inflammatory state, which can further worsen syndromes.
Although it has been recently evidenced that dysfunctional adipose tissue secretes inflammatory mediators that are able to influence relevant tissue for rheumatic diseases such as cartilage and synovium (13), here we present an updated overview of the function played by 2 of the main fat mass–induced adipokines, leptin and adiponectin, with particular emphasis on their role as mediators of cardiometabolic risk factors in the general population, but also analyzing their role in the most relevant rheumatic diseases.
Leptin is a 16-kd nonglycosylated peptide encoded by the obese (ob) gene (homolog of human LEP gene) mainly produced by adipocytes that act at the hypothalamic central level by inducing a decrease in food intake and an increase in energy consumption, and whose circulating levels directly correlate with adipose tissue mass (14). Leptin exerts its biologic actions through the activation of its cognate receptors, which are encoded by the diabetes (db) gene (15). Various tissues produce leptin and express its cognate receptors, including those of the cardiovascular system such as blood vessels and cardiomyocytes (14). Food intake, energy status, and several hormones but also inflammatory mediators mainly regulate leptin gene expression (15, 16). Genetic deficiency in the gene encoding for leptin or its receptors provokes severe obesity and diabetes mellitus. Indeed, in obese patients, leptin concentrations are high in consequence of the increased fat mass, and it has been suggested that high leptin levels themselves are able to induce leptin resistance (17). Elevated serum leptin concentrations in humans are associated with myocardial infarction and stroke independently of traditional cardiovascular risk factors and obesity status (18), as well as with insulin resistance, inflammation, disturbances in hemostasis (19), hypertension (20), and the extent of coronary artery calcification in women (21). On the other hand, leptin has been proven to be an efficient vasodilator in humans with coronary artery disease (22). It has been proposed that leptin could play a role in the pathogenesis of atheromatous plaques acting synergistically with other inflammatory mediators (23). The proposed proatherogenic actions of leptin are supported by the demonstration that, in vitro, leptin stimulates the proliferation and hypertrophy of vascular smooth muscle cells and the production of matrix metalloproteinase 2 (MMP-2), promotes vascular production of proliferative and profibrotic cytokines, increases the secretion of the proatherogenic lipoprotein lipase by cultured human and murine macrophages, enhances platelet aggregation (14), and is able to induce C-reactive protein expression in human coronary artery endothelial cells (24). At the cardiac level leptin regulates cardiac contractile function (25), metabolism (26), and cell dimension and production of extracellular matrix components (27) in cardiomyocytes; reduces reperfusion-induced cardiac cell death (28); and induces elongation of cardiac myocytes causing eccentric dilatation with compensation (29). A role for leptin in the regulation of cardiomyocyte hypertrophy has been also suggested (30).
Leptin and rheumatic diseases
It is well known that leptin exerts direct actions on immune response, as reviewed by Matarese et al (31). Leptin is able to modulate multiple immune cells, for instance, monocytes/macrophages, natural killers, dendritic cells, and Treg cells. In addition to these actions, leptin has also been related to rheumatic diseases due to its ability to regulate bone metabolism via the central sympathetic nervous system (32).
It seems that leptin plays a role in several autoimmune diseases such as RA. This idea is underpinned by several in vivo and in vitro findings: in RA patients, circulating leptin levels have been found to be higher than in healthy controls (33, 34); however, other studies reported unchanged levels. Low leptin levels associated with food restriction have been linked to CD4+ lymphocyte hyporeactivity and increased interleukin-4 (IL-4) secretion (35). Moreover, leptin has been involved in RA-induced hypoandrogenicity, since leptin levels were negatively correlated to androstenedione (36). Therefore, since leptin acts as a proinflammatory agent and androgens are generally considered as antiinflammatory molecules, the preponderance of leptin and hypoandrogenicity may help to perpetuate chronic rheumatic diseases such as RA. However, neither infliximab nor adalimumab treatment was able to affect plasma or serum leptin levels (37, 38). On the other hand, experiments carried out in arthritis animal models also strengthen the involvement of leptin in RA disease. Together with in vivo experiments, in vitro experiments also revealed a proinflammatory facet of leptin. Leptin increases IL-8 production by RA synovial fibroblast (39) and, in human-cultured chondrocytes, synergizes with IL-1 and interferon-γ (IFNγ) in the production of nitric oxide (NO) (40, 41).
In comparison to RA, OA has a lower immune component. Despite this aspect, leptin has also been related to this pathology. It is known that leptin expression is much higher in human OA cartilage than in normal cartilage. Moreover, leptin expression in chondrocytes, as in synovial fluid, correlates with the severity of the disease (42–44). Considering the sexual dimorphism of leptin circulating levels, it has been hypothesized that the increased predisposition of women to develop OA could be due to the higher circulating levels observed in women in comparison with men (45).
In vivo experiments also support the involvement of leptin in OA. Very recently it has been reported that induced obesity due to impaired leptin signaling is able to induce alterations in subchondral bone morphology without increasing the incidence of knee OA. These results imply that only adiposity is insufficient to develop OA, pointing to a pleiotropic role of leptin in the development of OA by regulating both the skeletal and immune systems (46). In agreement with these data, intraarticular injection of leptin in rat joints suggested that leptin plays a catabolic role on cartilage metabolism, since it induced cartilage levels of MMP-2, MMP-9, and proteoglycan depletion (47).
As for RA, in vitro experiments also pointed to a role of leptin in OA. Leptin increases IL-8 production by OA synovial fibroblast (39) and, in human-cultured chondrocytes, synergizes with IL-1 and IFNγ in the production of NO (40, 41). In addition, in human OA chondrocytes, leptin increases MMP-9 and MMP-13 expression (44). Moreover, in OA human cartilage explants, leptin enhances the production of NO, prostaglandin E2 (PGE2), IL-6, and IL-8 (48). Leptin has also been involved in bone metabolism. Actually, it has been suggested that abnormal production of leptin by OA osteoblasts could be responsible for an altered osteoblast function in OA (49).
Regarding the role of leptin in SLE, some controversy exists. At present most of the studies pointed to a role for leptin in this pathology. Circulating leptin levels have been found to be increased in SLE patients compared to healthy controls, even after BMI correction (50–55). To note, in some of these studies, the hyperleptinemia coexists with CVDs and with several features of the metabolic syndrome. Indeed, in a lupus animal model, both high-fat diet and leptin increase proinflammatory high-density lipoproteins scores, atherosclerosis, and proteinuria, suggesting that factors typically associated with the metabolic syndrome can accelerate the disease and its cardiovascular complications (56). Moreover, leptin has been involved in SLE-induced hypoandrogenicity, since leptin levels were negatively correlated with androstenedione (36). In contrast to these studies, other groups have reported lower or unchanged circulating leptin levels in SLE patients compared to healthy controls (57, 58).
The role of leptin in AS is still unclear and the data available are somewhat scarce and contradictory. In comparison to healthy controls, it has been described that higher circulating leptin levels in male AS patients were correlated with IL-6 levels and disease activity. In addition, the same authors also reported that peripheral blood mononuclear cells (PBMCs) of AS patients are more susceptible to leptin-mediated cytokine production and express and secrete more leptin than control PBMCs (59, 60). On the contrary, other groups have reported lower circulating leptin levels in male AS patients (61).
Little is known about the role of leptin in Sjögren's syndrome. However, recently it has been described that, in an animal model of Sjögren's syndrome, treatment of the disease through immunization with a heat-shock protein (Hsp60)–derived peptide decreases circulating leptin levels, which also correlated with disease amelioration (62).
Adiponectin is a 244 amino acid protein with structural homology to types VIII and X collagen and complement factor C1q that is prevalently synthesized by adipose tissue and that increases fatty acid oxidation and reduces the synthesis of glucose in the liver and other tissues (63). Removal of the adiponectin gene has no dramatic effect in mice on a normal diet, but a severe insulin resistance, together with lipid accumulation in muscles, has been observed when these animals were fed a high-fat/sucrose diet (63). Adiponectin exerts its biologic actions by means of 2 receptors leading to an increase of fatty acid oxidation and reducing liver glucose synthesis (63). Adiponectin circulates in the blood in large amounts and constitutes approximately 0.01% of the total plasma proteins, being present in serum as oligomeric isoforms (63).
Adiponectin levels are inversely proportional to obesity and insulin resistance, increasing with weight loss and with the use of insulin-sensitizing drugs (63). Its secretion is inhibited by proinflammatory cytokines (15), suggesting that inflammation might be an important factor contributing to hypoadiponectinemia in insulin-resistant and obese states; on the opposite side, physical training increases circulating adiponectin and expression of its receptors, which may mediate the improvement of insulin resistance and the metabolic syndrome in response to exercise (64).
It has been suggested that hypoadiponectinemia is an independent risk factor for hypertension (65) and has a detrimental effect on aortic stiffness (66). However, presently, it is not possible to elucidate if adiponectin has an etiologic role in the development of hypertension, since in patients with hypertension, hypoadiponectinemia may be associated with the presence of other cardiovascular risk factors (67).
Many studies have shown that dyslipidemia is also associated with low circulating levels of adiponectin, even in the absence of other metabolic syndrome risk factors (68).
Obesity-related hypoadiponectinemia has been associated with subclinical inflammation (69). There is a general consensus about a putative protective role of adiponectin from the inflammatory state, at least at the endothelial–vascular level (15). Hypoadiponectinemia has been linked to inflammatory atherosclerosis, suggesting that normal adiponectin levels are required to maintain a noninflammatory phenotype on the vascular wall (15). Adiponectin has antiinflammatory properties that might regulate many steps in the atherogenic process, as well as antiapoptotic actions on endothelial cells and angiogenic effects on the vasculature (70).
High plasma adiponectin levels are associated with a lower risk of myocardial infarction in men (71), a reduced coronary heart disease risk in patients with diabetes mellitus (72), and a lower risk of acute coronary syndrome (73) and, significantly, plasma adiponectin levels rapidly decline following acute myocardial infarction (74).
Many recent findings have suggested that adiponectin is able to influence cardiac remodeling in pathologic states, limiting the progression of myocardial hypertrophy (75). Other beneficial effects of adiponectin at the cardiac level are the protective actions against myocardial ischemia-reperfusion (75) and the protection against the development of systolic dysfunction after myocardial infarction observed in mice (76).
Adiponectin and rheumatic diseases
In contrast to the abovementioned “protective” role for adiponectin against CVDs and obesity, there is evidence that in skeletal joints adiponectin may act as a proinflammatory and catabolic agent. Adiponectin has been found to be higher in RA patients than in healthy controls (34, 77–81). Moreover, adiponectin levels are increased in early RA patients that had never taken disease-modifying antirheumatic drugs and in chronic RA patients (82). Circulating adiponectin levels correlate with the severity of RA evaluated by joint destruction and radiographic damage (83, 84). According to this, very recently it has been reported that adiponectin and adiponectin receptor 1 expression is higher in synovial fluids and the synovial tissues of RA patients compared to healthy controls (85).
It is noteworthy that several treatments might modulate adiponectin levels. In patients with chronic RA, Laurberg et al reported that methotrexate increases adiponectin levels (82). However, in anti-TNF therapy of RA patients, different authors reported contradictory results: unchanged adiponectin levels (37, 86, 87), increased levels (88–91), and decreased levels in combination with corticoids (92).
In vitro experiments performed in several joint tissues also supported the abovementioned proinflammatory and catabolic role for adiponectin. Adiponectin stimulates PGE2 and IL-8 production in RA synovial fibroblast (93, 94). In addition, it was also reported in RA synovial fibroblast that adiponectin is able to stimulate the production of IL-6, PGE2, vascular endothelial growth factor, and MMP-1 and MMP-13 (43, 95). In cultured chondrocytes, adiponectin also induces the production of NO, IL-6, MMP-3, MMP-9, and monocyte chemotactic protein 1 (MCP-1) (96). In other cell types also involved in the pathophysiology of RA, such as human lymphocytes and human macrovascular endothelial cells, adiponectin has a similar behavior. It promotes inflammation through increased TNFα, IL-6, IL-8, and RANTES secretion by human primary lymphocytes. Likewise, it induces IL-6, IL-8, growth-related oncogene α, MCP-1, and RANTES secretion by human macrovascular endothelial cells (97). On the contrary, Lee et al have reported in mice that adiponectin mitigates the severity of collagen-induced arthritis (98).
Adiponectin has also been related to OA disease. It has been reported that OA patients have higher circulating adiponectin levels in comparison to healthy controls and RA patients (82). Moreover, adiponectin levels have been correlated with the Lequesne index (99) and synovial fluid adiponectin has also been correlated with aggrecan degradation markers in OA (100). However, a recent study revealed that adiponectin levels are increased only in erosive OA (101).
Regarding the information provided by animal models, very recently it has been reported in mice that serum adiponectin levels correlate negatively with the severity of obesity-induced OA (102). According to this, the spontaneous osteoarthritis murine model (STR/Ort) also has low adiponectin levels associated with obesity (103). Both findings are in agreement with the already known inverse relationship between fat mass and adiponectin circulating levels.
In vitro experiments also support a link between adiponectin and OA. OA synovial fibroblasts express proinflammatory mediators after adiponectin treatment (104). Likewise, in cultured chondrocytes, as already mentioned for RA, adiponectin also induces the production of proinflammatory and matrix catabolic factors (96). In keeping with all of these activities for adiponectin in OA, it has been determined that the infrapatellar fat pad of knee OA has an increased synthesis of adiponectin that suggests the infrapatellar fat pad as a possible source of joint adiponectin (105).
Regarding the role of adiponectin in SLE, elevated levels of this adipokine in SLE patients have been described (51, 55, 57). In contrast, other authors did not find any difference in adiponectin levels between SLE patients and controls (53, 54). Interestingly, adiponectin levels are increased in SLE patients with carotid plaques (106) and in renal SLE-associated vasculopathy (107).
In vivo experiments provide important information about the role of adiponectin in SLE. It has been reported that adiponectin acts as a negative modulator of the autoimmune phenotype in a murine model of lupus, and this effect is more pronounced in female versus male mice (108). It was also reported that mice with lupus that lack adiponectin develop more severe disease than wild-type mice, which suggested that adiponectin is involved in regulating disease activity (109). Moreover, the same authors also reported that the beneficial effects of peroxisome proliferator–activated receptor γ agonist (rosiglitazone), by reducing autoantibody production, renal disease, and atherosclerosis in a mouse model of SLE, are mainly supported by adiponectin induction (109).
In other rheumatic diseases such as AS, little is known about the role of adiponectin. However, it has been described that serum adiponectin levels are not different between AS patients and healthy controls (61).
Only a few works have studied the role of adiponectin in Sjögren's syndrome. It has been described that adiponectin is expressed in salivary gland epithelial cells, and this expression is higher in patients with Sjögren's syndrome (110). In addition, very recently it has been reported by the same group that adiponectin is able to protect salivary gland epithelial cells from spontaneous and INFγ-induced apoptosis (111).
Fat mass produces adipokines that play multiple important roles in the body, and the increasing research in this area reveals the complex adipokine-mediated interaction among white adipose tissue, cardiometabolic disorders, and rheumatic diseases. The chronic increase of the inflammatory tone is frequently associated with an increased risk for the development of CVD, particularly in the special environment characteristic of rheumatic diseases. Indeed, chronically elevated lipid and glucose levels in patients with rheumatic disease establish unending stress on the vascular endothelium, which is further exasperated by inflammatory proteins and promotes the development of atherosclerosis. Therefore, adipokine dysregulation present in many rheumatic diseases might explain some of their associated cardiovascular comorbidities, pointing to adipokine physiology as a potential therapeutic target.
Nonetheless, we have to bear in mind that the main causes of abnormal fat mass accumulation and its dysfunction are generally due to a combination of bad nutritional and lifestyle habits such as overeating and physical inactivity, which is further worsened by rheumatic diseases. Therefore, the front-line treatment of fat mass–related cardiometabolic disorders in rheumatic diseases, as well in the general population, essentially involves the correction of these factors. Thus, the benefit of lifestyle modification, as well as other therapeutic interventions aimed to reduce visceral fat dysfunction and to obtain an adequate modulation of inflammatory response, might drastically reduce cardiovascular morbidity in patients with rheumatic diseases.
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published.
There are many additional relevant articles that were worthy of mention in this review; however, space considerations precluded their inclusion.