Sascha Gerdes, MD, Department of Dermatology, University Medical Center, Schittenhelmstr. 7, 24105 Kiel, Germany, Tel.: +49-431-5971512, Fax: +49-431-5971543, e-mail: email@example.com
Abstract: Adipose tissue is an active endocrine organ contributing to the regulation of multiple metabolic pathways via self-produced bioactive products called adipokines. These adipokines are key players in the pathogenesis of metabolic syndrome and cardiovascular diseases. Co-occurrence of obesity and psoriasis could lead to interactions of both diseases in which adipokines, at least in part, are involved and may contribute to associated comorbidities of psoriasis. Until today numerous adipokines have been identified of which the most important ones are discussed in the following within the context of obesity, chronic inflammation and their possible role in the pathogenesis of psoriasis. Adipokines could serve as a missing link in the causal relationship between psoriasis and comorbidities and may provide a biomarker for disease severity, risk of comorbidities and treatment success.
White adipose tissue (WAT) is the largest organ in the human adult body consisting primarily of adipocytes known to store energy in the form of triglycerides. Recent evidence indicates that adipose tissue (AT), in particular visceral AT, is an active endocrine organ contributing to the regulation of body functions such as insulin-mediated processes, lipid and glucose metabolism, vascular changes, coagulation and inflammation (1,2). Besides adipocytes, cells such as endothelial cells, leukocytes, fibroblasts and preadipocytes forming the stromal-vascular fraction are an important part of AT. Multiple metabolic pathways are mediated by adipocytokines, or adipokines, a general term commonly used for bioactive products produced by AT.
Obesity is becoming a worldwide epidemic burden for health care systems, leading to a variety of disorders subsumed in the metabolic syndrome. The physiological function of AT is impaired in obesity and an increase in particularly visceral obesity is associated with the development of metabolic syndrome and its consequences such as a higher prevalence of cardiovascular diseases and diabetes mellitus type 2 (3–5). Immune cells, predominantly inflammatory-type macrophages, infiltrating white AT create a microenvironment that perpetuates inflammation within AT and stimulate adipocytes to produce inflammatory mediators including adipokines creating a baseline inflammatory state in obesity. Affecting vascular function, immune regulation and adipocyte metabolism adipokines are key players in the pathogenesis of metabolic syndrome as a major risk factor for cardiovascular morbidity and mortality (6). As a consequence obesity itself through its concomitant inflammation adversely affects disorders in which immune-mediated inflammation is the pathophysiological background including inflammatory bowl disease (IBD), rheumatoid arthritis (RA) and chronic skin inflammation such as psoriasis.
Psoriasis is a complex chronic inflammatory skin disease affecting approximately 2% of people living in western civilisations (7). The disease is no longer regarded as a disease of the skin only. Psoriasis patients have been found to be at greater risk of developing comorbid diseases in particular metabolic syndrome and vascular disorders (8).
A fundamental pathological process that leads to skin manifestations and comorbidities is chronic inflammation. It has been demonstrated that psoriasis is significantly associated with obesity and obesity has been described as an independent risk factor for the development of psoriasis (9–11). In addition, first evidence is presented that HLA-Cw6, the most important genetic susceptibility locus for psoriasis, is linked to obesity. In a cohort study in Han-Chinese patients the presence of obesity and HLA-Cw6 increased the risk of developing psoriasis 35-fold as compared to normal weight, HLA-Cw6-negative people (12).
Co-occurrence of obesity and psoriasis could lead to interactions of both diseases in which adipokines, at least in part, are involved. Psoriasis and related comorbidities, in particular obesity, may provide the inflammatory basis of the ‘psoriatic march’ that describes the development of vascular long-term complications seen in psoriasis patients (13). As information on adipokines in the context of psoriasis is limited this summary provides some general information on the most important adipokines as well as ideas and speculations how these adipokines could possibly connect psoriasis with its major comorbidities.
Adiponectin (Acrp30) is mainly produced by adipocytes. The encoding gene is located in a susceptibility region for metabolic syndrome, type 2 diabetes and cardiovascular disease (14). A negative correlation between BMI and adiponectin plasma levels was described (15). In obesity adiponectin levels are decreased which may be in part be explained by elevated pro-inflammatory cytokines/adipokines such as tumor necrosis factor alpha (TNFα) and interleukin(IL)-6 which has been demonstrated in in vitro studies (16,17).
Clinical studies suggest a regulatory and anti-inflammatory role of adiponectin in atherosclerosis; it was shown to be decreased in patients with coronary artery disease (18). Prospective studies were able to show an increased risk of cardiovascular events in patients with low adiponectin levels (18).
TNFα-induced expression of adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1), E-selectin and intercellular adhesion molecule-1 (ICAM-1) was reduced by physiological concentrations of adiponectin leading to a decreased attachment of monocytes to endothelial cells, which is regarded as an initial step in atherosclerosis (19). In an in vivo study using adiponectin-deficient mice treatment with adiponectin lead to an improvement of abnormal neo-intimal thickening of injured arteries (20). In addition, adiponectin induced vascular remodelling of injured arteries (21).
Furthermore, patients with lower levels of adiponectin are at increased risk of developing type 2 diabetes and hypertension as well as dyslipidaemia (18,22).
In contrast, adiponectin levels are elevated in inflammatory/autoimmune diseases that are unrelated to increased AT, such as RA, systemic lupus erythematosus (SLE), IBD, type 1 diabetes and cystic fibrosis (17). Thus, adiponectin may be regulated in opposite direction in non-adiposity related chronic inflammatory conditions.
Adiponectin and psoriasis
In a study with 10 normal weight (BMI < 25) patients with psoriasis and 12 patients with obesity (BMI > 30) a correlation between obesity and decreased adiponectin levels was shown. Compared to 22 normal weight healthy controls adiponectin levels of normal weight patients with psoriasis were 2-fold increased whereas obese psoriasis patients had comparable adiponectin levels compared to healthy controls (23). The study demonstrates that obesity in patients with psoriasis leads to a decrease of circulating adiponectin levels. When correlated to the pro-inflammatory cytokine IL-6, a strong negative correlation to adiponectin was shown for obese psoriasis patients. A second study in a Japanese cohort showed a decrease of adiponectin in male psoriasis patients compared to healthy controls. Patients and controls with obesity or diabetes mellitus have been excluded from the study. No correlation to psoriasis severity was seen, however, patients with moderate to severe psoriasis (PASI > 10) showed a negative correlation between adiponectin and IL-6 (24). Both studies discussed the possibility that pro-inflammatory cytokines such as IL-6 suppress adiponectin production in patients with psoriasis. A Portuguese study in 56 psoriasis patients compared to 37 healthy controls showed a decrease in adiponectin levels in correlation to severity of the disease (25).
Takahashi et al. reported on a decrease in mean plasma level of adiponectin in 122 psoriasis patients. Adiponectin negatively correlated with PASI and TNFα levels (26).
Leptin is a 16-kDa adipokine mainly produced by adipocytes which can also be expressed in tissues such as placenta, ovaries, skeletal muscle, stomach, pituitary gland and liver (27). Circulating leptin levels differ between males and females, being two to three times higher in females (28). The main function of leptin seems to be an afferent signal of nutritional and fat mass status to the hypothalamus, thus controlling energy fat stores and regulating appetite and body weight in humans (29). Besides central effects leptin shows effects in the periphery with direct interactions of immune cells, adipocytes, muscle and blood cells, as well as effects on skin regeneration and hair growth (27,30). Patients with leptin deficiency are extremely obese and children with a congenital leptin deficiency remain prepubertal without exogenous leptin substitution (31,32). In contrast, in obese patients leptin levels are increased without effect of patient’s general food intake. Furthermore, the treatment of obese patients with exogenous leptin substitution is without effect. This led to the concept of leptin resistance in obesity similar to insulin resistance in type 2 diabetes (1).
Elevated leptin levels have been associated with intima-media thickness of the common carotid artery (33) and leptin was proposed to be an independent predictor of future cardiovascular events and coronary heart disease (34,35). In vitro studies in mice models support a direct and independent mechanism of leptin on the development of cardiovascular disease (36).
Furthermore, platelet aggregation and thrombus formation was found to be affected by leptin contributing to arterial thrombosis after vascular injury in mice (37).
As cardiovascular diseases are associated with an underlying inflammatory state the effect of leptin on pro-inflammatory cytokines has also been investigated. In a mouse model it was shown that exogenous leptin was able to increase cytokines such as TNFα, IL-6 and -12 (38). After incubation of human peripheral blood mononuclear cell (PBMCs) with high dose leptin concentrations an induction of a Th1-like cytokine response was seen (39). These data support a pathophysiological role of leptin in modulating inflammatory processes.
Leptin and psoriasis
In a study including 30 patients with plaque psoriasis (mean PASI of 15.33 and mean BMI of 30.5) leptin serum levels were measured prior and after narrowband UVB treatment. A correlation between BMI and waist circumference with serum leptin levels was shown whereas the leptin levels did not differ between patients and a matched healthy control group (40). In another study evaluating data from 144 psoriasis patients and 54 healthy controls a positive correlation between BMI and leptin levels but not with PASI was shown. In this study leptin levels for male and female patients were significantly higher in the psoriasis patients as compared with the controls and a role of leptin in the pathogenesis of psoriasis was proposed (28). In an additional study 43 patients with psoriasis, 10 patients with other skin diseases and 10 healthy controls, all with a normal BMI were analysed. In this study a significant increase in serum leptin in severely affected psoriasis patients was shown in comparison to mild to moderately affected patients and controls. Leptin and leptin receptor expression assessed by immunohistochemistry of skin biopsy samples showed an increased expression only in severely affected psoriasis patients. Furthermore, a positive correlation of serum leptin levels, tissue leptin and tissue leptin receptor expression was shown with disease duration. The authors conclude that leptin might serve as a marker of severity and chronicity in psoriasis (41).
In 77 Taiwanese psoriasis patients compared to 81 age- and sex-matched healthy controls psoriasis proved to be an independent risk factor for hyperleptinemia with an odds ratio of 4.57 (95% confidence interval, 1.47–14.23) (42). Another cohort study from Japan involving 122 psoriasis patients compared to 78 controls also showed an increase in mean leptin plasma level in psoriasis (26).
Resistin is an AT-derived adipokine with a link to inflammation, immunity, obesity and insulin resistance. In humans it is mainly produced by monocytes and macrophages residing in AT and by peripheral blood monocytes (43). It was shown that pro-inflammatory cytokines such as TNFα, IL-1beta, IL-6 as well as lipopolysaccharide can increase resistin expression and that resistin itself can increase the production of TNFα and IL-12 (44). The induction of pro-inflammatory cytokines by resistin seems to be mediated via the nuclear factor kappa of activated B cells (NF-kappaB) pathway. Adipocytes may serve as target cells for resistin as the resistin-mediated induction of the expression of IL-6, IL-8 and TNFα by white AT was shown (44). Thus, resistin might enhance its own activity by a positive feedback mechanism.
Resistin has been originally described as a potential link between obesity and diabetes. But studies in humans have been controversial (45). Studies have shown, that neither fat cell mass, nor percent body fat is related to serum resistin levels (46), no good correlation between resistin and adiposity or insulin resistance could be identified (44).
In RA patients resistin was found in serum and synovial fluid and injection of resistin into joints of mice induced an arthritis-like condition, a correlation of resistin levels and inflammatory markers such as C-reactive protein (CRP) in RA patients was described (47). Thus, resistin is discussed to be involved in RA pathogenesis (48). Besides RA, resistin is also found in higher concentrations in IBD (49). CRP, white blood cell counts and disease activity score correlated with resistin levels in Crohn’s disease and ulcerative colitis. In Crohn’s disease resistin was shown to be an independent predictor for active disease (49). In RA as well as in IBD resistin levels decreased after TNFα blocking therapy leading to the idea of resistin being a marker for successful therapy in IBD (50). Furthermore, resistin was suggested as a mediator for endothelial dysfunction in humans as an early sign for atherosclerosis (44).
It is known that successful anti-TNFα therapy can improve cardiovascular risk of RA patients (51). Resistin itself was shown to be a predictive factor for coronary atherosclerosis and a marker of the severity of myocardial ischemic injury (52,53). It can be speculated that a reduction of cardiovascular risk might in part be the result of a reduction in resistin levels.
Taken together resistin may be much more closely related to inflammation and to resulting atherosclerosis as to obesity and insulin resistance.
Resistin and psoriasis
In several studies an increase of resistin in psoriasis patients as well as a correlation to disease severity were observed. In 39 patients with moderate-to-severe plaque psoriasis resistin levels showed a statistical significant correlation (P < 0.05) to PASI (54). A second study found an increase of serum resistin levels and a correlation to disease severity (P < 0.05) in 30 patients with psoriasis (40). In a Portuguese study in 66 patients with psoriasis an increase of resistin levels was shown, particularly in more severe forms of the disease which could be decreased by anti-psoriatic therapy (25). Corbetta and co-workers were able to show increased serum resistin levels in untreated psoriasis patients normalizing after 1 and 3 months of acitretin therapy (55). Unfortunately not all studies controlled their results for BMI or WHR to demonstrate whether the increase of resistin in psoriasis was independent of obesity. As severely affected patients with psoriasis are at an increased risk for coronary artery calcification (56) and cardiovascular diseases (57,58), resistin might, similar to RA and IBD, be of value as a predictive factor for atherosclerosis in this patient cohort.
Visfatin [also known as preB-cell-colony-enhancing factor (PBEF)] is a 52-kDa protein mainly produced by macrophages in visceral AT (59). It was described that visfatin shows insulin-like effects by binding to insulin receptors (60). Few studies suggested that visfatin decreases blood glucose levels and that visfatin itself is regulated by glucose (61).
Furthermore, visfatin is a pro-inflammatory cytokine that dose-dependently up-regulates the production of IL-6, IL-1β and TNFα in human monocytes (62). By induction of co-stimulatory molecules such as CD80, CD40 and ICAM-1 visfatin promotes the activation of T cells (63). Subsequent work has shown that various cells of innate immunity such as neutrophils, monocytes, macrophages as well as epithelial and endothelial cells can be a source of visfatin after induction with inflammatory stimuli (61).
Visfatin has been identified in a variety of chronic inflammatory disease. Several studies have shown that visfatin is an active player in the inflammatory process in RA. Otero et al. demonstrated an increase of plasma visfatin levels in RA patients and Matsui et al. found an increase of mRNA expression for visfatin in synovial tissue and peripheral blood leukocytes of RA patients (64,65). Moschen and co-workers showed in patients with Crohn’s disease and ulcerative colitis that plasma levels of visfatin were elevated and its mRNA expression was significantly increased in colonic tissue of patients compared with healthy controls (62).
The relationship between visfatin and obesity is inconsistent. In the literature studies reporting elevated, unchanged and reduced levels of visfatin can be found. Weight loss was reported either to increase or to decrease visfatin levels (61). A better correlation seems to be present to vascular diseases. Dahl and co-workers showed that visfatin expression is up-regulated in atherosclerotic plaques and at sites of plaque rupture in patients with acute myocardial infarction suggesting a role of visfatin in atherogenesis and plaque destabilization (66).
Visfatin and psoriasis
Data on visfatin in psoriasis are sparse. A gene expression profiling of PBMC was carried out in 10 severely affected patients with psoriasis. Patients included in the study presented with more than 60% involved body surface area and PBMC were isolated before and after treatment. It was shown that gene expression of visfatin was strongly up-regulated in the diseased state (67). The same result was observed in a second study analysing gene expression from psoriatic and control skin samples by interrogating the full set of Affymetrix GeneChip (68).
Retinol-binding protein (RBP) is a 21-kDa transport protein for vitamin A. RBP4 is produced and secreted by adipocytes and hepatocytes, with visceral adipocytes being the main source of RBP4 (69). Today, RBP4 is considered a key protein in the development of insulin resistance (70). It was shown that elevation of RBP4 causes systemic insulin resistance and reduction improves insulin action. It was possible to induce insulin resistance in a mouse model with normal mice by increasing the average serum level of RBP4 by approximately three times over a period of 9–21 days (70). In humans it was observed that serum RBP4 levels are increased in obese–non-diabetic and obese–diabetic subjects. The magnitude of RBP4 levels did not differ between the two groups. It was suggested that obesity and insulin resistance, rather than obesity and hyperglycaemia, are associated with elevated serum RBP4 levels (70). In humans the role of RBP4 as a mediator of insulin resistance and diabetes was underlined by showing that serum RBP4 level correlated with the magnitude of insulin resistance in subjects with obesity, impaired glucose tolerance, or type 2 diabetes and in non-obese, non-diabetic subjects with a strong family history of type 2 diabetes (71). As RBP4 is elevated before the onset of diabetes it raised interest as a predictor of insulin resistance and as a therapeutic target for anti-diabetic therapy (70). As serum RBP4 levels are also positively correlated with several cardiovascular risk factors such as BMI, WHR, serum triglycerides and systolic blood pressure, and inversely with plasma high-density lipoproteins it might play a role in cardiovascular disease in obesity (72).
RBP4 and psoriasis
In a study from 1985 Rollman and Vahlquist investigated levels of retinol-binding protein (RBP) in the serum of 107 patients with psoriasis. They found a normal mean serum concentration of RBP in patients with less than 25% body surface area affected and a significant lower serum RBP concentration in patients with a more extensive disease or pustular/erythrodermic psoriasis in comparison to 37 healthy controls (73). Methods to determine RBP4 in human serum have developed since 1985 but current data on RBP4 using more recent determination techniques in psoriasis are missing. It could be speculated that RBP4 which is a marker for insulin resistance and diabetes may be increased in severely affected patients with psoriasis as diabetes is a well known comorbidity in this patient population. Further investigations are necessary to answer this possible association.
Omentin is a protein of approximately 38–40 kDa which is mainly produced by stromal-vascular cells of visceral AT (74). It was shown that omentin increases insulin sensitivity by stimulating insulin-mediated glucose uptake in human adipocytes (74). Therefore, omentin might be involved in the pathogenesis of obesity and its related diseases. De Souza Batista and co-workers were able to show a relation between omentin levels and measures of obesity, insulin resistance and related features. In a group of 94 healthy volunteers plasma omentin levels showed to be inversely related to obesity. Omentin correlated negatively with BMI, leptin, waist circumference, fasting insulin, and homeostatic model assessment (HOMA) and positively with adiponectin and high density lipoprotein (HDL). Thus, the authors concluded that omentin levels may be seen as a positive marker that opposes the obese state (75).
A study comparing 33 patients with RA to 33 patients with osteoarthritis, levels of omentin were determined in synovial fluid. It was shown, that omentin levels were significantly lower in patients with RA but did not correlate to BMI of the patients. In a second study in 12 patients with Crohn’s disease mRNA expression for omentin was investigated by real-time polymerase chain reaction (RT-PCR). In 75% of patients no or low omentin expression was found. As a conclusion the authors proposed omentin to be involved in chronic IBD and absence of omentin might facilitate transmural inflammation (76).
Omentin and psoriasis
No information on omentin in the context of psoriasis was found.
Tumor necrosis factor alpha
TNFα is a pro-inflammatory cytokine found as a 17-kDa soluble molecule in the circulation (77). It is produced by a variety of different cell types such as activated monocytes/macrophages, lymphocytes, mast cells and natural killer cells. In obesity the primary source of TNFα are macrophages from the stromal-vascular fraction of AT (78). TNFα can increase its own production and of IL-6, resistin, visfatin and monocyte chemotactic protein-1 (MCP-1) (79). Adiponectin and leptin concentrations generated from adipocytes are reduced by TNFα (80). This cytokine has strongly been implicated in the pathogenesis of insulin resistance. Several studies have shown that TNFα levels are increased in obesity and that TNFα can impair insulin signalling in various tissues (81). Most effects of TNFα on AT are mediated by the TNFα receptor 1 subtype (TNFR1) and subsequent activation of the NF-kappaB and the c-Jun NH2-terminal kinase (JNK) pathway. Although an established TNFα-mediated link between inflammation and insulin resistance exists in obese rodent models, the same link in humans has not yet been substantiated. Few TNFα-neutralization studies in obese humans failed to show an involvement of TNFα in insulin resistance in vivo (82). Interestingly, information gathered from inflammatory diseases, such as RA in which anti-TNFα therapies are often used, strongly support a role of TNFα in insulin sensitivity (82,83).
As a pro-inflammatory cytokine, TNFα contributes to an inflammatory state when over-produced. TNFα not only up-regulates other inflammatory cytokines such as IL-6 but also down-regulates anti-inflammatory mediators such as adiponectin. In human omental adipocytes cultured in media conditioned by stromal-vascular cells from AT an overproduction of pro-inflammatory adipokines was shown. When TNFα was neutralized in this media, the effect was abrogated. The authors concluded that TNFα may be crucial for adipokine dysregulation in adipocytes (84).
Tumor necrosis factor alpha and psoriasis
TNFα is of major importance for the generation of psoriatic skin lesions. When psoriatic skin is grafted onto immunodeficient mice (AGR mice), psoriatic lesions spontaneously develop. This effect can be abrogated by administration of anti-TNFα agents (85). As anti-TNFα agents are widely used in the therapy of moderate to severe plaque psoriasis with high efficacy the role of TNFα in the pathogenesis of psoriasis has been substantiated (86).
As TNFα is produced by macrophages from the stromal-vascular fraction of AT it may also be regarded as an adipokine. In contrast to other adipokines AT is not the only source for TNFα and cells from other tissue are involved in its production. In chronic inflammatory diseases such as psoriasis TNFα derived from AT can at least in part contribute to the inflammatory state of the disease. Studies in psoriasis that intend to investigate TNFα levels exclusively generated by AT are difficult to undertake and to our knowledge have not been performed yet.
Human IL-6 is a cytokine/adipokine with a molecular weight that ranges between 21 and 28 kDa, depending on the state of glycosylation and phosphorylation. It is regarded as a major inflammatory mediator with pro- and anti-inflammatory effects, as well as a central player in haematopoiesis, immune response and host defence mechanisms (87). A variety of cells can produce IL-6 including fibroblasts, endothelial cells, monocytes, and adipocytes (82). Up to 30% of the circulating level of IL-6 has been estimated to originate from stromal-vascular cells of white AT (88). The highest levels of IL-6 have been documented in cases of severe stress, sepsis and major surgery with concentrations up to 1000-fold of the normal level (89). Elevated levels of IL-6 are also found in obesity. It was shown that in obese humans IL-6 expression and secretion from AT increases with BMI and body fat (72). The release of IL-6 into the circulation in obesity has linked this adipokine to insulin resistance and IL-6 is a possible predictor of type 2 diabetes (72). In mice maintained on a high-fat diet the increased production of IL-6 by AT induced hepatic insulin resistance (90). In contrast, IL-6 infusions in humans increased skeletal muscle insulin sensitivity, a potential explanation for this contradiction might be that chronic elevation of IL-6 has a weaker influence in muscle while it contributes to insulin resistance in liver and AT (82,91). Furthermore, acute-phase reactants, such as CRP, fibrinogen and plasminogen activator inhibitor-I (PAI-I), are up-regulated by IL-6 which is another link between AT and inflammation (92).
Interleukin 6 and psoriasis
IL-6 has been described to be over-expressed in psoriatic skin as well as in the circulation (93). In the pathogenesis of psoriasis the cutaneous and systemic over-expression of several pro-inflammatory cytokines, including IL-6, has been suggested to be responsible for initiation and maintenance of skin lesions. As IL-6 has the ability to induce acute inflammatory reactions and to maintain chronic inflammatory phases it is found to play a role not only in psoriasis but also in numerous autoimmune and chronic inflammatory diseases such as Crohn’s disease and RA for which an antibody against IL-6 proved to be an effective therapy (93–96). Yet, a link between IL-6, AT and psoriasis has not been established.
Obesity is a common and prominent comorbidity in psoriasis (10). An obese state itself is associated with a background systemic inflammation characterized by an increase of pro-inflammatory markers such as TNFα and IL-6. Furthermore, adipokines are dysregulated which may provide the basis of metabolic disorders and long-term consequences such as vascular diseases (81).
Major adipokines such as adiponectin, leptin, resistin and visfatin that are known to be dysregulated in obesity are also found to be abnormal in psoriasis. Table 1 provides an overview about the current literature of the most common adipokines within the context of psoriasis. Although some studies provide controversial data it seems that the alterations of adipokine levels are similar to changes found in obesity but independently associated with psoriasis.
Table 1. Adipokines and reported changes in psoriasis
Reported changes in psoriasis
Decreased in obese compared with normal weight psoriasis patients
Adiponectin that has anti-inflammatory and anti-atherogenic effects is down-regulated in psoriasis and obesity. This is in contrast to other autoimmune and chronic inflammatory diseases such as RA, IBD, SLE and type 1 diabetes (17), where increased levels of adiponectin are found. As patients with psoriasis, in contrast to most other chronic inflammatory diseases, tend to be obese their metabolic background seems to be different. Thus, lower adiponectin levels in psoriasis could contribute to the development of concomitant diseases like the metabolic syndrome or cardiovascular diseases independently from obesity as well as synergistically with obesity if present.
Leptin is independently involved in vascular remodelling and cardiovascular diseases as well as in modulating inflammatory processes, possibly via inflammatory cytokines such as TNFα, IL-6 and IL-12. In psoriasis an obesity independent increase of leptin levels has been found and was correlated to psoriasis severity. Thus, leptin may be involved in psoriasis pathophysiology and contribute to the diseases itself as to the development of comorbidities particularly cardiovascular diseases.
Resistin and visfatin are adipokines that might be more strongly related to inflammation than to metabolic disorders. In chronic inflammatory diseases such as RA and IBD as well as in psoriasis resistin and visfatin levels are increased. These adipokines have a potential role of mediating vascular diseases in psoriasis.
Other adipokines such as RBP4 and omentin are not well investigated in the context of psoriasis but associated with insulin resistance and type 2 diabetes. It is by chance that these adipokines play a role in metabolic comorbidities of psoriasis.
Adipokines are key players in many physiological mechanisms. In chronic inflammatory diseases such as psoriasis they may be involved in disease onset and maintenance as well as in the development of comorbidities in particular insulin resistance, diabetes and cardiovascular diseases (Table 2). The complicated interplay between the major adipokines in psoriasis is depicted in Fig. 1. To better understand the role of adipokines in psoriasis pathophysiology and their contribution to concomitant diseases more research is needed. Adipokines could serve as a missing link in the causal relationship between psoriasis and comorbidities and may provide a biomarker for disease severity, risk of comorbidities and treatment success.
Table 2. Possible consequences due to altered adipokines in psoriasis
Status in psoriasis
Development of vascular diseases and metabolic syndrome
Control of fat stores, regulation of appetite and body weight; pro-inflammatory
Development of vascular diseases
Development of vascular diseases
Insulin-like effects, pro-inflammatory, T cell activation
Development of vascular diseases
Transport protein for vitamin A, development of insulin resistance
If up-regulated: Development of metabolic diseases (e.g. insulin resistance, type 2 diabetes)
Increase of insulin sensitivity
If down-regulated: Development of metabolic diseases (e.g. insulin resistance, type 2 diabetes)
Development of vascular diseases and metabolic syndrome
Pro- and anti-inflammatory
Development of insulin resistance, type 2 diabetes and vascular diseases
Conflict of interest
This work has not been funded; the authors have no conflict of interest to declare that may be relevant to the subject matter.