Over the past decade, extensive research has highlighted the role of WAT in the development of psoriatic lesions. Specifically, WAT exacerbates the severity of these lesions by increasing inflammatory levels, promoting epidermal proliferation and facilitating angiogenesis through the action of adipokines, extracellular vesicles (EVs) and free fatty acids (FFAs; Fig. 1).

Adipokines are bioactive molecules secreted by WAT that are essential in modulating various physiological processes, such as metabolism, inflammation and immune responses. To date, >600 adipokines have been identified and they are generally categorized into two categories, proinflammatory and anti-inflammatory (25). During the expansion of WAT, proinflammatory adipokines such as leptin, resistin, TNF-α, monocyte chemoattractant protein-1 (MCP-1), visfatin, chemerin and IL-6 are secreted in increased amounts. By contrast, anti-inflammatory adipokines such as adiponectin and C1q/tumor necrosis factor-related protein (CTRP) 3 are secreted in reduced quantities (26–28). These alterations in adipokine levels collectively contribute to increased systemic inflammation, ultimately promoting the pathological development of inflammatory diseases such as psoriasis (Fig. 2).

Adiponectin, a hormone secreted by WAT, exhibits both anti-inflammatory and insulin-sensitizing effects. Its role in psoriasis is complex, involving various mechanisms related to immune cells and inflammatory pathways. In patients with psoriasis, plasma, skin and subcutaneous adiponectin levels are markedly lower than those observed in healthy individuals (29–31). Despite these diminished levels, there is a weak association between adiponectin concentrations and the severity of psoriasis, as assessed by the Psoriasis Activity Score Index (PASI) (30,32). Furthermore, clinical treatments that improve psoriasis symptoms do not seem to normalize adiponectin levels (30). This suggests that reduced adiponectin levels might be more closely associated with WAT dynamics during obesity rather than with psoriasis itself.

Animal studies provide evidence that adiponectin may play a pathogenic role in the development of psoriasis. For instance, mice lacking adiponectin show increased susceptibility to psoriasiform lesions (31). Adiponectin is considered to involve the promotion of M2 macrophage differentiation and suppression of IL-17/IL-23 production, which could help alleviate psoriatic inflammation (19,31,33). Notably, lower adiponectin levels are negatively associated with IL-23 gene expression (34). In the skin of adiponectin-deficient mice treated with imiquimod, an increase in IL-23p19 and IL-17 production has been observed (31). Conversely, administering adiponectin has been shown to inhibit IL-17 production in adiponectin-deficient mice and suppress IL-17 production from dermal γδ T cells in vitro (31). Additionally, a peptide derived from adiponectin, known as P5, interacts with the AdipoR1 receptor to inhibit IL-17 and mitigate imiquimod-induced psoriasiform lesions in mouse models (35,36).

Adiponectin also influences psoriasis by affecting the expression of human β-defensin 2 (hBD2), a marker involved in inflammatory pathways, and may indirectly modulate IL-23 levels (19,37). Furthermore, adiponectin promotes the expansion of regulatory T cell (Treg) populations (38). Adiponectin stimulates AMP-activated protein kinase, and this activation is associated with decreased skin thickness and reduced psoriasis severity (39,40).

Overall, the diverse functions of adiponectin indicate its potential protective role in psoriasis. However, the reduction of adiponectin due to WAT expansion diminishes its protective effects, resulting in heightened inflammation and worsening of psoriatic lesions. Future studies could consider focusing on longitudinal human data and exploring therapeutic strategies, such as AdipoR1 agonists or adiponectin mimetics, as potential approaches to address both the metabolic and inflammatory components of psoriasis.

Leptin is a hormone produced by WAT that regulates appetite and energy balance, with its levels being associated with fat stores and involvement in inflammatory diseases such as psoriasis. Elevated leptin levels are commonly observed in the plasma and skin of patients with psoriasis, particularly in severe cases, and these levels are associated with disease severity as indicated by the PASI (29,41,42). The primary contribution of leptin to psoriasis lies in its ability to enhance inflammation by stimulating the production of proinflammatory cytokines, including IL-1, IL-6, CXCL8 and TNF-α, which are pivotal in driving the inflammatory response (19,43). This cascade promotes a Th1/Th17 immune response, leading to increased levels of IL-17 and IL-23, which exacerbate the characteristic symptoms of the disease (44,45).

Leptin also modulates immune cell function by promoting the differentiation of Th17 cells. This effect is mediated through the upregulation of retinoic acid receptor-related orphan receptor γ t, a key transcription factor involved in Th17 cell development, thereby contributing to the accumulation of IL-17 (46). Moreover, leptin reduces the numbers and functionality of Tregs, diminishing their production of IL-10 and further exacerbating inflammation (47). Anti-leptin monoclonal antibodies have been shown to enhance Treg proliferation, while leptin receptor antagonists can increase Foxp3 expression and inhibit IL-17 production, highlighting the role of leptin in immune regulation (19,48,49). Furthermore, leptin activates the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling pathway, which amplifies the inflammatory response and promotes angiogenesis in psoriatic lesions, thereby supporting ongoing inflammation and disease progression (50).

In keratinocytes, leptin influences proliferation and function by stimulating the release of amphiregulin, a growth factor that accelerates keratinocyte proliferation, contributing to the hyperproliferation observed in psoriatic lesions (51). Additionally, leptin upregulates the expression of chemokines such as CXCL8, CXCL1 and CCL20, further stimulating keratinocyte proliferation and inflammation (52). It acts synergistically with IL-17A to enhance the expression of these chemokines and hBD2 through mitogen-activated protein kinase (MAPK) and JAK2 pathways, leading to impaired keratinocyte maturation and excessive expression of disease-related genes (19,53).

In summary, leptin serves a critical mediating role in WAT and psoriatic lesions by promoting inflammatory responses, enhancing immune cell activity, influencing keratinocyte proliferation and maturation, and promoting angiogenesis. These actions collectively exacerbate the pathological progression of psoriasis. Future research should further explore the heterogeneity of leptin signaling pathways in specific patient subgroups, such as obese and non-obese individuals, and assess the clinical translational potential of targeting leptin.

In rodents, resistin is primarily produced by WAT, while in humans it is mainly secreted by immune and epithelial cells. Although WAT is not the primary source of resistin in humans, its production in WAT increases during obesity (43,54). Elevated levels of resistin have been observed in patients with psoriasis and are positively associated with disease severity (29,55). The role of resistin in psoriasis initiates through its binding to Toll-like receptor (TLR) 4 and cysteine-rich ankle-like protein 1 receptors, activating crucial signaling pathways such as nuclear factor κB (NF-κB) (56,57). This activation induces the production of proinflammatory cytokines such as TNF-α, IL-6 and IL-1β, which play a central role in the inflammatory cascade observed in psoriasis (58). As a result, immune cell recruitment to the skin is promoted, exacerbating inflammation (2,58).

Furthermore, resistin directly influences keratinocyte behavior, which is crucial for the development of psoriatic lesions. It activates the NF-κB and Phosphoinositide 3-kinase/Protein kinase B (PI3K/AKT) signaling pathways, leading to the upregulation of genes associated with cell cycle progression and survival, such as human telomerase reverse transcriptase and caveolin-1 (56,59,60). This process results in increased keratinocyte proliferation and impaired differentiation, contributing to the formation and persistence of psoriatic lesions. Additionally, resistin affects cellular apoptosis, disrupting the balance necessary for maintaining skin homeostasis. By inhibiting apoptosis pathways, such as PI3K/AKT and MAPK/Extracellular Signal-Regulated Kinase, resistin leads to increased keratinocyte survival and impaired turnover, further exacerbating plaque development (56,61).

Finally, resistin promotes angiogenesis in psoriatic lesions by activating signaling pathways that enhance endothelial cell proliferation and modulate the expression of angiogenesis-related genes and chemokines, including vascular endothelial growth factor (VEGF) receptor (VEGFR) 1, VEGFR2, VEGFA and matrix metalloproteinases (56,62).

To conclude, resistin serves a critical mediating role in WAT and psoriatic lesions by promoting inflammatory responses, enhancing immune cell activity, influencing keratinocyte proliferation and maturation, and promoting angiogenesis. These actions collectively exacerbate the pathological progression of psoriasis. Future studies could evaluate the potential of metabolic interventions, such as weight loss or insulin-sensitizing treatments, in jointly regulating resistin levels and psoriasis pathology.

TNF-α, a proinflammatory adipokine, is markedly upregulated during the expansion of WAT and exerts widespread effects on various tissues through endocrine and paracrine mechanisms. Increased concentrations of TNF-α are frequently observed in the plasma and skin of patients with psoriasis, and are associated with disease severity (55,63). TNF-α is vital in establishing the inflammatory milieu of psoriatic lesions, initiating and sustaining the disease process through complex interactions among various cell types and signaling pathways. It activates DCs, resulting in increased production of IL-12, which facilitates the differentiation of naive T cells into Th1 cells (6,64,65). These Th1 cells then produce notable amounts of IFN-γ and TNF-α, amplifying the inflammatory response and creating a feedback loop that exacerbates the condition (63).

Additionally, TNF-α directly affects keratinocytes, inducing their hyperproliferation and increasing the production of proinflammatory cytokines such as IL-1, IL-6 and CXCL8, along with NF-κB (65,66). It also upregulates adhesion molecules such as E-selectin, P-selectin and intercellular adhesion molecule-1, facilitating the recruitment of immune cells into psoriatic lesions (65,67). Furthermore, TNF-α collaborates with IL-17A, stabilizing IL-17A mRNA and enhancing IL-17 receptor expression on keratinocytes, which increases the cellular response to IL-17A (68). This interaction sustains an inflammatory cascade, as IL-17A also promotes the expression of TNF receptors (6,69).

Moreover, TNF-α influences angiogenesis in psoriatic lesions by inducing the secretion of VEGF, promoting new blood vessel formation (66). This contributes to the increased vascularity observed in psoriatic lesions, further supporting the ongoing inflammatory process.

To summarize, TNF-α is a central mediator in psoriasis, orchestrating a complex network of immune cell activation, cytokine production, keratinocyte proliferation and angiogenesis, all of which drive the chronic inflammation and lesion formation characteristic of the disease. Although TNF-α inhibitors have shown marked efficacy in the treatment of psoriasis, the mechanisms of resistance in some patients remain unclear. Future research should further investigate the synergistic effects of TNF-α targeted therapy and metabolic interventions, such as glucagon-like peptide-1 receptor agonists, to improve both skin symptoms and systemic metabolic function and inflammation levels in patients.

In addition to the aforementioned adipokines, several other adipokines have been identified as being expressed at high levels in expanded WAT and have been extensively studied for their roles and mechanisms in psoriatic lesions.

MCP-1 levels are increased in the serum and skin of patients with psoriasis (70,71). MCP-1 contributes to psoriasis by promoting the migration and activation of macrophages in the skin, thereby driving inflammation. This process involves MCP-1 working in conjunction with TNF-α to initiate and sustain the inflammatory environment, influencing immune cell recruitment, and maintaining the inflammatory cycle in psoriatic lesions (70). Visfatin levels are also increased in the serum of patients with psoriasis, showing a positive association with disease severity (72). Visfatin amplifies the inflammatory responses in keratinocytes triggered by TNF-α by upregulating CXCL8, CXCL10, CCL20 and antimicrobial peptides (73,74). Additionally, serum chemerin concentrations are elevated in patients with psoriasis (75). Chemerin exacerbates psoriasis by promoting the migration of pDCs to psoriatic lesions, activating NF-κB, and upregulating proinflammatory cytokines such as TNF-α, IL-6 and CXCL8 (19,76). Furthermore, chemerin increases keratin 16 expression, which is associated with keratinocyte proliferation and contributes to psoriasis pathogenesis (77). Elevated levels of IL-6 have also been observed in the plasma and skin of patients with psoriasis, and these levels are associated with disease severity as indicated by PASI (63,78). IL-6 contributes to psoriatic lesions by promoting Th17 cell differentiation, inhibiting the suppressive functions of Tregs and inducing angiogenesis through the upregulation of VEGF production (63).

In psoriasis, reduced levels of adipocyte-derived CTRP3 in the blood lead to decreased anti-inflammatory effects, as CTRP3 typically exerts its protective role through the lysosomal-associated membrane protein 1-STAT3 axis, mitigating inflammation in the skin lesions (79).

In conclusion, various adipokines, including MCP-1, visfatin, chemerin, IL-6 and CTRP3, play notable roles in psoriasis by influencing inflammation, immune cell dynamics, keratinocyte proliferation and angiogenesis. These adipokines interact within a complex network that affects disease severity and progression. Further investigation is required to clarify the synergistic roles of these adipokines in the development of psoriatic lesions.

EVs are tiny membrane-bound particles released by cells into the extracellular environment. They can be categorized into four primary types: i) Exosomes; ii) apoptotic bodies; iii) microvesicles; and iv) oncosomes (80). EVs are vital for intercellular communication, transporting proteins, lipids and nucleic acids that influence various biological processes, including immune responses, disease progression and potential therapeutic strategies (81).

In obese patients, the levels of EVs in peripheral blood are markedly higher compared with those in healthy individuals, contributing to increased systemic inflammation (82). EVs derived from WAT primarily contain adipokines such as IL-6, MCP-1, adiponectin and resistin (82,83). Given that these adipokines are widely involved in the inflammatory response associated with psoriatic lesions, it is hypothesized that adipose-derived EVs also play a role in the pathological development of psoriasis. Furthermore, EVs derived from WAT in obesity contain a single-exon circular RNA known as circ_0075932, which can promote inflammation by activating the NF-κB pathway in the skin (84).

Notably, exosomes derived from mesenchymal stem cells of healthy WAT have been shown to suppress local inflammation in psoriatic lesions and improve clinical symptoms (85). This finding supports the notion that WAT can interact with the skin through EVs. The differences in the composition of EVs released by WAT under various conditions may represent a critical regulatory factor in the pathological changes observed in psoriatic lesions. However, research on the role of EVs in mediating crosstalk between WAT and skin remains limited. Further studies are needed to elucidate the role of EVs in the onset, progression and resolution of psoriatic lesions.

During the expansion of WAT, FFAs increase due to enhanced lipolysis from adipocyte, reflecting marked metabolic changes (86). Elevated serum FFA levels, particularly saturated FFAs, are associated with the severity of skin lesions in both patients and mice models (87,88). An in vitro study showed that FFAs sensitize DCs, enhancing the secretion of cytokines during proinflammatory stimulation (89).

Additionally, FFAs directly stimulate the secretion of key inflammatory cytokines, including IL-1β and IL-23 from TLR-activated myeloid cells (90). Notably, dermal γδ T cells, which are implicated in psoriatic lesions, exhibit higher lipid content and uptake than their IFN-γ-producing counterparts. This suggests that FFAs not only enhance inflammatory signaling, but also favor the differentiation and accumulation of pathogenic T cells (91).

Moreover, the preferential uptake of elevated levels of long-chain FFAs by Tregs leads to cellular mitochondrial dysfunction, oxidative stress and lipotoxicity (92). This ultimately reduces the population of Tregs and is associated with diminished regulation of dermal γδ T cell-mediated inflammation, exacerbating the inflammatory response associated with psoriatic lesions (92).

Collectively, the expansion of WAT can facilitate the pathological progression of psoriatic lesions through elevated levels of FFAs, suggesting that targeting FFA metabolism may offer promising therapeutic avenues for managing psoriasis and its associated inflammatory responses in the future.