Obesity-associated metabolic dysfunction is characterized by sustained elevation of pro-inflammatory cytokines within adipose tissue and systemic circulation. Hypertrophic adipocytes and infiltrating macrophages form an inflammatory microenvironment that promotes chronic activation of immune signaling cascades. Among the key mediators, TNF-α plays a pivotal role in linking inflammation to insulin resistance. Increased TNF-α expression in adipose tissue correlates with body mass index and systemic insulin resistance [13]. Mechanistically, TNF-α impairs insulin signaling by inducing serine phosphorylation of IRS-1, thereby inhibiting its normal tyrosine phosphorylation by the insulin receptor. This modification attenuates downstream PI3K/Akt activation and reduces glucose transporter type 4 (GLUT4) translocation, ultimately decreasing cellular glucose uptake [14]. TNF-α also enhances lipolysis and increases circulating free fatty acids, further aggravating hepatic insulin resistance and metabolic stress.

IL-6 exhibits a dual and context-dependent role in metabolic regulation. Acute, transient increases in IL-6, such as those observed during physical exercise, may enhance glucose uptake and lipid oxidation. In contrast, chronic elevation of IL-6 in obesity contributes to hepatic gluconeogenesis, adipose tissue inflammation, and systemic insulin resistance [15]. Persistent IL-6 signaling sustains activation of intracellular pathways that interfere with insulin receptor signaling and amplify inflammatory gene expression. Thus, while IL-6 may exert protective effects in physiological contexts, its prolonged overproduction in obesity promotes metabolic dysregulation. IL-1β is another critical mediator of metabolic inflammation, particularly in pancreatic islets. Elevated IL-1β levels impair β-cell function by inducing nitric oxide production, oxidative stress, and apoptosis [16]. In obesity and type 2 diabetes, activation of the NLRP3 inflammasome enhances cleavage of pro-IL-1β into its mature form, intensifying local islet inflammation and progressive β-cell failure [17]. Collectively, TNF-α, IL-6, and IL-1β establish a chronic inflammatory milieu that disrupts insulin signaling across multiple metabolic tissues.

The JAK/STAT pathway serves as a central conduit for cytokine-mediated metabolic effects. The binding of IL-6 to its receptor complex, composed of IL-6 receptor α (IL-6Rα) and glycoprotein 130 (gp130), induces conformational changes that activate associated JAK kinases, primarily JAK1 and JAK2. Activated JAKs phosphorylate specific tyrosine residues on the receptor cytoplasmic domain, creating docking sites for STAT3. Subsequent phosphorylation of STAT3 promotes its dimerization and nuclear translocation, where it regulates transcription of genes involved in inflammation, cell survival, and metabolic control [18].

One of the principal STAT3 target genes is SOCS3, a classical negative feedback regulator. SOCS3 binds to phosphorylated JAKs and receptor complexes to attenuate further STAT activation, thereby limiting cytokine signaling. However, in chronic inflammatory states such as obesity, sustained IL-6-JAK-STAT3 activation leads to persistent SOCS3 expression, which paradoxically contributes to insulin resistance [19]. SOCS3 can interact directly with the insulin receptor and IRS proteins, inhibiting their tyrosine phosphorylation and promoting ubiquitin-mediated degradation. Elevated SOCS3 expression in liver and adipose tissue has been associated with impaired insulin signaling and glucose intolerance in experimental models [20].

Thus, while the JAK/STAT pathway is physiologically essential for immune regulation, its chronic activation in metabolic disease promotes maladaptive signaling loops that exacerbate insulin resistance. Persistent STAT3 activity and SOCS3 overexpression represent critical molecular links between cytokine dysregulation and metabolic impairment.

In parallel with JAK/STAT activation, the NF-κB pathway functions as a master regulator of inflammatory gene transcription in obesity. Elevated levels of circulating saturated fatty acids and lipopolysaccharide (LPS) in obese individuals stimulate toll-like receptor (TLR4) signaling on adipocytes and macrophages [21]. Activation of TLR4 recruits adaptor proteins such as MyD88, leading to stimulation of the IκB kinase (IKK) complex. Phosphorylation and subsequent degradation of IκB release NF-κB dimers, allowing their nuclear translocation and transcriptional activation of pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1β.

This NF-κB-mediated cytokine production establishes an amplification loop in which newly synthesized cytokines further activate JAK/STAT signaling and reinforce inflammatory responses. Crosstalk between NF-κB and STAT3 intensifies this effect, as STAT3 can cooperate with NF-κB at promoter regions to enhance transcription of inflammatory genes [22]. Such coordinated signaling sustains chronic low-grade inflammation and perpetuates insulin resistance in metabolic tissues.

The convergence of TLR4/NF-κB and IL-6/JAK/STAT pathways therefore constitutes a mechanistic nexus in obesity-associated metabolic dysfunction. Targeting these interconnected signaling networks offers a rational strategy for restoring immune-metabolic balance in metabolic disease.

Chickpea is one of the most widely cultivated and consumed grain legumes worldwide, serving as a major source of plant-based protein in Asia, the Middle East, the Mediterranean region, and parts of Africa. It is broadly classified into two main types, Desi and Kabuli, which differ in seed morphology and phytochemical composition. Beyond its macronutrient profile, chickpea contains a diverse array of bioactive constituents with potential metabolic and immunomodulatory properties. Its nutritional matrix includes high-quality proteins (18–24%), complex carbohydrates, dietary fiber, essential amino acids, unsaturated fatty acids, vitamins, and minerals [23, 24]. Importantly, chickpea also provides a rich spectrum of phytochemicals that may influence inflammatory signaling pathways implicated in metabolic disease.

Chickpea seeds contain substantial quantities of polyphenolic compounds, including phenolic acids (such as ferulic, caffeic, and p-coumaric acids) and flavonoids. These compounds exhibit antioxidant and anti-inflammatory activities that can modulate redox-sensitive signaling cascades. Polyphenols are known to inhibit NF-κB activation, reduce reactive oxygen species (ROS) production, and attenuate pro-inflammatory cytokine release in experimental models [25].

Isoflavones, structurally similar to estrogenic compounds, are also present in chickpea, although in lower concentrations compared to soybeans. Isoflavones such as biochanin A and formononetin have demonstrated anti-inflammatory effects through modulation of cytokine production and inhibition of pro-inflammatory transcription factors [26]. By influencing intracellular kinase activity and transcriptional regulators, chickpea-derived polyphenols may indirectly affect JAK/STAT signaling dynamics under inflammatory conditions.

Saponins constitute another important class of bioactive phytochemicals in chickpea. These amphipathic glycosides possess cholesterol-lowering, antioxidant, and anti-inflammatory properties. Chickpea saponins, particularly soyasaponins, have been reported to modulate immune cell activity and suppress production of TNF-α and IL-6 in inflammatory models [27]. Mechanistically, saponins may alter membrane microdomain organization, interfere with receptor-mediated signaling, and inhibit activation of NF-κB and mitogen-activated protein kinase (MAPK) pathways. Through attenuation of upstream inflammatory stimuli, saponins may indirectly reduce activation of cytokine-driven JAK/STAT signaling in metabolic tissues.

Enzymatic hydrolysis and gastrointestinal digestion of chickpea proteins generate bioactive peptides with functional properties extending beyond basic nutrition. These peptides have been shown to exert angiotensin-converting enzyme (ACE) inhibitory, antioxidant, and anti-inflammatory activities [28]. Certain legume-derived peptides can suppress pro-inflammatory cytokine expression and modulate macrophage polarization, thereby influencing systemic inflammatory tone. Although direct evidence linking chickpea peptides to JAK/STAT pathway modulation remains limited, their capacity to reduce TNF-α and IL-6 production suggests a plausible role in attenuating cytokine-mediated metabolic disturbances.

Chickpea is particularly rich in dietary fiber, including soluble fiber and resistant starch, which escape digestion in the small intestine and undergo fermentation by colonic microbiota. This fermentation process produces SCFAs such as acetate, propionate, and butyrate. SCFAs exert anti-inflammatory effects by enhancing gut barrier integrity, reducing endotoxemia, and modulating immune cell function [29]. Butyrate, in particular, has been shown to inhibit NF-κB activation and promote regulatory T-cell differentiation, thereby contributing to systemic immune homeostasis [30].

By altering gut microbiota composition and decreasing LPS-mediated TLR4 activation, chickpea fiber may reduce downstream cytokine production and inflammatory signaling cascades. This gut-immune-metabolic axis represents an indirect yet potentially powerful mechanism through which chickpea consumption may influence cytokine dysregulation in metabolic disease. Collectively, the major chickpea bioactives and their proposed molecular targets within cytokine signaling pathways are summarized in Table 1.

Accumulating experimental evidence suggests that chickpea-derived bioactive compounds attenuate the production of key pro-inflammatory cytokines implicated in metabolic disease, particularly TNF-α and IL-1β. In vitro studies using legume extracts have demonstrated suppression of LPS-induced TNF-α release in activated macrophages, largely through inhibition of upstream inflammatory signaling pathways [48]. Phenolic-rich fractions isolated from chickpea have been shown to reduce oxidative stress and downregulate inflammatory mediators in cellular models, indicating a potential role in dampening cytokine overproduction [49]. In animal models of diet-induced obesity, incorporation of chickpea into high-fat diets has been associated with reduced circulating TNF-α levels and decreased adipose tissue inflammation [50]. These effects are likely mediated by combined actions of polyphenols, saponins, and fiber components that limit macrophage infiltration and shift macrophage polarization away from the pro-inflammatory M1 phenotype. By lowering TNF-α availability, chickpea bioactives may indirectly preserve IRS-1 function and improve downstream insulin signaling.

IL-1β, a cytokine closely linked to inflammasome activation and β-cell dysfunction, may also be influenced by legume-derived compounds. Although direct mechanistic studies specifically evaluating chickpea and IL-1β maturation remain limited, plant-derived polyphenolic compounds have demonstrated inhibitory effects on NLRP3 inflammasome activation and IL-1β secretion in experimental systems [51]. Given the structural and functional similarities among legume phytochemicals, it is plausible that chickpea bioactives exert comparable modulatory effects on inflammasome-mediated cytokine release, thereby contributing to protection against metabolic inflammation.

Moreover, chronic elevation of IL-6 is a hallmark of obesity-related metabolic dysfunction. Dietary intervention studies incorporating chickpea or chickpea-based products have reported reductions in systemic inflammatory markers, including C-reactive protein (CRP), a downstream surrogate of IL-6 signaling [52]. While direct measurements of IL-6 in human chickpea intervention trials remain relatively sparse, improvements in inflammatory status and insulin sensitivity suggest modulation of upstream cytokine networks. In preclinical models, legume-rich diets have been shown to attenuate IL-6 expression in adipose tissue and liver [53]. These effects may be attributed to decreased activation of NF-κB and reduced oxidative stress.

In addition to suppressing pro-inflammatory cytokines, emerging evidence indicates that legume-derived bioactives may influence immunoregulatory cytokines such as IL-10, which plays a critical role in limiting excessive immune activation. Polyphenols and dietary fiber have been reported to enhance IL-10 production and promote anti-inflammatory immune responses in experimental models [54, 55]. Although direct evidence specific to chickpea remains limited, such effects may contribute to the restoration of cytokine balance and immune regulation in metabolic disease.

Additionally, chickpea consumption has been associated with improvements in metabolic and inflammatory profiles, which may indirectly influence adipokine regulation through modulation of gut microbiota and systemic inflammation [56]. Because adipokines interact closely with cytokine signaling pathways, normalization of adiponectin-leptin balance may further suppress IL-6 production and downstream JAK/STAT activation. The fiber fraction of chickpea also contributes indirectly to IL-6 regulation through modulation of gut microbiota composition. Fermentation of resistant starch generates SCFAs, which have been shown to reduce systemic inflammatory cytokines and enhance metabolic homeostasis [57]. By decreasing endotoxemia and TLR4 stimulation, chickpea fiber may attenuate IL-6 synthesis at its source.

Beyond their anti-inflammatory and antioxidant properties, chickpea bioactives may exert broader immunomodulatory effects by influencing immune cell function and cytokine balance. Emerging evidence suggests that dietary polyphenols and saponins can modulate macrophage polarization, promoting a shift from pro-inflammatory M1 phenotype toward an anti-inflammatory M2 phenotype. This transition is associated with restoration of immune homeostasis rather than generalized immune suppression. In addition, chickpea-derived components may contribute to balancing pro- and anti-inflammatory cytokines, thereby maintaining appropriate immune responsiveness while limiting chronic low-grade inflammation. Such immunoregulatory effects are particularly relevant in metabolic disease, where persistent immune activation rather than acute immune response drives pathology [58].

Moreover, chickpea bioactives may also exert context-dependent immunomodulatory effects that differ between metabolically compromised and healthy individuals. In individuals with normal immune function, dietary polyphenols and fiber-rich foods are not associated with immunosuppression but rather contribute to the maintenance of immune homeostasis. These compounds primarily attenuate chronic low-grade inflammation without impairing acute immune responses required for host defense against pathogens. Evidence from nutritional immunology suggests that plant-based diets rich in legumes support balanced cytokine responses and immune resilience, partly through modulation of gut microbiota and systemic inflammatory tone [59, 60]. Molecular mechanisms linking chickpea bioactives to cytokine signaling modulation in metabolic disease is illustrated in Figure 1.