With rapid economic development and lifestyle changes, obesity has become a notable global public health problem. Since 1990, the prevalence of adult obesity has doubled worldwide, whereas adolescent obesity has tripled (1). According to the latest data released by the World Health Organization in 2022, >1 billion individuals worldwide are affected by obesity, of whom ~65% are adults, 34% are adolescents and <1% are children. This alarming prevalence markedly increases the risk of developing insulin resistance (IR), type II diabetes mellitus (T2DM), cardiovascular disease, non-alcoholic fatty liver disease and various types of cancer, including gastric, esophageal, liver, pancreatic, bladder and breast cancer (1–3). Obesity is more than a simple imbalance between energy intake and expenditure; rather, it arises from complex interactions among genetic, immune and metabolic factors. Elucidating the molecular mechanisms underlying the onset and progression of obesity is therefore of notable importance for both prevention and therapeutic intervention.

Adipose tissue is not merely an energy storage depot but also an active endocrine and immune organ. In addition to adipocytes, it harbors a variety of immune cells, including macrophages, T lymphocytes, B lymphocytes and dendritic cells (4–7). Under conditions of obesity, anti-inflammatory resident immune cells decline, whereas pro-inflammatory immune cells accumulate and become activated, leading to chronic low-grade inflammation in adipose tissue, a key step in the development of obesity-related metabolic disorders. Thus, the immune cell network within the adipose tissue plays a marked role in maintaining tissue homeostasis and metabolic function (8,9). Over the years, the role of B cells in obesity and its associated metabolic complications has attracted increasing attention. B lymphocytes regulate the adipose tissue immune microenvironment through multiple mechanisms, including interactions with T cells and macrophages, secretion of antibodies such as IgM and IgG, and production of cytokines, including IL-10, TNF-α and IL-6, thereby shaping local inflammatory responses and metabolic homeostasis (10–12). During obesity, B cells in adipose tissue undergo numerical expansion and aberrant activation, thereby exacerbating tissue inflammation and IR. Understanding the heterogeneity, functional diversity and regulatory mechanisms of adipose tissue B cells is essential for unraveling the pathogenesis of obesity and related metabolic diseases. The present review aimed to comprehensively summarize the roles of B-cell subsets in adipose tissue inflammation and metabolic dysregulation during obesity, highlight the underlying mechanisms and discuss the therapeutic potential of targeting B cells in obesity-associated metabolic disorders.

Under metabolic perturbations such as obesity, the adipose tissue microenvironment undergoes notable remodeling, leading to the disruption of immune homeostasis. In this context, marked alterations are observed in B-cell abundance, spatial organization and functional phenotypes. Although accumulating evidence suggests that obesity-associated B-cell changes are generally characterized by enhanced pro-inflammatory activity accompanied by impaired immunoregulatory capacity, these findings are not entirely consistent across different experimental models, species or adipose depots, highlighting a pronounced context-dependent regulation. In high-fat diet (HFD)-induced obese C57BL/6J mice, both the number and size of FALCs are markedly increased within visceral adipose tissue (VAT) (29,30). Concomitant with the expansion of FALCs, a substantial number of B cells are recruited from the circulation and bone marrow into adipose tissue, resulting in an increase in the proportion of B cells within the stromal vascular fraction from ~10% in lean conditions to ~20% in obesity. These recruited cells predominantly exhibit a conventional B-2 cell phenotype (31). In addition to white adipose tissue, an increased proportion of B cells has also been observed in murine brown adipose tissue (BAT) under HFD conditions; however, the precise functional roles of B cells in BAT remain largely undefined (32). To date, studies addressing B-cell function within BAT are notably limited, and it remains unclear whether these cells actively participate in metabolic regulation or merely reflect the spillover of systemic inflammation. Consequently, this area represents a substantial gap in current knowledge. Of note, in human adipose tissue, systematic quantitative analyses of B-cell abundance and spatial distribution are still lacking, which substantially constrains the direct extrapolation of findings derived from animal models.

In VAT, B-cell accumulation occurs at an early stage of obesity. As early as 4 weeks of HFD feeding, both B-1 and B-2 cell numbers are markedly increased in murine epididymal adipose tissue (33). However, despite the numerical expansion of B-1 cells, their functional protective properties, such as the production of natural IgM, are often attenuated in obesity settings, suggesting that the obesogenic microenvironment may drive a state of functional exhaustion in B-1 cells. In parallel, pro-inflammatory B-2 cells and T-bet+CD21-CD23- age-associated B cells (ABCs) progressively accumulate during weight gain in mice and with increasing body mass index (BMI) in humans (14,34,35). Concomitantly, B cell-derived antibody profiles shift from predominantly protective IgM toward pathogenic IgG isotypes. These ABCs are hypothesized to exacerbate chronic inflammation and IR by promoting IgG antibody production and pro-inflammatory cytokine secretion. Nevertheless, in human studies, the definition of ABCs remains heterogeneous, and direct evidence for their presence and functional relevance within adipose tissue is still limited (36).

In human studies, data regarding Breg subsets remain relatively limited. Available evidence indicates that patients with T2DM exhibit reduced Breg frequencies and IL-10 production in the peripheral blood and certain tissues (37–40), suggesting a compromised immunosuppressive capacity. However, most of these studies are cross-sectional in nature, and can therefore not establish whether alterations in Bregs are a cause or a consequence of metabolic dysregulation. Furthermore, findings derived from peripheral blood may not fully reflect the local immune landscape within adipose tissue.

By contrast, murine studies have provided stronger causal support for the protective role of Bregs, as the adoptive transfer of Bregs has been shown to ameliorate adipose tissue inflammation and IR in diet-induced obesity (DIO) models. Mechanistically, obesity-associated chronic inflammation and the senescence-associated secretory phenotype have been implicated in driving B-cell polarization toward pro-inflammatory phenotypes while suppressing Breg function through sustained activation of the NF-κB and Janus kinase-signal transducer and activator of transcription (JAK/STAT) signaling pathways (10,41,42). In addition, the persistent activation of the p38 mitogen-activated protein kinase (p38/MAPK) and protein phosphatase 2A signaling pathways disrupts the balance between B-cell proliferation and differentiation, thereby impairing the maintenance of Breg function (43).

FALCs are considered notable microenvironmental niches that support aberrant B-cell expansion and activation in obesity. Under homeostatic conditions, M2-polarized macrophages promote the recruitment of B-1 cells into adipose tissue through the secretion of C-X-C motif chemokine ligand 13 (CXCL13) (44,45). In the obese state, group 2 ILCs within mesenteric adipose tissue-associated FALCs secrete IL-5, thereby enhancing natural IgM production by B-1 cells and potentially exerting metabolically protective effects. However, with the progression of obesity, sustained increases in CXCL13, IL-7 and other stromal-derived factors from adipocyte progenitors and fibroblasts drive excessive B-cell recruitment and activation. Activated B cells, in turn, reinforce chemokine production by stromal cells, establishing a positive feedback loop between B cells and the stromal compartment that promotes pathological FALC expansion and the maintenance of chronic inflammation (46). In aged mice, the reduced mRNA stability of E47 (TCF3) in visceral adipose tissue impairs activation-induced cytidine deaminase-mediated somatic hypermutation and class-switch recombination, leading to defective germinal center responses and limited antibody affinity maturation. These alterations collectively contribute to obesity-associated inflammation and immune dysregulation (47). Nevertheless, most of the available evidence is derived from global knockout or pharmacological intervention models, making it difficult to disentangle B-cell-intrinsic effects from systemic inflammatory changes.

Inflammatory cytokines exert a ‘double-edged sword’ effect on B-cell chemotaxis and functional remodeling. In obese mice, adipocytes within VAT secrete a range of chemokines, including CXCL10, C-C motif chemokine ligand 2 (CCL2) and CCL5, which preferentially recruit B-2 cells through their corresponding receptors, such as C-C motif chemokine receptor 2 (CCR2) and CCR3 (11,48). In HFD mice, the lipid-derived inflammatory mediator leukotriene B4 promotes the recruitment of B-2 cells into adipose tissue via leukotriene B4 receptor 1 and directly induces a pro-inflammatory B-cell phenotype. This, in turn, exacerbates IR through the activation of CD4+ and CD8+ T cells as well as M1-polarized macrophages (31). IL-6 and TNF-α, produced by both adipocytes and B cells, are widely recognized as key drivers of pro-inflammatory B-cell polarization (15,49). Of note, IL-6 exhibits context-dependent effects, as it has also been shown to improve lipid metabolism and insulin sensitivity in murine models (50,51). In addition, the IL-6 family member cardiotrophin-like cytokine factor 1 is upregulated in the BAT of obese mice and suppresses mitochondrial biogenesis and thermogenic capacity by activating STAT3 and inhibiting PGC-1α/β transcription, thereby promoting BAT ‘whitening’, as indicated by adipocyte hypertrophy, lipid droplet accumulation, uncoupling protein 1 (UCP-1) suppression, and mitochondrial dysfunction, initiates and accelerates obesity progression (52). In patients with T2DM, TNF-α acts as a major driver of adipose tissue inflammation by inducing immune cell polarization and suppressing regulatory immune functions. Furthermore, TNF-α enhances lipolysis and increases free fatty acid release, further aggravating IR (53).

Adipocytes not only serve as energy storage units, but also function as endocrine cells, secreting a variety of adipokines that play notable regulatory roles in B-cell biology. In obese individuals, leptin, a key adipocyte-derived hormone, is positively associated with BMI. B cells express leptin receptor (LEPR/Ob-Rb) on their surface, and leptin binding activates B cells from both young and elderly peripheral blood, inducing the secretion of pro-inflammatory cytokines, including IL-6 and TNF-α, primarily through the activation of the JAK2/STAT3 and p38 MAPK/ERK1/2 signaling pathways (54,55). In addition, in obese individuals, leptin secreted by adipose tissue mediates the metabolic reprogramming of B cells through the activation of the mechanistic target of rapamycin complex 1 pathway, enhancing glycolytic and biosynthetic activity and driving differentiation toward a pro-inflammatory phenotype. This is characterized by the upregulation of CD25 and human leukocyte antigen DR expression and increased secretion of IL-6 and TNF-α (56). Clinical studies have indicated that adiponectin levels are reduced in obese individuals, and that exerts anti-inflammatory effects by inhibiting AMP-activated protein kinase signaling, thereby enhancing signal transduction and STAT3 activity to promote IL-10 transcription (57–59). Furthermore, adiponectin can induce B1 cells to secrete the peptide inhibitor of transendothelial migration, derived from the 14-3-3ζδ protein, which modulates endothelial adhesion molecules and sphingosine-1-phosphate signaling, thereby limiting T-cell trafficking and inflammatory responses (60,61). In HFD-fed mice, adiponectin indirectly suppresses the pro-inflammatory phenotype of B cells through multilayered immunoregulatory mechanisms. On one hand, adiponectin upregulates Sirtuin 1 and peroxisome proliferator-activated receptor γ whereas inhibiting the Th17 lineage-specifying transcription factor retinoic acid-related orphan receptor γt markedly suppressing Th1 and Th17 differentiation and pro-inflammatory cytokine production, and concurrently promoting FoxP3 expression; this leads to an expansion of the number and function of Tregs, which shifts immune responses toward tolerance. On the other hand, adiponectin remodels dendritic cell phenotypes by downregulating major histocompatibility complex (MHC) class II and costimulatory molecules CD80/CD86, suppressing the secretion of pro-inflammatory cytokines such as IL-12, and upregulating inhibitory molecules such as programmed cell death ligand 1 (PD-L1). This attenuates the dendritic cell-mediated activation of effector T cells while promoting Treg induction. Within this immunoregulatory environment, Treg-mediated suppression and reduced pro-inflammatory T-cell responses collectively constrain aberrant B-cell activation and pro-inflammatory function, thereby indirectly limiting B-cell inflammatory phenotypes (62–64). Furthermore, obesity-associated hyperglycemia, cell death and lipid spillover can activate antigen-specific B cells, leading to their expansion and pathogenic antibody production. In db/db mice, elevated glucose concentrations inhibit IgM secretion by B-1 cells and promote apoptosis (65). Free fatty acids, such as palmitate, enhance B-cell IL-10 secretion and survival in adipose tissue via Toll-like receptor 4 (TLR4) signaling, indicating that tissue-derived metabolic cues regulate the fate of B-cell (21,38).

The ‘gut-adipose axis’ also plays a notable role in B-cell immunoregulation (66). High-fat diets alter the gut microbiota in humans and mice, compromise intestinal barrier integrity and lead to endotoxemia, which activates adipose tissue B cells and induces the expansion of IL-10+ Breg cells (57,67). In DIO mice, gut-derived lipopolysaccharide (LPS) activates the TLR4-myeloid differentiation primary response 88-NF-κB signaling pathway, inducing the high expression of pro-inflammatory cytokines such as TNF-α and IL-6, thereby amplifying B-cell–mediated inflammatory responses. Although fatty acids themselves are not direct TLR4 ligands, they can indirectly activate this pathway by promoting LPS translocation or altering cellular metabolism, exacerbating B-cell inflammatory activation (68–70). Peritoneal B-1a cells aberrantly activated by commensal bacteria promote insulin resistance (IR) by enhancing systemic and adipose tissue inflammation, facilitating macrophage polarization toward the pro-inflammatory M1 phenotype, and impairing insulin signaling through sustained activation of inflammatory pathways, including NF-κB, JNK and p38 MAPK; following bariatric surgery, the gut microbiota shifts toward a lean phenotype, characterized by reduced adiposity, improved insulin sensitivity, normalized glucose metabolism, and attenuated inflammatory responses, thereby restoring adipose tissue B-cell function (58,71). Obesity also reduces the number of intestinal IgA+ B cells and decreases secretory IgA levels (66), IgA deficiency accelerates B-cell senescence, leading to impaired B-cell function and increased autoantibody production, further aggravating glucose intolerance and reducing insulin sensitivity. In addition, in obesity settings, elevated 25-hydroxycholesterol levels in Peyer's patches inhibit antigen-specific IgA+ B-cell differentiation, whereas cholesterol-25-hydroxylase deficiency alleviates this effect (72) (Fig. 2).

Collectively, current evidence supports that obesity drives B-cell dysfunction through the synergistic actions of inflammatory cytokines, adipokines, metabolic products and gut microbiota, thereby promoting chronic adipose tissue inflammation and metabolic dysregulation. However, most mechanistic conclusions are primarily based on murine models, and the temporal relationships, causality and tissue specificity in humans remain incompletely elucidated. Further integrative multi-omics and functional validation studies are warranted to address these knowledge gaps.

In obesity-related metabolic diseases, adipose tissue B cells are increasingly recognized as a notable regulatory node linking immune inflammation and metabolic dysregulation. Accumulating evidence indicates that, under obese conditions, aberrantly activated B cells engage in complex interactions with adipocytes, T cells and macrophages through antigen presentation, cytokine secretion and antibody production, thereby exacerbating adipose tissue inflammation and promoting IR (10). Clinical studies have shown that patients with T2DM exhibit increased B-cell activation in peripheral blood, accompanied by elevated secretion of inflammatory mediators such as IL-8, which is closely associated with chronic inflammatory responses (39,73). In aged mice, the local depletion of VAT-resident B cells markedly improves insulin sensitivity (5). Under HFD conditions, the deletion of the B cell-specific Oct co-activator from B cells, a key regulator of B-cell development, notably ameliorates adipose tissue inflammation and IR in mice (74,75). Similarly, the deletion of the inhibitor of DNA binding 3 gene increases B-1 cell abundance in white adipose tissue, leading to reduced adipose inflammation and improved glucose tolerance (24). Adoptive transfer of B-1 cells into HFD-fed B cell-deficient obese mice also alleviates VAT inflammation and improves IR (12). Collectively, these findings provide direct evidence of the pathogenic role of adipose tissue B cells in metabolic homeostasis disruption; however, the applicability of these strategies in humans remains to be determined.

Studies have further demonstrated that distinct B-cell subsets exert divergent effects on adipose tissue and cardiovascular homeostasis. In HFD-fed apolipoprotein E (Apoe)-/- mice, B-1a and B-1b cells secrete natural IgM antibodies in the spleen and adipose tissue to neutralize oxidized low-density lipoprotein (oxLDL) and promote macrophage polarization toward an anti-inflammatory phenotype, thereby suppressing myocardial inflammation and atherosclerosis. By contrast, B-2 cells secrete TNF-α, IL-6 and TGF-β, activate cardiac fibroblasts and promote collagen deposition and ventricular remodeling (11,76). In addition, B cells can modulate T-cell responses by promoting pro-atherogenic Th1 immunity while suppressing anti-atherogenic interleukin-17 production, thereby accelerating atherosclerosis progression (77). Clinical and experimental studies have also revealed the presence of large B-cell clusters in epicardial adipose tissue of patients with coronary artery disease (78). Of note, as early as 3 days after myocardial infarction, B-cell numbers are markedly increased in murine pericardial adipose tissue, with no notable changes observed in the myocardium itself, suggesting that local B-cell proliferation is the predominant source. These B cells secrete granulocyte-macrophage colony-stimulating factor (GM-CSF), which promotes the recruitment and maintenance of dendritic cells in pericardial adipose tissue and accelerates post-infarction fibrosis (79).

Adipose tissue B cells further contribute to metabolic dysfunction by releasing pathogenic IgG antibodies and inflammatory mediators, thereby promoting monocyte infiltration into FALCs and sustaining the release of pro-inflammatory factors, ultimately leading to adipose tissue dysfunction and metabolic imbalance (11,80). In obese mice, B-2 cell infiltration into mesenteric adipose tissue precedes that of T cells and macrophages (81). In HFD-induced obese mice, activated B cells produce large amounts of pro-inflammatory cytokines, including TNF-α and GM-CSF, which recruit macrophages and promote their differentiation toward an inflammatory phenotype, thereby inducing IR (33,82). During obesity, B cells within FALCs become activated and function as APCs, presenting internalized lipids or other antigens to TFH cells. TFH cells subsequently provide key costimulatory signals, such as CD40L and IL-21, thereby promoting B-cell differentiation into plasma cells and driving the production of pro-inflammatory Immunoglobulin G2c (IgG2c) antibodies. These IgG2c antibodies accumulate within adipocyte crown-like structures, where they form immune complexes with oxidatively modified lipoproteins (such as oxLDL) or adipose tissue-derived self-antigens. The resulting immune complexes activate macrophages through Fc γ receptor receptors, thereby amplifying adipose tissue inflammation. Of note, the adoptive transfer of IgG isolated from DIO mice into B cell-deficient mice is sufficient to induce macrophage polarization toward the M1 phenotype, leading to the increased production of pro-inflammatory mediators (33,39,83). Furthermore, B cell-derived IgG can drive Th1/Th2 polarization through MHC-dependent mechanisms, leading to the secretion of TNF-α and IFN-γ, which further stimulate B cells and establish a positive feedback loop that exacerbates IR and adipose tissue inflammation (84).

In metabolic diseases such as obesity and diabetes, both the number and function of Bregs are markedly reduced, resulting in decreased IL-10 production, impaired anti-inflammatory capacity, increased release of pro-inflammatory factors and exacerbation of adipose tissue inflammation and IR (85). By contrast, in autoimmune diseases and cancer, B-1 and Breg cells can exert anti-inflammatory effects by expressing immune checkpoint molecules, such as programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1) and CD39/CD73, and by secreting IgM antibodies and IL-10 (86). Of note, infection with Schistosoma japonicum induces a marked upregulation of IL-10 production in CD19+CD9+ B cells, promoting the expansion of Tregs and Th2 cells, while reducing Th1 and Th17 responses. This immune shift alleviates inflammation and improves insulin sensitivity in HFD-fed mice, suggesting that enhancing CD9+ B cells or IL-10-producing Breg function may represent a novel strategy for modulating obesity-associated inflammation and metabolic dysregulation (87,88). Consistently, studies have demonstrated that in HFD-fed mice and patients with T2DM, IL-10 suppresses pro-inflammatory cytokine production through the activation of the STAT3 signaling pathway, promotes Treg differentiation, induces macrophage polarization toward the M2 phenotype, protects adipose tissue from inflammation and counteracts IR (23,89,90).

In summary, B cells exert dual pro- and anti-inflammatory roles in obesity-related metabolic diseases. While pathogenic B-cell responses exacerbate inflammation and metabolic dysfunction, protective B-cell subsets contribute to the maintenance of metabolic homeostasis. These findings provide a theoretical basis for the development of B cell-targeted therapeutic strategies in metabolic diseases (91,92).

Direct B-cell-depleting therapeutic strategies have been widely applied in the treatment of B-cell non-Hodgkin lymphoma and autoimmune diseases such as rheumatoid arthritis (93). Given the pivotal role of B cells in obesity-associated chronic inflammation and metabolic dysregulation, B-cell-targeted interventions are increasingly recognized as a potential metabolic therapeutic strategy. Although current evidence is largely derived from animal models and studies conducted in other disease contexts, these findings provide an important theoretical foundation for the application of B-cell-targeted therapies in obesity-related metabolic disorders.

Adipose tissue B cells have emerged as key drivers of obesity-associated metabolic diseases, shifting from protective regulators under homeostatic conditions to pathogenic ‘disruptors’ in the obese state. Through both antibody-dependent and antibody-independent mechanisms, B cells promote chronic adipose tissue inflammation and metabolic dysregulation. Targeting B cells, particularly specific pathogenic subsets or functional programs, therefore represents a promising therapeutic avenue for the treatment of obesity and its related complications.

Future studies should prioritize the establishment of comprehensive human adipose tissue B-cell atlases, coupled with an in-depth characterization of the heterogeneity of adipose tissue B-cell subsets. Elucidating the molecular mechanisms through which distinct B-cell populations contribute to obesity-associated metabolic diseases will be essential for the precise targeting of pathogenic B-cell subsets, such as ABCs, while preserving protective populations including B-1 cells and Bregs. In parallel, efforts should be directed toward accelerating the clinical translation of these insights.

In conclusion, as notable regulators within the adipose tissue immune microenvironment, B cells play a central role in shaping obesity-related inflammatory responses. A deeper understanding of their functional diversity not only advances our mechanistic insight into obesity-associated inflammation but also provides an important theoretical foundation and practical guidance for the development of more precise and safer immunometabolic therapeutic strategies.