AIF-1, an inflammatory factor first identified in rat cardiac graft chronic rejection (1, 2), with particular emphasis on its emerging roles in metabolic dysregulation. Originally implicated in xenograft rejection and macrophage activation (3), AIF-1’s pleiotropic functions now encompass rheumatoid arthritis, fibrotic, cardiovascular, neoplastic, and renal pathologies through multifaceted mechanisms (4–7). Crucially, its actin crosslinking capacity enables cytoskeletal remodeling that fundamentally alters cellular kinematics (8, 9), establishing mechanistic connections to systemic metabolic processes.

Currently, AIF-1 is extensively utilized in function researching (Figure 1). Its involvement in allogeneic transplantation responses, regulation of immune responses, multifunctional cytokine roles, and promotion of cell proliferation offer valuable targets and insights for exploring disease mechanisms and developing therapies (2). Some studies offer evidence linking AIF-1 to obesity, although the mechanism of action is sitll unclear. At first, a single nucleotide polymorphism research showed AIF-1 gene is associated with body weight (10). Additionally, loss of AIF-1 limits diet induced obesity and insulin resistance (11). Furthermore, AIF1-like (AIF1L) affects food intake and obesity, especially for high fat diet (HFD) induced obesity (12).

On the other hand, AIF-1 is a portein that regulates the function of macrophages and refers to inflammation response (13). Besides, AIF-1 is also as a calcium-banding protein participants in activation of macrophages (14). Meanwhile, AIF-1 may be a new adipokine associated with adipose inflammation in obese individuals (15).

Of particular significance, AIF-1 directly interacts with adipocytes to coordinate inflammatory signaling and insulin pathway modulation (7), mechanistically explaining its capacity to induce insulin resistance through multi-target disruption (15) and oxidative stress potentiation (16).

In this review, we focus on the function of AIF-1, especially in obesity, inflammation, macrophages and adipocytes dysfunction, and insulin resistance. This synthesis evaluates current evidence while proposing novel research trajectories, ultimately aiming to translate mechanistic insights into targeted therapeutic strategies for metabolic disorders.

AIF-1 has been reported to play a significant role in immune response and inflammatory pathology. Immunohistochemical studies have shown that AIF1 is present in all macrophage subpopulations except for alveolar macrophages and sperm cells (17). Considering the role in macrophages, AIF-1 was indicated to be crucial for cell survival and proinflammatory activities (18). In vitro, studies reported that AIF-1 level increase promoted macrophages cell migration, but downregulation of AIF-1 reduced nitric oxide (NO) production and led to macrophages apoptosis (18). In published papers, overxpressed AIF-1 in the macrophage cell line (RAW 264.7) produced a large number of inflammatory factor, such as interlukin (IL)-6 and IL-10 (19). Furthermore, inhibiting expression of AIF-1 resulted in a decrease in migration, proliferation, and signal transduction of Akt and MAPK signal pathway (20).

AIF-1 engages in multifaceted crosstalk with adipocytes through inflammatory and metabolic regulatory axes. Emerging evidence implicates TLR4/MD2 complexes as primary AIF-1 receptors in adipocytes, with binding initiating NF-κB and JNK signaling cascades that drive inflammatory responses (21, 22). This receptor-mediated activation establishes a feedforward loop between macrophage-derived AIF-1 and adipocyte dysfunction.

AIF-1 is a protein that induces inflammatory responses and macrophages migration (14). Previous studies indicated taht AIF-1 promotes inflammatory cytokines releasion in mice macrophages (27, 28). AIF-1 promoted vascular smooth muscle cells dedifferentiation into macrophage-like state, enhancing the production of inflammatory cytokines TNF-α and IL-6 by PKC/NF-κB pathway (29). Furthermore, Loss of AIF-1 femal mouse showed increased expression of pro-inflammatory cytokines, such as TNF-α and IL-6. Then, aggravation of cardiac inflammation (30). However, AIF-1 regulation induced the releasion of inflammatory cytokines TNF-α and IL-6 in diabetic mouse model (31). The differences in the results might be due to the different subjects of the research.

An adipocyte-secreted polypeptide, adiponectin, playing a key role in the inhibition of metabolic derangements (32). In contrast to adiponectin, the level of resistin was increased in individuals with IR (33). Meanwhile, the study demonstrated that AIF-1 increased the resistin production, while reduced adiponectin secretion from 3T3L1 adipocytes probably through NF-κB pathway activation, and inhibiting PPARγ level (16).

Some studies indicated AIF-1 was associated with metabolic conditions in different subjects (Table 1). First, the serum AIF-1 levels linked to waist circumference in Japanese (21). Second, sequence variants near the AIF-1 gene locus are correlated with adult obesity in Greeks (35). Third, a recent study shows AIF-1secreted by macrophages in white adipose tissue for obese female (15). Additionally, in vivo studies reported that loss of AIF-1 limited HFD induced obesity and diabetes (11). Furthermore, AIFIL could accelerated HFD-induced obesity in some settings (12). However, one studies showed that loss of AIF1L did not affect HFD-induced weight gain or recover glucose sensitivity (34). The reasons for the differences in results may be as follows: (1) different genetic backgrounds and experimental models; and (2) discrepancies in dietary protocols or metabolic stress contexts for mouse.

Although evidence suggests that AIF-1 is related to obesity, the specific mechanism is still less clear. The existing literature indicates relationship between AIF-1 and obesity focus on inflammatory mediation—a hallmark of obesity-associated metabolic dysfunction (36, 37). As a key driver of localized and systemic insulin resistance, inflammation is profoundly regulated by AIF-1, predominantly secreted by adipose tissue macrophages (38). Mechanistically, AIF-1 modulates macrophage catecholamine activity to suppress energy expenditure while enhancing storage capacity, thereby promoting adiposity (11). During obesity progression, adipose-resident macrophages undergo functional polarization from anti-inflammatory to pro-inflammatory phenotypes, driving tissue infiltration and inflammatory exacerbation (39). This phenotypic shift correlates with macrophage-derived pro-inflammatory mediator production, wherein AIF-1 emerges as a critical molecular orchestrator (10, 16).

Clinical evidence demonstrates elevated AIF-1 expression in obese individuals, particularly within adipose depots (10, 40). This upregulation likely originates from obesity-associated chronic inflammation (22), with heightened AIF-1 levels correlating with increased obesity susceptibility (23). Importantly, studies have shown that decreased AIF-1 levels inhibit adipocyte differentiation and reduce the secretion of adipokines such as leptin and resistin, which are critical mediators of metabolic dysfunction in obesity (15, 16, 41). For instance, Lorente-Cebrián et al. demonstrated that AIF-1 knockdown in adipocytes led to a significant reduction in leptin and resistin expression, highlighting its role in regulating adipokine production (15). Similarly, Ren et al. reported that AIF-1 deficiency in macrophages attenuated pro-inflammatory cytokine release and improved insulin sensitivity in obese mice (16). These findings collectively support the notion that AIF-1 might be a key regulator of adipocyte function and inflammatory signaling in obesity (Figure 3).

Inhibiting AIF-1 presents a compelling therapeutic strategy for combating obesity and its metabolic complications. Preclinical studies demonstrate that AIF-1 deficiency protects mice from diet-induced obesity by elevating local catecholamine levels in adipose tissue, reducing macrophage expression of the degradation enzyme MAOA. This enhances noradrenergic signaling, stimulates energy expenditure, and promotes a thermogenic phenotype. Concurrently, AIF-1 drives adipose tissue inflammation and directly impairs insulin signaling in adipocytes. Human genetic studies and analyses of adipose tissue samples consistently link elevated AIF-1 expression to obesity and insulin resistance, suggesting conserved biological relevance. However, while these human associative data are promising, critical discussion must note the current lack of robust clinical data validating AIF-1 as a reliable diagnostic biomarker or a therapeutically actionable target in human obesity. Its potential hinges on these compelling preclinical and correlative human findings, which await validation through prospective clinical trials.

However, translating this promising target into a safe and effective therapy is fraught with significant challenges, which are further compounded by the limited human clinical evidence. The primary risk of serious off-target effects arises because AIF-1 is not adipose-specific; it is a key functional protein in immune cells throughout the body and serves critical roles in brain microglia. Systemic inhibition could therefore disrupt central nervous system function and compromise innate immunity. Furthermore, the precise molecular pathway by which AIF-1 regulates MAOA expression remains unclear, and potential gender-specific responses add complexity. The absence of clinical trial data makes it difficult to predict efficacy, optimal dosing, or long-term safety in humans. Overcoming these hurdles will require not only the development of highly targeted delivery systems to confine therapeutic action to relevant adipose tissue macrophages but also a substantial investment in clinical research to bridge the gap between promising mechanistic biology and validated human therapeutic application.

In summary, AIF-1 has emerged as a critical and multifaceted regulator at the intersection of inflammation and metabolism, presenting a novel and compelling target for the management of obesity (Figure 5). The pathophysiology of AIF-1 may include following: (1) metabolic dysregulation: orchestrating adipose tissue inflammation through macrophage; (2) insulin signaling interference: impairing GLUT4 translocation and Akt phosphorylation induced insulin signal impairment in adipocyte; and (3) inflammation activation: stimulating inflammatory cytokines releasion in macrophage for diet-induced obesity.

However, the translation of these mechanistic insights into clinical applications faces challenges. Population genetics and human adipose tissue analyses strongly associate AIF-1 with obesity, but robust clinical data validating it as a diagnostic biomarker or a directly druggable target remain a critical gap. The primary translational challenge lies in the precise targeting of AIF-1’s pathogenic actions without incurring off-target effects, given its role in general immunity. Future strategies may involve developing tissue-selective delivery systems or exploiting the nuanced biology of its paralog, AIF1L. Besides, for translational potential, we suggest to interrupte the effect of AIF-1 on gene expression as an effective way to alleviate obesity.