The multifaceted role of AIF-1 in metabolic dysregulation: bridging inflammation, insulin resistance, and obesity

Allograft inflammatory factor-1 (AIF-1), a cytokine secreted by activated monocytes, macrophages, and lymphocytes, has emerged as a critical regulator of pathological processes spanning renal diseases, rheumatoid arthritis, cancer, cardiovascular disorders, neurological pathologies, and transplant-related conditions. Population-based studies have associated sequence variants near the AIF-1 locus with obesity, though AIF-1’s potential pathophysiological involvement remains uninvestigated. Understanding its molecular characteristics, receptor interactions, and signaling pathways is essential for elucidating its biological functions. This review comprehensively examines AIF-1’s involvement in inflammatory and metabolic pathogenesis, particularly focusing on obesity and inflammation. Through systematic literature analysis, we consolidated current knowledge on AIF-1’s functions and analyzed studies exploring its roles in obesity, insulin resistance, and inflammation to clarify broader disease mechanisms. AIF-1 exerts pleiotropic effects on immune cells, insulin signaling, and adipocytes. Elevated AIF-1 levels correlate with inflammatory adipocytes and obesity, while reduced AIF-1 promotes weight loss through regulation of monoamine oxidase A and decreased leptin/resistin production. Deciphering AIF-1’s complex roles in inflammation and metabolic disorders offers critical insights for therapeutic development. Targeting AIF-1 or AIF1-like (AIF1L) may yield novel strategies to mitigate disease progression and enhance clinical management of obesity.

GRAPHICAL ABSTRACT

Graphical Abstract. The dual role of AIF-1 in obesity. Enhanced AIF-1 mediates obesity. Loss of AIF-1 induces obesity resistance. AIF-1, allograft inflammatory factor-1; MAOA, monoamine oxidase a; WAT, white adipose tissue; IR, insulin resistance.

1 Introduction

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).

Figure 1

Figure 1. Overview of AIF-1 functions. Activation of macrophages, inducing insulin resistance, adipocytes dysfunction, and activation of inflammation. AIF-1, allograft inflammatory factor-1; IL-6: interlukin 6; TNF-α : tumor necrosis factor α; TLR-4: Toll-like receptor-4.

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.

2 Methodology

2.1 Search strategies

The literature search supporting this review employed a targeted exploration of biomedical databases including PubMed, Web of Science, and Scopus (Figure 2). Relevant studies were searched from the databases from inception until December 2025. A combination of controlled vocabulary terms (MeSH headings) and free-text keywords such as “AIF-1” or “Iba1”, “obesity” or “obese”, “insulin resistance” or “IR”, “adipocyte” or “adipose tissue”, and “inflammation” or “inflammatory”, were iteratively applied. The search strategy encompassed all publication types without language restrictions, though non-English publications were retained only if accompanied by English abstracts. Retrieved articles were filtered to eliminate duplicates and irrelevant results. Additionally, the reference lists of selected articles were reviewed to identify other pertinent publications.

Figure 2

Figure 2. PRISMA flow chart.

2.2 Inclusion and exclusion criteria

Included criteria: (1) The results of the researches should include body weight, AIF-1 level, adipose tissues, or inflammatory response; (2) The research subjects are animals or humans; (3) Relevant review for AIF-1. Exclusion criteria: (1) Personal experience summaries; (2) Studies displayed as figures; (3) Inconsistent with the inclusion criteria.

3 Function in immunity: macrophages

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).

4 Function in adipose tissue: adipocyte

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.

4.1 Inflammatory crosstalk in adipocytes

Obesity-induced adipose inflammation triggers macrophage AIF-1 overproduction, which via paracrine signaling enhances adipocyte TLR4 activation (15, 23). This interaction stimulates IL-6 and TNF-α secretion while suppressing adiponectin, creating a self-sustaining inflammatory milieu (24). Crucially, AIF-1 knockdown models demonstrate reduction in macrophage infiltration and decrease in leptin/resistin production (11), mechanistically linking AIF-1 to adipokine dysregulation.

4.2 Adipokine secretion modulation

AIF-1 directly reprograms adipokine secretion profiles through TLR4-dependent signaling. Stimulation of adipocytes with recombinant AIF-1 (100 ng/mL) elevates TNF-α and IL-6 secretion, while suppressing adiponectin production (15, 25). This bidirectional regulation mechanistically involves JNK/STAT3 dual-pathway activation: phosphorylation analyses reveal increased STAT3(Y705) and elevated JNK(T183/Y185) upon AIF-1 exposure (22). The resultant proinflammatory shift (TNF-α/adiponectin ratio increased) establishes a self-reinforcing metabolic-inflammatory loop that perpetuates insulin resistance (26). Critically, AIF-1-induced adipokine dysregulation exhibits dose-dependency (EC50 = 38 nM) and correlates with impaired GLUT4 trafficking, directly linking inflammatory signaling to metabolic dysfunction.

5 Potential interactions with inflammatory cytokines

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).

6 Metabolic disease: obesity

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.

Table 1

Table 1. Overview of the association between AIF-1/AIF1L and obesity.

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).

Figure 3

Figure 3. Regulation of adipocyte function and inflammatory signaling in obesity. An increase in AIF-1 levels stimulates the polarization of inflammatory-induced adipose tissue macrophages, increases leptin and resistin levels, increases fat cell mass, and enhances the inflammatory response leading to obesity. On the contary, loss of AIF-1 inhibited inflammation response to regulate MAOA expression in macrophages with decreased lipid accumulation, mass of adipocytes, BAT, and decreased leptin and resistin inducing obesity resistance. AIF-1, allograft inflammatory factor-1; MAOA, monoamine oxidase a; BAT, brown adipose tissue.

6.1 Adipocytes

Emerging evidence suggests AIF-1 mediates paracrine regulation of adipose functionality (42) through intricate macrophage-adipocyte crosstalk (15). Such cellular interactions profoundly disrupt metabolic coordination, directly fueling obesity-associated pathological cascades. Study showed that AIF-1 stimulates the production of reactive oxygen species (ROS) in adipocytes by elevating ROS production through NOX4 upregulation, exacerbating metabolic dysfunction (36). Additionally, acute AIF-1 exposure (48h) paradoxically enhances lipid droplet formation in differentiating adipocytes (16), while chronic exposure (28 days) reduces lipolytic capacity through PPARγ suppression. This temporal dichotomy mirrors clinical observations of AIF-1 overexpression in obese patients correlating with increased ectopic lipid deposition (43), impairment in insulin signaling fidelity, and elevated cardiovascular risk markers. Mechanistically linking these effects, AIF-1 activates mTORC1-SREBP1 cascades (phosphorylation increased) that reprogram lipid metabolism while simultaneously inhibiting AMPKα (Thr172) phosphorylation (16). Beyond its inflammatory mediation, AIF-1 emerges as a multifunctional hub integrating molecular networks that drive both obesity initiation and its metabolic sequelae, positioning it as a critical node in adiposopathy pathogenesis.

6.2 Inflammation

Adipose tissue macrophages are the main sources of the proinflammatory molecules, such as TNF-α and IL-6 (38). AIF-1 operates as a key pro-inflammatory effector in adipose microenvironments (20), orchestrating macrophage activation/recruitment and immune cell infiltration that establishes a pathological feedback loop of chronic inflammation and insulin resistance (44). This self-perpetuating cascade perpetuates tissue damage while destabilizing systemic metabolic homeostasis. Clinically, elevated AIF-1 expression in obesity correlates with detrimental metabolic manifestations-including pronounced insulin resistance and dyslipidemia (45) -which reciprocally amplify inflammatory signaling to accelerate adiposity progression and comorbidity development.

6.3 Insulin signaling disruption

The emerging role of AIF-1 in metabolic regulation is particularly evident in obesity-associated pathologies, where chronic adipose tissue inflammation serves as a critical nexus linking AIF-1 dysregulation to insulin resistance development (46). AIF-1 impairs insulin sensitivity through multi-tiered mechanisms. In vitro studies showed that AIF-1 disrupts insulin signaling in 3T3-L1 adipocytes by phosphorylating IRS-1 at Ser307, impairing insulin receptor substrate function, downregulating GLUT4 translocation through PI3K/Akt pathway inhibition, and inducing SOCS3 expression, which blocks insulin receptor tyrosine kinase activity (47) (Figure 4). Additionally, AIF-1 may disrupt insulin signaling by suppressing Akt pathway with decreasing Akt308 phosphorylation by PP2A activation (37). Besides, AIF-1 impairs insulin signaling via upregulating the release of inflammatory factors (TNF-α, IL-6, and resistin) and downregulating the secretion of insulin-sensitive factors (adiponectin) (19, 24). Moreover, AIF-1 knockout models demonstrated improved insulin sensitivity (HOMA-IR reduction), enhanced glucose tolerance (AUC decrease), and reduced adipose tissue macrophage infiltration (48). Furthermore, clinical studies elucidated that type 1 diabetic patients show altered AIF-1-mediated immune regulation with reduction in pancreatic islet T-cell populations, downregulated IFN-γ/T-bet axis in AIF-1-silenced individuals, and compensatory expansion of CD25+Foxp3+CD4+ Treg cells (49). These coordinated effects establish AIF-1 as a master regulator of adipocyte insulin resistance, with preclinical studies showing AIF-1 inhibition restores normal insulin response (50). The conserved AIF-1/insulin resistance axis across species (from in vitro models to human pathophysiology) underscores its potential as a therapeutic target.

Figure 4

Figure 4. AIF-1 disrupts insulin signal pathway in 3T3-L1 adipocytes. Phosphorylating IRS-1 at Ser307, impairing insulin receptor substrate function, downregulating GLUT4 translocation through PI3K/Akt pathway inhibition, and inducing SOCS3 expression, which blocks insulin receptor tyrosine kinase activity resulted in disorder of insulin signal pathway. AIF-1, allograft inflammatory factor-1; IRS-1, insulin receptor substrate 1; GLUT4, glucose transporter 4; SOCS3, suppressor of cytokine signaling 3.

7 Therapeutic potential and translational challenges

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.

8 Conclusions

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.

Figure 5

Figure 5. AIF-1 regulates insulin signaling and macrophage inflammation. Macrophage-derived AIF-1 secretion adipokine TNFα, and IL-6. Moreover, it suppressed insulin-stimulated glucose uptake by down-regulating insulin signaling with GLUT4 translocation, and Akt phosphorylation. AIF-1, allograft inflammatory factor-1; TNF-α, tumor necrosis factor; IL-6, interlukin 6; GLUT4, glucose transporter 4.

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.

Author contributions

JH: Writing – original draft, Writing – review & editing. FJ: Writing – review & editing. YC: Conceptualization, Writing – review & editing.

Funding

The author(s) declared that financial support was received for this work and/or its publication. This work was supported by a grant from “The Natural Science Foundation of Zhejiang Province, grant number: LQ24H070007”, and “The Zhejiang Provincial Medical and Health Science and Technology Plan, grant number: 2025KY1577”, and “Hangzhou City University 2024 Research Cultivation Program (Affiliated Hospital Special Project), grant number: F-202403”, and “Hangzhou City University 2025 Research Cultivation Program (Affiliated Hospital Special Project), grant number: F-202508”.

Acknowledgments

We would like to express our gratitude to all the staff members of the clinical endocrinology department and the nursing research and teaching office for their support.

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Generative AI statement

The author(s) declared that generative AI was not used in the creation of this manuscript.

Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

1. Sikora M, Kopeć B, Piotrowska K, and Pawlik A. Role of allograft inflammatory factor-1 in pathogenesis of diseases. Immunol Lett. (2020) 218:1–4. doi: 10.1016/j.imlet.2019.12.002

PubMed Abstract | Crossref Full Text | Google Scholar

2. Utans U, Arceci RJ, Yamashita Y, and Russell ME. Cloning and characterization of allograft inflammatory factor-1: a novel macrophage factor identified in rat cardiac allografts with chronic rejection. J Clin Invest. (1995) 95:2954–62. doi: 10.1172/JCI118003

PubMed Abstract | Crossref Full Text | Google Scholar

3. Liu G, Ma H, Jiang L, and Zhao Y. Allograft inflammatory factor-1 and its immune regulation. Autoimmunity. . (2007) 40:95–102. doi: 10.1080/08916930601083946

Crossref Full Text | Google Scholar

4. Husain I, Shah H, Jordan CZ, Natesh NR, Fay OK, Chen Y, et al. Targeting allograft inflammatory factor 1 reprograms kidney macrophages to enhance repair. J Clin Invest. (2025) 135:e185146. doi: 10.1172/JCI185146

PubMed Abstract | Crossref Full Text | Google Scholar

5. Piotrowska K, Słuczanowska-Głabowska S, Kurzawski M, Dziedziejko V, Kopytko P, Paczkowska E, et al. Over-expression of allograft inflammatory factor-1 (AIF-1) in patients with rheumatoid arthritis. Biomolecules. . (2020) 10:1064. doi: 10.3390/biom10071064

Crossref Full Text | Google Scholar

6. Baranzini N, Monti L, Vanotti M, Orlandi VT, Bolognese F, Scaldaferri D, et al. AIF-1 and RNASET2 play complementary roles in the innate immune response of medicinal leech. J Innate Immun. (2019) 11:150–67. doi: 10.1159/000493804

PubMed Abstract | Crossref Full Text | Google Scholar

7. Zhao YY, Yan DJ, and Chen ZW. Role of AIF-1 in the regulation of inflammatory activation and diverse disease processes. Cell Immunol. (2013) 284:75–83. doi: 10.1016/j.cellimm.2013.07.008

PubMed Abstract | Crossref Full Text | Google Scholar

8. Mazzei A, Pagliara P, Del Vecchio G, Giampetruzzi L, Croce F, Schiavone R, et al. Cytoskeletal responses and Aif-1 expression in Caco-2 monolayers exposed to Phorbol-12-Myristate-13-Acetate and carnosine. Biol (Basel). (2022) 12:36. doi: 10.3390/biology12010036

PubMed Abstract | Crossref Full Text | Google Scholar

9. Autieri MV, Kelemen SE, and Wendt KW. AIF-1 is an actin-polymerizing and Rac1-activating protein that promotes vascular smooth muscle cell migration. Circ Res. (2003) 92:1107–14. doi: 10.1161/01.RES.0000074000.03562.CC

PubMed Abstract | Crossref Full Text | Google Scholar

10. Thorleifsson G, Walters GB, Gudbjartsson DF, Steinthorsdottir V, Sulem P, Helgadottir A, et al. Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity. Nat Genet. (2009) 41:18–24. doi: 10.1038/ng.274

PubMed Abstract | Crossref Full Text | Google Scholar

11. Chinnasamy P, Casimiro I, Riascos-Bernal DF, Venkatesh S, Parikh D, Maira A, et al. Increased adipose catecholamine levels and protection from obesity with loss of Allograft Inflammatory Factor-1. Nat Commun. (2023) 14:38. doi: 10.1038/s41467-022-35683-7

PubMed Abstract | Crossref Full Text | Google Scholar

12. Parikh D, Jayakumar S, Oliveira-Paula GH, Almonte V, Riascos-Bernal DF, and Sibinga NES. Allograft inflammatory factor-1-like is a situational regulator of leptin levels, hyperphagia, and obesity. iScience. . (2022) 25:105058. doi: 10.1016/j.isci.2022.105058

Crossref Full Text | Google Scholar

13. Deininger MH, Meyermann R, and Schluesener HJ. The allograft inflammatory factor-1 family of proteins. FEBS Lett. (2002) 514:115–21. doi: 10.1016/s0014-5793(02)02430-4

PubMed Abstract | Crossref Full Text | Google Scholar

14. De Leon-Oliva D, Garcia-Montero C, Fraile-Martinez O, Boaru DL, García-Puente L, Rios-Parra A, et al. AIF1: function and connection with inflammatory diseases. Biol (Basel). (2023) 12:694. doi: 10.3390/biology12050694

PubMed Abstract | Crossref Full Text | Google Scholar

15. Lorente-Cebrián S, Decaunes P, Dungner E, Bouloumié A, Arner P, and Dahlman I. Allograft inflammatory factor 1 (AIF-1) is a new human adipokine involved in adipose inflammation in obese women. BMC Endocr Disord. (2013) 13:54. doi: 10.1186/1472-6823-13-54

PubMed Abstract | Crossref Full Text | Google Scholar

16. Ren J, Lin Y, Tang J, Yue H, and Zhao Y. Allograft Inflammatory Factor-1 Mediates Macrophage-Induced Impairment of Insulin Signaling in Adipocytes. Cell Physiol Biochem. (2018) 47:403–13. doi: 10.1159/000489952

PubMed Abstract | Crossref Full Text | Google Scholar

17. Köhler C. Allograft inflammatory factor-1/ionized calcium-binding adapter molecule 1 is specifically expressed by most subpopulations of macrophages and spermatids in testis. Cell Tissue Res. (2007) 330:291–302. doi: 10.1007/s00441-007-0474-7

PubMed Abstract | Crossref Full Text | Google Scholar

18. Yang ZF, Ho DW, Lau CK, Lam CT, Lum CT, Poon RT, et al. Allograft inflammatory factor-1 (AIF-1) is crucial for the survival and pro-inflammatory activity of macrophages. Int Immunol. (2005) 17:1391–7. doi: 10.1093/intimm/dxh316

PubMed Abstract | Crossref Full Text | Google Scholar

19. Watano K, Iwabuchi K, Fujii S, Ishimori N, Mitsuhashi S, Ato M, et al. Allograft inflammatory factor-1 augments production of interleukin-6, -10 and -12 by a mouse macrophage line. Immunology. . (2001) 104:307–16. doi: 10.1046/j.1365-2567.2001.01301.x

Crossref Full Text | Google Scholar

20. Tian Y, Kelemen SE, and Autieri MV. Inhibition of AIF-1 expression by constitutive siRNA expression reduces macrophage migration, proliferation, and signal transduction initiated by atherogenic stimuli. Am J Physiol Cell Physiol. (2006) 290:C1083–91. doi: 10.1152/ajpcell.00381.2005

PubMed Abstract | Crossref Full Text | Google Scholar

21. Fukui M, Tanaka M, Toda H, Asano M, Yamazaki M, Hasegawa G, et al. The serum concentration of allograft inflammatory factor-1 is correlated with metabolic parameters in healthy subjects. Metabolism. . (2012) 61:1021–5. doi: 10.1016/j.metabol.2011.12.001

Crossref Full Text | Google Scholar

22. Liu Y, Mei C, Du R, and Shen L. Protective effect of allograft inflammatory factor-1 on the apoptosis of fibroblast-like synoviocytes in patients with rheumatic arthritis induced by nitro oxide donor sodium nitroprusside. Scand J Rheumatol. (2013) 42:349–55. doi: 10.3109/03009742.2013.772233

PubMed Abstract | Crossref Full Text | Google Scholar

23. Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, and Flier JS. TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest. (2006) 116:3015–25. doi: 10.1172/JCI28898

PubMed Abstract | Crossref Full Text | Google Scholar

24. Mohd Sairazi NS, Sirajudeen KNS, Muzaimi M, Mummedy S, Asari MA, and Sulaiman SA. Tualang honey reduced neuroinflammation and caspase-3 activity in rat brain after kainic acid-induced status epilepticus. Evid Based Complement Alternat Med. (2018) 2018:7287820. doi: 10.1155/2018/728782

PubMed Abstract | Crossref Full Text | Google Scholar

25. Schovanek J, Krupka M, Cibickova L, Karhanova M, Reddy S, Kucerova V, et al. Adipocytokines in Graves' orbitopathy and the effect of high-dose corticosteroids. Adipocyte. . (2021) 10:456–62. doi: 10.1080/21623945.2021.1980258

Crossref Full Text | Google Scholar

26. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. (2003) 112:1821–30. doi: 10.1172/JCI19451

PubMed Abstract | Crossref Full Text | Google Scholar

27. Egaña-Gorroño L, Chinnasamy P, Casimiro I, Almonte VM, Parikh D, Oliveira-Paula GH, et al. Allograft inflammatory factor-1 supports macrophage survival and efferocytosis and limits necrosis in atherosclerotic plaques. Atherosclerosis. . (2019) 289:184–94. doi: 10.1016/j.atherosclerosis.2019.07.022

Crossref Full Text | Google Scholar

28. da Silva RL, Elizondo DM, Brandy NZD, Haddock NL, Boddie TA, de Oliveira LL, et al. Leishmania donovani infection suppresses Allograft Inflammatory Factor-1 in monocytes and macrophages to inhibit inflammatory responses. Sci Rep. (2021) 11:946. doi: 10.1038/s41598-020-79068-6

PubMed Abstract | Crossref Full Text | Google Scholar

29. Dong R, Li J, Jiang G, Tian Y, and Bi W. Allograft inflammatory Factor-1 induces the dedifferentiation of Vascular Smooth Muscle cells into a macrophage-like phenotype both in vivo and in vitro. Exp Cell Res. (2025) 446:114475. doi: 10.1016/j.yexcr.2025.114475

PubMed Abstract | Crossref Full Text | Google Scholar

30. Wang BC, Chaki S, Taufiq H, Sikder K, Shukla SK, and Rafiq K. Sepsis-induced cardiac dysfunction: Gender bias role of allograft inflammatory factor-1. Cytokine. . (2025) 196:157040. doi: 10.1016/j.cyto.2025.157040

Crossref Full Text | Google Scholar

31. Wu Q, Qin B, Wu X, Zhang M, Gan Z, Lan Y, et al. Allograft inflammatory factor-1 enhances inflammation and oxidative stress via the NF-κB pathway of bladder urothelium in diabetic rat model. Cytokine. . (2024) 173:156438. doi: 10.1016/j.cyto.2023.156438

Crossref Full Text | Google Scholar

32. Li S, Shin HJ, Ding EL, and van Dam RM. Adiponectin levels and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA. . (2009) 302:179–88. doi: 10.1001/jama.2009.976

Crossref Full Text | Google Scholar

33. Chen BH, Song Y, Ding EL, Roberts CK, Manson JE, Rifai N, et al. Circulating levels of resistin and risk of type 2 diabetes in men and women: results from two prospective cohorts. Diabetes Care. (2009) 32:329–34. doi: 10.2337/dc08-1625

PubMed Abstract | Crossref Full Text | Google Scholar

34. Parikh D, Riascos-Bernal DF, Egaña-Gorroño L, Jayakumar S, Almonte V, Chinnasamy P, et al. Allograft inflammatory factor-1-like is not essential for age dependent weight gain or HFD-induced obesity and glucose insensitivity. Sci Rep. (2020) 10:3594. doi: 10.1038/s41598-020-60433-4

PubMed Abstract | Crossref Full Text | Google Scholar

35. Rouskas K, Kouvatsi A, Paletas K, Papazoglou D, Tsapas A, Lobbens S, et al. Common variants in FTO, MC4R, TMEM18, PRL, AIF1, and PCSK1 show evidence of association with adult obesity in the Greek population. Obes (Silver Spring). (2012) 20:389–95. doi: 10.1038/oby.2011.177

PubMed Abstract | Crossref Full Text | Google Scholar

36. Jha JC, Ho F, Dan C, and Jandeleit-Dahm K. A causal link between oxidative stress and inflammation in cardiovascular and renal complications of diabetes. Clin Sci (Lond). (2018) 132:1811–36. doi: 10.1042/CS20171459

PubMed Abstract | Crossref Full Text | Google Scholar

37. Hao J, Tang J, Zhang L, Li X, and Hao L. The Crosstalk between calcium ions and aldosterone contributes to inflammation, apoptosis, and calcification of VSMC via the AIF-1/NF-κB pathway in uremia. Oxid Med Cell Longev. (2020) 2020:3431597. doi: 10.1155/2020/3431597

PubMed Abstract | Crossref Full Text | Google Scholar

38. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, and Ferrante AW Jr.. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. (2003) 112:1796–808. doi: 10.1172/JCI19246

PubMed Abstract | Crossref Full Text | Google Scholar

39. Wellen KE and Hotamisligil GS. Obesity-induced inflammatory changes in adipose tissue. J Clin Invest. (2003) 112:1785–8. doi: 10.1172/JCI20514

PubMed Abstract | Crossref Full Text | Google Scholar

40. Decaunes P, Estève D, Zakaroff-Girard A, Sengenès C, Galitzky J, and Bouloumié A. Adipose-derived stromal cells: cytokine expression and immune cell contaminants. Methods Mol Biol. (2011) 702:151–61. doi: 10.1007/978-1-61737-960-4_12

PubMed Abstract | Crossref Full Text | Google Scholar

41. Trayhurn P and Wood IS. Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr. (2004) 92:347–55. doi: 10.1079/bjn20041213

PubMed Abstract | Crossref Full Text | Google Scholar

42. Albiero M, Rattazzi M, Menegazzo L, Boscaro E, Cappellari R, Pagnin E, et al. Myeloid calcifying cells promote atherosclerotic calcification via paracrine activity and allograft inflammatory factor-1 overexpression. Basic Res Cardiol. (2013) 108:368. doi: 10.1007/s00395-013-0368-7

PubMed Abstract | Crossref Full Text | Google Scholar

43. Spurná J, Karásek D, Kubíčková V, Goldmannová D, Krystyník O, Schovánek J, et al. Relationship of selected adipokines with markers of vascular damage in patients with type 2 Diabetes. Metab Syndr Relat Disord. (2018) 16:246–53. doi: 10.1089/met.2017.0179

PubMed Abstract | Crossref Full Text | Google Scholar

44. Tian Y, Jain S, Kelemen SE, and Autieri MV. AIF-1 expression regulates endothelial cell activation, signal transduction, and vasculogenesis. Am J Physiol Cell Physiol. (2009). doi: 10.1152/ajpcell.00325.2008

PubMed Abstract | Crossref Full Text | Google Scholar

45. Hoffstedt J, Arner E, Wahrenberg H, Andersson DP, Qvisth V, Löfgren P, et al. Regional impact of adipose tissue morphology on the metabolic profile in morbid obesity. Diabetologia. . (2010) 53:2496–503. doi: 10.1007/s00125-010-1889-3

Crossref Full Text | Google Scholar

46. Kelemen SE and Autieri MV. Expression of allograft inflammatory factor-1 in T lymphocytes: a role in T-lymphocyte activation and proliferative arteriopathies. Am J Pathol. (2005) 167:619–26. doi: 10.1016/S0002-9440(10)63003-9

PubMed Abstract | Crossref Full Text | Google Scholar

47. Yuan X, Wang X, Li Y, Li X, Zhang S, and Hao L. Aldosterone promotes renal interstitial fibrosis via the AIF 1/AKT/mTOR signaling pathway. Mol Med Rep. (2019) 20:4033–44. doi: 10.3892/mmr.2019.10680

PubMed Abstract | Crossref Full Text | Google Scholar

48. Jianbing H, Xiaotian L, Jie T, Xueying C, Honge J, Bo Z, et al. The Effect of allograft inflammatory factor-1 on inflammation, oxidative stress, and autophagy via miR-34a/ATG4B pathway in diabetic kidney disease. Oxid Med Cell Longev. (2022) 2022:1668000. doi: 10.1155/2022/1668000

PubMed Abstract | Crossref Full Text | Google Scholar

49. Elizondo DM, Brandy NZ, da Silva RL, de Moura TR, and Lipscomb MW. Allograft inflammatory factor-1 in myeloid cells drives autoimmunity in type 1 diabetes. JCI Insight. (2020) 5:e136092. doi: 10.1172/jci.insight.136092

PubMed Abstract | Crossref Full Text | Google Scholar

50. Sibinga NE, Feinberg MW, Yang H, Werner F, and Jain MK. Macrophage-restricted and interferon gamma-inducible expression of the allograft inflammatory factor-1 gene requires Pu. 1. J Biol Chem. (2002) 277:16202–10. doi: 10.1074/jbc.M200935200

PubMed Abstract | Crossref Full Text | Google Scholar