Adipokines as New Biomarkers of Immune Recovery: Apelin Receptor, RBP4 and ZAG Are Related to CD4+ T-Cell Reconstitution in PLHIV on Suppressive Antiretroviral Therapy.

A significant proportion of people living with HIV (PLHIV) who successfully achieve virological suppression fail to recover CD4+ T-cell counts. Since adipose tissue has been discovered as a key immune organ, this study aimed to assess the role of adipokines in the HIV immunodiscordant response. This is a multicenter prospective study including 221 PLHIV starting the first antiretroviral therapy (ART) and classified according to baseline CD4+ T-cell counts/µL (controls > 200 cells/µL and cases ≤ 200 cells/µL). Immune failure recovery was considered when cases did not reach more than 250 CD4+ T cells/µL at 144 weeks (immunological nonresponders, INR). Circulating adipokine concentrations were longitudinally measured using enzyme-linked immunosorbent assays. At baseline, apelin receptor (APLNR) and zinc-alpha-2-glycoprotein (ZAG) concentrations were significantly lower in INRs than in immunological responders (p = 0.043 and p = 0.034), and they remained lower during all ART follow-up visits (p = 0.044 and p = 0.028 for APLNR, p = 0.038 and p = 0.010 for ZAG, at 48 and 144 weeks, respectively). ZAG levels positively correlated with retinol-binding protein 4 (RBP4) levels (p < 0.01), and low circulating RBP4 concentrations were related to a low CD4+ T-cell gain (p = 0.018 and p = 0.039 at 48 and 144 weeks, respectively). Multiple regression adjusted for clinical variables and adipokine concentrations confirmed both low APLNR and RBP4 as independent predictors for CD4+ T cells at 144 weeks (p < 0.001). In conclusion, low APLNR and RBP4 concentrations were associated with poor immune recovery in treated PLHIV and could be considered predictive biomarkers of a discordant immunological response.

The CTRP3-AdipoR2 Axis Regulates the Development of Experimental Autoimmune Encephalomyelitis by Suppressing Th17 Cell Differentiation.

C1q/TNF-related proteins (CTRP) including CTRP3 are a group of secreted proteins which have a complement C1q-like domain in common, and play versatile roles in lipid metabolism, inflammation, tumor metastasis and bone metabolism. Previously, we showed that the expression of C1qtnf3, encoding CTRP3, is highly augmented in joints of autoimmune arthritis models and CTRP3-deficiency exacerbates collagen-induced arthritis in mice. However, the mechanisms how CTRP3-deficiency exacerbates arthritis still remain to be elucidated. In this study, we showed that CTRP3 was highly expressed in Th17 cell, a key player for the development of autoimmune diseases, and Th17 cell differentiation was augmented in C1qtnf3-/- mice. Th17 cell differentiation, but not Th1 cell differentiation, was suppressed by CTRP3 and this suppression was abolished by the treatment with a receptor antagonist against AdipoR2, but not AdipoR1, associated with suppression of Rorc and Stat3 expression. Furthermore, AdipoR1 and AdipoR2 agonist, AdipoRon suppressed Th17 cell differentiation via AdipoR2, but not AdipoR1. The development of myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis was enhanced in C1qtnf3-/- mice associated with increase of Th17 cell population. CTRP3 inhibited MOG-induced IL-17 production from T cells by affecting both T cells and dendritic cells. These results show that CTRP3 is an endogenous regulator of Th17 differentiation, suggesting that the CTRP3-AdipoR2 axis is a good target for the treatment of Th17 cell-mediated diseases.

Body mass index and adipokines/cytokines dysregulation in systemic sclerosis.

Body fat has regulatory functions through producing cytokines and adipokines whose role in the pathogenesis of systemic sclerosis (SSc) is currently emerging. Changes in body mass, either over- or underweight, entail a dysregulation of the cytokine/adipokine network that may impact upon SSc disease activity. We evaluated serum levels of adipokines and cytokines in SSc patients and correlated them to clinical features and body mass index (BMI) categories. The study included 89 SSc patients and 26 healthy donors (HD). Serum levels of adiponectin, leptin, resistin, visfatin, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-2, IL-10 and IL-17A were measured by multiplex immunoassay and correlated to BMI and disease-specific features. Student's t-test or analysis of variance (ANOVA) were used for comparisons between groups. Spearman's or Pearson's tests were used for correlation analysis. Serum levels of TNF-α, IL-2, leptin and resistin were significantly higher in SSc than in HD. Leptin levels were significantly higher in interstitial lung disease (ILD)- and pulmonary arterial hypertension (PAH)-SSc subgroups. The highest levels of IL-17A, IL-2, IL-10, leptin and visfatin were detected in SSc patients with obesity (p < 0.01). Conversely, underweight SSc patients showed the highest TNF-α levels (p < 0.05). Adipokines, IL-2, IL-10 and IL-17A were found to be increased in SSc patients with obesity, but whether or not they play a role in the pathogenesis of the disease remains to be investigated. Intriguingly, underweight patients had the highest TNF-α levels, suggesting a potential role of TNF-α in inducing the cachexia observed in long-lasting disease.

Anti-Inflammatory Effects of C1q/Tumor Necrosis Factor-Related Protein 3 (CTRP3) in Endothelial Cells.

The C1q/TNF-related protein 3 (CTRP3) represents a pleiotropic adipokine reciprocally associated with obesity and type 2 diabetes mellitus and exhibits anti-inflammatory properties in relation to lipopolysaccharides (LPS)-mediated effects in adipocytes, as well as monocytes/macrophages. Here, we focused on the influence of CTRP3 on LPS-mediated effects in endothelial cells in order to expand the understanding of a possible anti-inflammatory function of CTRP3 in a setting of endotoxemia. An organ- and tissue-specific expression analysis by real-time PCR revealed a considerable Ctrp3 expression in various adipose tissue compartments; however, higher levels were detected in the aorta and in abundantly perfused tissues (bone marrow and the thyroid gland). We observed a robust Ctrp3 expression in primary endothelial cells and a transient upregulation in murine endothelial (MyEND) cells by LPS (50 ng/mL). In MyEND cells, CTRP3 inhibited the LPS-induced expression of interleukin (Il)-6 and the tumor necrosis factor (Tnf)-α, and suppressed the LPS-dependent expression of the major endothelial adhesion molecules Vcam-1 and Icam-1. The LPS-induced adhesion of monocytic cells to an endothelial monolayer was antagonized by CTRP3. In C57BL/6J mice with an LPS-induced systemic inflammation, exogenous CTRP3 did not affect circulating levels of TNF-α, ICAM-1, and VCAM-1. In conclusion, we characterized CTRP3 beyond its function as an adipokine in a setting of vascular inflammation. CTRP3 inhibited LPS-induced endothelial expression of adhesion molecules and monocyte cell adhesion, indicating an important vascular anti-inflammatory role for CTRP3 in endotoxemia.

Adipocytes, Innate Immunity and Obesity: A Mini-Review.

The role of adipose tissue (AT) inflammation in obesity and its multiple related-complications is a rapidly expanding area of scientific interest. Within the last 30 years, the role of the adipocyte as an endocrine and immunologic cell has been progressively established. Like the macrophage, the adipocyte is capable of linking the innate and adaptive immune system through the secretion of adipokines and cytokines; exosome release of lipids, hormones, and microRNAs; and contact interaction with other immune cells. Key innate immune cells in AT include adipocytes, macrophages, neutrophils, and innate lymphoid cells type 2 (ILC2s). The role of the innate immune system in promoting adipose tissue inflammation in obesity will be highlighted in this review. T cells and B cells also play important roles in contributing to AT inflammation and are discussed in this series in the chapter on adaptive immunity.

Are adipokines the missing link between obesity, immune response, and outcomes in severe COVID-19?

INTRODUCTION: Obesity is commonly reported in COVID-19 patients and is associated with poorer outcomes. It is suggested that leptin could be the missing link between obesity and severe COVID-19. Our study aimed to unravel the link between adipokines, COVID-19 status, immune response, and outcomes in severe pneumonia. METHODS: In this prospective observational single-center study, 63 immunocompetent patients with severe pneumonia (36 non-COVID-19 and 27 COVID-19) were enrolled, most required intensive care. Clinical and biological characteristics (glucose metabolism, plasma adipokines, and cytokine concentrations) and outcomes were compared. RESULTS: At similar baseline severity, COVID-19 patients required mechanical ventilation for significantly longer than non-COVID-19 patients (p = 0.0049). Plasma concentrations of leptin and adiponectin were respectively positively and negatively correlated with BMI and glucose metabolism (glycemia and insulinemia), but not significantly different between the two groups. Leptin levels were negatively correlated with IL-1ß and IL-6, but the adipokines were not correlated with most other inflammatory mediators, baseline severity (SOFA score), or the duration of mechanical ventilation. CONCLUSION: Adipokine levels were correlated with BMI but not with most inflammatory mediators, severity, or outcomes in severe pneumonia, regardless of the origin. The link between obesity, dysregulated immune response, and life-threatening COVID-19 requires further investigation. CLINICAL TRIAL: ClinicalTrials.gov: NCT03505281.

Adipokine role in physiopathology of inflammatory and degenerative musculoskeletal diseases.

We performed a systematic literature review to summarize the underlying pathogenic mechanisms by which adipokines influence rheumatological diseases and the resulting clinical manifestations. Increasing evidence display that numerous adipokines may significantly influence the development or clinical course of various rheumatological diseases. Despite the normal anti- or pro-inflammatory role of the cytokines, the serum level varies enormously in various rheumatological diseases. The expression of high levels of pro-inflammatory cytokines such as leptin or visfatin, respectively in systemic lupus erythematosus and in rheumatoid arthritis, represents a negative prognostic factor; other adipokines such as adiponectin, broadly known for their anti-inflammatory effects, showed a correlation with disease activity in rheumatoid arthritis. In the near future pro-inflammatory cytokines may represent a potential therapeutic target to restrain the severity of rheumatological diseases. Further studies on adipokines may provide important information on the pathogenesis of these diseases, which are not yet fully understood. The mechanisms by which adipokines induce, worsen, or suppress inflammatory and degenerative musculoskeletal pathologies and their clinical significance will be discussed in this review.

Cancer-Associated Adipocytes in Breast Cancer: Causes and Consequences.

Breast cancer progression is highly dependent on the heterotypic interaction between tumor cells and stromal cells of the tumor microenvironment. Cancer-associated adipocytes (CAAs) are emerging as breast cancer cell partners favoring proliferation, invasion, and metastasis. This article discussed the intersection between extracellular signals and the transcriptional cascade that regulates adipocyte differentiation in order to appreciate the molecular pathways that have been described to drive adipocyte dedifferentiation. Moreover, recent studies on the mechanisms through which CAAs affect the progression of breast cancer were reviewed, including adipokine regulation, metabolic reprogramming, extracellular matrix remodeling, and immune cell modulation. An in-depth understanding of the complex vicious cycle between CAAs and breast cancer cells is crucial for designing novel strategies for new therapeutic interventions.

Association of Maternal Microbiota and Diet in Cord Blood Cytokine and Immunoglobulin Profiles.

Mothers confer natural passive immunization to their infants through the transplacental pathway during the gestation period. The objective of the present study was to establish at birth the maternal and cord plasma concentration and relationship of immunoglobulins (Igs), cytokines (CKs), and adipokines. In addition, the impact of the maternal microbiota and diet was explored. The plasma profile of these components was different between mothers and babies, with the levels of many CKs, IgM, IgG2a, IgE, IgA, and leptin significantly higher in mothers than in the cord sample. Moreover, the total Igs, all IgG subtypes, IgE, and the Th1/Th2 ratio positively correlated in the mother-infant pair. Maternal dietary components such as monounsaturated fatty acids-polyunsaturated fatty acids and fiber were positively associated with some immune factors such as IgA in cord samples. The microbiota composition clustering also influenced the plasma profile of some factors (i.e., many CKs, some Ig, and adiponectin). In conclusion, we have established the concentration of these immunomodulatory factors in the maternal-neonatal pair at birth, some positive associations, and the influence of maternal diet and the microbiota composition, suggesting that the immune status during pregnancy, in terms of CKs and Igs levels, can influence the immune status of the infant at birth.

Metabolic mediators determine the association of antinuclear antibody subtypes with specific clinical symptoms in systemic sclerosis.

PURPOSE: The aim of this study was to investigate the possible link between different types of systemic sclerosis-specific antinuclear antibodies, adipokines and endothelial molecules which were recently found to have a pathogenic significance in systemic sclerosis. MATERIALS/METHODS: Serum concentration of adiponectin, resistin, leptin, endothelin-1, fractalkine and galectin-3 were determined in the sera of patients with systemic sclerosis (n â€‹= â€‹100) and healthy controls (n â€‹= â€‹20) using ELISA. RESULTS: The following associations between antinuclear antibodies and increased serum concentrations were identified: anticentromere antibodies with endothelin-1 (p â€‹< â€‹0.0001; mean level in patients 2.21 vs control group 1.31 â€‹pg/ml), anti-topoisomerase I antibodies with fractalkine (p â€‹< â€‹0.0001; 3.68 vs 1.68 â€‹ng/ml) and galectin-3 (p â€‹= â€‹0.0010, 6.39 vs 3.26 â€‹ng/ml). Anti-RNA polymerase III antibodies were associated with increased resistin (p â€‹< â€‹0.0001; 15.13 vs 8.54 â€‹ng/ml) and decreased adiponectin (p â€‹< â€‹0.0001; 2894 vs 8847 â€‹ng/ml). CONCLUSION: In systemic sclerosis metabolic and vascular factors may serve as mediators between immunological abnormalities and non-immune driven clinical symptoms.

Obesity and immune status in children.

PURPOSE OF REVIEW: Childhood obesity, with persistent chronic inflammation, is a worldwide epidemic. Obesity causes dysregulation throughout the immune system, affecting the balance and levels of cytokines, adipokines, and innate and adaptive immune cells. The present review focuses on the impact of obesity on immune function in children: altering the baseline activation state of immune cells and affecting the ability of the host to combat pathogens and malignancy and respond appropriately to vaccination. RECENT FINDINGS: Obesity causes dysregulation of the immune system. Single-cell RNA-sequencing of adipose tissue and resident immune cells is quantifying the impact of obesity on the frequency of immune cell subsets and their states. The system-wide alterations in immune function in obesity are most evident upon perturbation, including the response to infection (e.g. increased risk of severe COVID-19 in the ongoing pandemic), vaccination, and malignancy. However, mechanistic research in pediatric obesity is limited and this impacts our ability to care for these children. SUMMARY: We must better understand baseline and perturbed immune health in obese children to determine how to account for altered frequency and function of humoral and cellular immune components in acute infection, during vaccine design and when considering therapeutic options for this complex, medically vulnerable group.

Impact of Helminth Infection on Metabolic and Immune Homeostasis in Non-diabetic Obesity.

Several epidemiological and immunological studies indicate a reciprocal association between obesity/metabolic syndrome and helminth infections. Numerous studies demonstrated that obesity is concomitant with chronic low-grade inflammation, which is marked by vital changes in cellular composition and function of adipose tissue. However, the effect of helminth infection on the homeostatic milieu in obesity is not well-understood. To determine the relationship between Strongyloides stercoralis (Ss) infection and obesity, we examined an array of parameters linked with obesity both before and at 6 months following anthelmintic treatment. To this end, we measured serum levels of pancreatic hormones, incretins, adipokines and Type-1, Type-2, Type-17, and other proinflammatory cytokines in those with non-diabetic obesity with (INF) or without Ss infection (UN). In INF individuals, we evaluated the levels of these parameters at 6 months following anthelmintic treatment. INF individuals revealed significantly lower levels of insulin, glucagon, C-peptide, and GLP-1 and significantly elevated levels of GIP compared to UN individuals. INF individuals also showed significantly lower levels of Type-1, Type-17 and other pro-inflammatory cytokines and significantly increased levels of Type-2 and regulatory cytokines in comparison to UN individuals. Most of these changes were significantly reversed following anthelmintic treatment. Ss infection is associated with a significant alteration of pancreatic hormones, incretins, adipokines, and cytokines in obese individuals and its partial reversal following anthelmintic treatment. Our data offer a possible biological mechanism for the protective effect of Ss infection on obesity.

COVID-19: Underlying Adipokine Storm and Angiotensin 1-7 Umbrella.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the third coronavirus leading to a global health outbreak. Despite the high mortality rates from SARS-CoV-1 and Middle-East respiratory syndrome (MERS)-CoV infections, which both sparked the interest of the scientific community, the underlying physiopathology of the SARS-CoV-2 infection, remains partially unclear. SARS-CoV-2 shares similar features with SARS-CoV-1, notably the use of the angiotensin conversion enzyme 2 (ACE2) as a receptor to enter the host cells. However, some features of the SARS-CoV-2 pandemic are unique. In this work, we focus on the association between obesity, metabolic syndrome, and type 2 diabetes on the one hand, and the severity of COVID-19 infection on the other, as it seems greater in these patients. We discuss how adipocyte dysfunction leads to a specific immune environment that predisposes obese patients to respiratory failure during COVID-19. We also hypothesize that an ACE2-cleaved protein, angiotensin 1-7, has a beneficial action on immune deregulation and that its low expression during the SARS-CoV-2 infection could explain the severity of infection. This introduces angiotensin 1-7 as a potential candidate of interest in therapeutic research on CoV infections.

Autoantibody Production in Obesity: Is There Evidence for a Link Between Obesity and Autoimmunity?

PURPOSE OF REVIEW: During the last decades, obesity and autoimmune disorders have shown a parallel significant rise in industrialized countries. This review aims at providing a comprehensive update of the relationship between the adipose tissue in obesity and autoimmune disorders, highlighting the underlying mechanisms with a particular emphasis on adipokines and pro-inflammatory cytokines, the impaired B cell activity, and the production of natural and pathogenic autoantibody repertoire in the context of obesity. RECENT FINDINGS: Obesity is related to a higher risk of rheumatoid arthritis, psoriasis and psoriatic arthritis, multiple sclerosis, and Hashimoto's thyroiditis, while it may promote inflammatory bowel disorders and type 1 diabetes mellitus. Interestingly, subjects with obesity present more severe forms of these autoimmune disorders as well as decreased therapeutic response. Both obesity and autoimmune disorders present elevated levels of leptin, resistin, and visfatin. Autoantibody production, a hallmark of autoimmune disorders, has been demonstrated in obese animal models and human subjects. Obesity results in deficiencies of the human self-tolerance mechanisms by promoting pro-inflammatory processes, reducing Bregs as well as Tregs, and the latter resulting in increased Th17 and Th1 cells, creating the perfect milieu for the development of autoimmune disorders. More mechanistic, animal, and clinical studies are required to delineate the exact mechanisms underlying auto-reactivity in obesity as well as the adipose-immune crosstalk for potential successful therapeutic strategies.

Biomarkers of vascular disease in diabetes: the adipose-immune system cross talk.

Experimental and clinical studies aimed at investigating the mechanism(s) underlying vascular complications of diabetes indicate that a great number of molecules are involved in the pathogenesis of these complications. Most of these molecules are inflammatory mediators or markers generated by immune or adipose tissue. Some of them, i.e. resistin and sortilin, have been shown to be involved in the cross talk between adipocytes and inflammatory cells. This interaction is an attractive area of research, particularly in type 2 diabetes and obesity. Other proteins, such as adiponectin and visfatin, appear to be more promising as possible vascular markers. In addition, some molecules involved in calcium/phosphorus metabolism, such as klotho and FGF23, have an involvement in the pathogenesis of diabetic vasculopathy, which appears to be dependent on the degree of vascular impairment. Inflammatory markers are a promising tool for treatment decisions while measuring plasma levels of adipokines, sortilin, Klotho and FGF23 in adequately sized longitudinal studies is expected to allow a more precise characterization of diabetic vascular disease and the optimal use of personalized treatment strategies.

Adipokines, Cardiovascular Risk, and Therapeutic Management in Obesity and Psoriatic Arthritis.

Psoriatic arthritis is a chronic inflammatory disease with skin and joint pathology as the dominant characteristics. Scientific evidence supports its systemic nature and relevant relationship with obesity, metabolic syndrome, and associated conditions. Metabolic syndrome and obesity share common signaling pathways with joint inflammation, reinforcing the idea that adipose tissue is a major contributor to disease development and severity. The adipose tissue is not a mere energy store but also an endocrine organ participating in the immune response. In the search for the best therapeutic strategy for a patient, we should appraise the adipose tissue as an endocrine and immune organ responsible for mild chronic inflammation. Today, our challenge is not only to achieve disease remission but to control the associated comorbidities as well. In light of the high prevalence of obesity in psoriatic arthritis patients and the importance of the adipose tissue in the development of chronic inflammation, we aimed to identify the most relevant articles in this regard published in English until June 2020 using the PubMed database. Search terms included psoriatic arthritis, in combination with metabolic syndrome, obesity, adipokines, cardiovascular disease, and treatment. This review summarizes the current evidence regarding the role of adipose tissue as an adipokine-secreting endocrine organ, discussing its influence on disease development and severity, and ultimately in meeting successful disease management.

Potential role of adipose tissue and its hormones in burns and critically III patients.

Obesity has become a world-wide pandemic and is considered a major risk factor for various diseases. Despite this, recent intriguing clinical observations have been made suggesting that being overweight has some advantages. Overweight and some obese patients were reported to have significantly lower all-cause mortality, described as the 'obesity paradox'. This phenomenon resulted in increased research aimed at investigating the influence of adipose tissue on outcomes of various clinical states including critical illness. In this review, we summarise research findings on the effect burn injury and trauma-related critical illness have on adipose tissue and discuss potential mechanisms by which adipose tissue influences outcomes in burn and other critically ill patients. Burn injury and critical illness influence adipose tissue functionally and morphologically, with circulating levels of fat derived hormones, adipokines, altered in patients following injury and/or critical illness. As adipokines regulate a variety of processes including inflammation and metabolism, this disruption in the adipokine axis may explain the obesity paradox phenomenon observed in critically ill patients. We conclude that further research on the influence of individual adipokines on prognosis in burn and critically ill patients and the mechanisms involved is required to increase understanding of their therapeutic potential.

Visfatin and Rheumatoid Arthritis: Pathogenetic Implications and Clinical Utility.

OBJECTIVE: Analysis and generalization of data related to visfatin involvement in the pathogenesis of inflammation at various stages of rheumatoid arthritis. DATA SYNTHESIS: Visfatin is an adipocytokine which has also been identified in non-adipose tissues. It influences directly on the maturation of B cells, which are involved in autoantibody production and T cell activation. Visfatin can promote inflammation via regulation of pro-inflammatory cytokines including TNF, IL-1ß and IL-6. The concentration of circulating visfatin in rheumatoid arthritis patients is higher compared to healthy individuals. Several studies suggest that visfatin level is associated with rheumatoid arthritis activity, and its elevation may precede clinical signs of the relapse. In murine collagen-induced arthritis, visfatin levels were also found to be elevated both in inflamed synovial cells and in joint vasculature. Visfatin blockers have been shown to confer fast and long-term attenuation of pathological processes; however, most of their effects are transient. Other factors responsible for hyperactivation of the immune system can participate in this process at a later stage. Treatment of rheumatoid arthritis with a combination of these blockers and inhibitors of other mediators of inflammation can potentially improve treatment outcomes compared to current therapeutic strategies. Recent advances in the treatment of experimental arthritis in mice as well as the application of emerging treatment strategies obtained from oncology for rheumatoid arthritis management could be a source of novel adipokine-mediated anti-rheumatic drugs. CONCLUSION: The ongoing surge of interest in anticytokine therapy makes further study of visfatin highly relevant as it may serve as a base for innovational RA treatment.

CXCL13 is a differentiation- and hypoxia-induced adipocytokine that exacerbates the inflammatory phenotype of adipocytes through PHLPP1 induction.

Hypoxia in adipose tissue is regarded as a trigger that induces dysregulation of the secretory profile in adipocytes. Similarly, local dysregulation of adipocytokine secretion is an initial event in the deleterious effects of obesity on metabolism. We previously reported that CXCL13 is highly produced during adipogenesis, however little is known about the roles of CXCL13 in adipocytes. Here, we found that hypoxia, as modeled by 1% O2 or exposure to the hypoxia-mimetic reagent desferrioxamine (DFO) has strong inductive effects on the expression of CXCL13 and CXCR5, a CXCL13 receptor, in both undifferentiated and differentiated adipocytes and in organ-cultured white adipose tissue (WAT). CXCL13 was also highly expressed in WAT from high fat diet-fed mice. Hypoxic profile, typified by increased expression of interleukin-6 (IL-6) and plasminogen activator inhibitor-1 (PAI-1) and decreased expression of adiponectin, was significantly induced by CXCL13 treatment during adipogenic differentiation. Conversely, the treatment of adipocytes with a neutralizing-antibody against CXCL13 as well as CXCR5 knockdown by specific siRNA effectively inhibited DFO-induced inflammation. The phosphorylation of Akt2, a protective factor of adipose inflammation, was significantly inhibited by CXCL13 treatment during adipogenic differentiation. Mechanistically, CXCL13 induces the expression of PHLPP1, an Akt2 phosphatase, through focal adhesion kinase (FAK) signaling; and correspondingly we show that CXCL13 and DFO-induced IL-6 and PAI-1 expression was blocked by Phlpp1 knockdown. Furthermore, we revealed the functional binding sites of PPARγ2 and HIF1-α within the Cxcl13 promoter. Taken together, these results indicate that CXCL13 is an adipocytokine that facilitates hypoxia-induced inflammation in adipocytes through FAK-mediated induction of PHLPP1 in autocrine and/or paracrine manner.