Role and mechanism of PVN-sympathetic-adipose circuit in depression and insulin resistance induced by chronic stress.

Chronic stress induces depression and insulin resistance, between which there is a bidirectional relationship. However, the mechanisms underlying this comorbidity remain unclear. White adipose tissue (WAT), innervated by sympathetic nerves, serves as a central node in the interorgan crosstalk through adipokines. Abnormal secretion of adipokines is involved in mood disorders and metabolic morbidities. We describe here a brain-sympathetic nerve-adipose circuit originating in the hypothalamic paraventricular nucleus (PVN) with a role in depression and insulin resistance induced by chronic stress. PVN neurons are labelled after inoculation of pseudorabies virus (PRV) into WAT and are activated under restraint stress. Chemogenetic manipulations suggest a role for the PVN in depression and insulin resistance. Chronic stress increases the sympathetic innervation of WAT and downregulates several antidepressant and insulin-sensitizing adipokines, including leptin, adiponectin, Angptl4 and Sfrp5. Chronic activation of the PVN has similar effects. ß-adrenergic receptors translate sympathetic tone into an adipose response, inducing downregulation of those adipokines and depressive-like behaviours and insulin resistance. We finally show that AP-1 has a role in the regulation of adipokine expression under chronic stress.

Single-Nucleus Transcriptomic Atlas of Human Pericoronary Epicardial Adipose Tissue in Normal and Pathological Conditions.

BACKGROUND: Pericoronary epicardial adipose tissue (EAT) is a unique visceral fat depot that surrounds the adventitia of the coronary arteries without any anatomic barrier. Clinical studies have demonstrated the association between EAT volume and increased risks for coronary artery disease (CAD). However, the cellular and molecular mechanisms underlying the association remain elusive. METHODS: We performed single-nucleus RNA sequencing on pericoronary EAT samples collected from 3 groups of subjects: patients undergoing coronary bypass surgery for severe CAD (n=8), patients with CAD with concomitant type 2 diabetes (n=8), and patients with valvular diseases but without concomitant CAD and type 2 diabetes as the control group (n=8). Comparative analyses were performed among groups, including cellular compositional analysis, cell type-resolved transcriptomic changes, gene coexpression network analysis, and intercellular communication analysis. Immunofluorescence staining was performed to confirm the presence of CAD-associated subclusters. RESULTS: Unsupervised clustering of 73 386 nuclei identified 15 clusters, encompassing all known cell types in the adipose tissue. Distinct subpopulations were identified within primary cell types, including adipocytes, adipose stem and progenitor cells, and macrophages. CD83high macrophages and FOSBhigh adipocytes were significantly expanded in CAD. In comparison to normal controls, both disease groups exhibited dysregulated pathways and altered secretome in the primary cell types. Nevertheless, minimal differences were noted between the disease groups in terms of cellular composition and transcriptome. In addition, our data highlight a potential interplay between dysregulated circadian clock and altered physiological functions in adipocytes of pericoronary EAT. ANXA1 (annexin A1) and SEMA3B (semaphorin 3B) were identified as important adipokines potentially involved in functional changes of pericoronary EAT and CAD pathogenesis. CONCLUSIONS: We built a complete single-nucleus transcriptomic atlas of human pericoronary EAT in normal and diseased conditions of CAD. Our study lays the foundation for developing novel therapeutic strategies for treating CAD by targeting and modifying pericoronary EAT functions.

Obesity-induced thymic involution and cancer risk.

Declining thymic functions associated either with old age (i.e., age-related thymic involution), or with acute involution as a result of stress, infectious disease, or cytoreductive therapies (e.g., chemotherapy/radiotherapy), have been associated with cancer development. A key mechanism underlying such increased cancer risk is the thymus-dependent debilitation of adaptive immunity, which is responsible for orchestrating immunoediting mechanisms and tumor immune surveillance. In the past few years, a blooming set of evidence has intriguingly linked obesity with cancer development and progression. The majority of such studies has focused on obesity-driven chronic inflammation, steroid/sex hormone and adipokine production, and hyperinsulinemia, as principal factors affecting the tumor microenvironment and driving the development of primary malignancy. However, experimental observations about the negative impact of obesity on T cell development and maturation have existed for more than half a century. Here, we critically discuss the molecular and cellular mechanisms of obesity-driven thymic involution as a previously underrepresented intermediary pathology leading to cancer development and progression. This knowledge could be especially relevant in the context of childhood obesity, because impaired thymic function in young individuals leads to immune system abnormalities, and predisposes to various pediatric cancers. A thorough understanding behind the molecular and cellular circuitries governing obesity-induced thymic involution could therefore help towards the rationalized development of targeted thymic regeneration strategies for obese individuals at high risk of cancer development.

Acylation stimulating protein/C3adesArg in the metabolic states: role of adipocyte dysfunction in obesity complications.

Adipose tissue, as an endocrine organ, secretes several adipocyte-derived hormones named 'adipokines' that are implicated in regulating energy haemostasis. Substantial evidence shows that white adipose tissue-derived adipokines mediate the link between obesity-related exogenous factors (like diet and lifestyle) and various biological events (such as pre- and postmenopausal status) that have obesity consequences (cardiometabolic disorders). One of the critical aetiological factors for obesity-related diseases is the dysfunction of adipokine pathways. Acylation-stimulating protein (ASP) is an adipokine that stimulates triglyceride synthesis and storage in adipose tissue by enhancing glucose and fatty acid uptake. ASP acts via its receptor C5L2. The primary objective of this review is to address the existing gap in the literature regarding ASP by investigating its diverse responses and receptor interactions across multiple determinants of obesity. These determinants include diet composition, metabolic disorders, organ involvement, sex and sex hormone levels. Furthermore, this article explores the broader paradigm shift from solely focusing on adipose tissue mass, which contributes to obesity, to considering the broader implications of adipose tissue function. Additionally, we raise a critical question concerning the clinical relevance of the insights gained from this review, both in terms of potential therapeutic interventions targeting ASP and in the context of preventing obesity-related conditions, highlighting the potential of the ASP-C5L2 interaction as a pharmacological target. In conclusion, these findings validate that obesity is a low-grade inflammatory status with multiorgan involvement and sex differences, demonstrating dynamic interactions between immune and metabolic response determinants.

Circulating Sex-Specific Markers of Plaque Instability in Women and Men With Severe Carotid Atherosclerosis.

BACKGROUND: Sex-specific differences in plaque composition and instability underscore the need to explore circulating markers for better prediction of high-risk plaques. This cross-sectional study aims to (1) investigate differences in lipid, immune, and adipokine circulating profiles between men and women with stable versus unstable plaques and (2) identify circulating markers that can better classify men and women according to plaque instability. METHODS: Preoperative blood samples and plaque specimens were collected from consecutive men and women with carotid artery stenosis ≥50% and who underwent a carotid endarterectomy between 2009 and 2018. Adipokine, lipid, and immune profiling was conducted. Plaque stability was determined by gold-standard histological classifications. Statistical analyses, including χ2, ANOVA, Kruskal-Wallis, and logistic regression, assessed differences in plaque features and blood parameters between men and women with stable and unstable plaques. RESULTS: Of 470 recruited patients (aged 70.8±9.2 years), the final study analyses included 317 men and 143 women (aged 71.0±9.0 years). Men exhibited more unstable plaques (P<0.001), characterized by increased plaque hemorrhage, larger lipid core, and inflammation (P<0.001), along with less favorable circulating profiles. Antagonistic interactions between sex and white blood cell (WBC) counts, basophil-to-WBC ratio, and platelet counts influenced plaque instability. In men, low WBC counts, high monocyte-to-WBC ratio, low basophil-to-WBC ratio, and high LDL-C (low-density lipoprotein cholesterol) levels were associated with greater plaque instability (odds ratio, 0.827 [95% CI, 0.713-0.926], 1.158 [95% CI, 1.027-1.305], 0.495 [95% CI, 0.281-0.871], and 1.564 [95% CI, 1.001-2.443], respectively) and more unstable features (ie, inflammation, foam cells, and neovascularization). In women, a high basophil-to-WBC ratio was associated with greater plaque instability (3.142 [95% CI, 1.220-8.093]), hemorrhage, and thrombosis, while a high molecular weight-to-total adiponectin ratio was associated with decreased instability (0.014 [95% CI, 0.000-0.646]) and inflammation. CONCLUSIONS: Our findings demonstrated sex-specific differences, with women displaying more stable plaque phenotypes and favorable circulating profiles compared with men. This proof-of-concept study was also designed as the key first step in exploring novel sex-specific associations between circulating lipid, immune, and adipokine profiles and carotid plaque instability.

Adipokine receptor expression in mast cells is altered by specific ligands and proinflammatory cytokines.

Adipokines play essential roles in regulating a range of biological processes, but growing evidence indicates that they are also fundamental in immunological mechanisms and, primarily, inflammatory responses. Adipokines mediate their actions through specific receptors. However, although adipokine receptors are widely distributed in many cell and tissue types, limited data are available on their expression in mast cells (MCs) and, consequently, adipokine's significance in the modulation of MC activity within the tissues. In this study, we demonstrate that rat peritoneal MCs constitutively express the leptin receptor (i.e. LEPR), adiponectin receptors (i.e. ADIPOR1 and ADIPOR2) and the chemerin receptor (i.e. CMKLR1). We also found that LEPR, ADIPOR1, ADIPOR2 and CMKLR1 expression in MCs changes in response to stimulation by their specific ligands and some cytokines with potent proinflammatory properties. Furthermore, the involvement of intracellular signaling molecules in leptin-, adiponectin- and chemerin-induced MC response was analyzed. Overall, our findings suggest that adipokines leptin, adiponectin and chemerin can significantly affect the activity of MCs in various processes, especially during inflammation. These observations may contribute significantly to understanding the relationship between adipokines, immune mechanisms and diseases or conditions with an inflammatory component.

The sex-dependent impact of adipose tissue and inflammation on chronic pain - A cross-sectional study from the all of us research program.

Emerging evidence suggests an association between chronic pain and elevated body fat. We sought to determine if individuals with higher body fat, measured by hip circumference (HC) and waist circumference (WC), are at risk for chronic pain when they demonstrate higher expression of inflammatory markers. We investigated the incidence and severity of pain in patients with varying WC/HC and inflammatory markers (C-Reactive Protein, IL-6, leptin) using the NIH-sponsored All of Us Database. For each inflammatory marker and sex, participants were divided into four groups based on combinations of normal/high marker levels and small/large WC/HC. We used statistical analysis to compare WC/HC and pain severity (mean NRS pain score) between groups of the same sex. In females, but not males, combinations of elevated CRP with large WC/HC exerted additive effects on the incidence of chronic pain (p < 0.01) and severe pain (p < 0.001), as well as on the severity of pain evaluated by the mean NRS pain score (p < 0.01). This relationship held true for females with high IL-6 or leptin and large WC or HC (p < 0.001 for chronic pain and severe pain incidence, and p < 0.05 for pain severity). Neither IL-6 nor leptin showed any significant impact on pain in males. Obesity status and CRP exert additive prognostic effects for chronic pain in females, but not in males. The concomitant evaluation of other inflammatory factors, such as IL-6 or leptin in females, may further augment the prediction of chronic pain. PERSPECTIVE: This article investigates the relationship between chronic pain, obesity, and inflammatory markers. It could help elucidating sex difference in pain mechanisms, as well as the risk factors for chronic pain, potentially improving patient diagnosis, follow-up and treatment.

Obesity, diabetes and risk of bone fragility: How BMAT behavior is affected by metabolic disturbances and its influence on bone health.

PURPOSE: Osteoporosis is a metabolic bone disease characterized by decreased bone strength and mass, which predisposes patients to fractures and is associated with high morbidity and mortality. Like osteoporosis, obesity and diabetes are systemic metabolic diseases associated with modifiable risk factors and lifestyle, and their prevalence is increasing. They are related to decreased quality of life, functional loss and increased mortality, generating high costs for health systems and representing a worldwide public health problem. Growing evidence reinforces the role of bone marrow adipose tissue (BMAT) as an influential factor in the bone microenvironment and systemic metabolism. Given the impact of obesity and diabetes on metabolism and their possible effect on the bone microenvironment, changes in BMAT behavior may explain the risk of developing osteoporosis in the presence of these comorbidities. METHODS: This study reviewed the scientific literature on the behavior of BMAT in pathological metabolic conditions, such as obesity and diabetes, and its potential involvement in the pathogenesis of bone fragility. RESULTS: Published data strongly suggest a relationship between increased BMAT adiposity and the risk of bone fragility in the context of obesity and diabetes. CONCLUSION: By secreting a broad range of factors, BMAT modulates the bone microenvironment and metabolism, ultimately affecting skeletal health. A better understanding of the relationship between BMAT expansion and metabolic disturbances observed in diabetic and obese patients will help to identify regulatory pathways and new targets for the treatment of bone-related diseases, with BMAT as a potential therapeutic target.

Adipo-oncology: adipocyte-derived factors govern engraftment, survival, and progression of metastatic cancers.

Conventional therapies for metastatic cancers have limited efficacy. Recently, cancer therapies targeting noncancerous cells in tumor microenvironments have shown improved clinical outcomes in patients. However, further advances in our understanding of the metastatic tumor microenvironment are required to improve treatment outcomes. Adipocytes are distributed throughout the body, and as a part of the metastatic tumor microenvironment, they interact with cancer cells in almost all organs. Adipocytes secrete various factors that are reported to exert clinical effects on cancer progression, including engraftment, survival, and expansion at the metastatic sites. However, only a few studies have comprehensively examined their impact on cancer cells. In this review, we examined the impact of adipocytes on cancer by describing the adipocyte-secreted factors that are involved in controlling metastatic cancer, focusing on adipokines, such as adiponectin, leptin, visfatin, chemerin, resistin, apelin, and omentin. Adipocyte-secreted factors promote cancer metastasis and contribute to various biological functions of cancer cells, including migration, invasion, proliferation, immune evasion, and drug resistance at the metastatic sites. We propose the establishment and expansion of "adipo-oncology" as a research field to enhance the comprehensive understanding of the role of adipocytes in metastatic cancers and the development of more robust metastatic cancer treatments.

Targeting Adipokines: A Promising Therapeutic Strategy for Epilepsy.

Epilepsy affects 65 million people globally and causes neurobehavioral, cognitive, and psychological defects. Although research on the disease is progressing and a wide range of treatments are available, approximately 30% of people have refractory epilepsy that cannot be managed with conventional medications. This underlines the importance of further understanding the condition and exploring cutting-edge targets for treatment. Adipokines are peptides secreted by adipocyte's white adipose tissue, involved in controlling food intake and metabolism. Their regulatory functions in the central nervous system (CNS) are multifaceted and identified in several physiology and pathologies. Adipokines play a role in oxidative stress and neuroinflammation which are associated with brain degeneration and connected neurological diseases. This review aims to highlight the potential impacts of leptin, adiponectin, apelin, vaspin, visfatin, and chimerin in the pathogenesis of epilepsy.

Ischemic Heart-Derived Small Extracellular Vesicles Impair Adipocyte Function.

BACKGROUND: Patients with acute myocardial infarction suffer systemic metabolic dysfunction via incompletely understood mechanisms. Adipocytes play critical role in metabolic homeostasis. The impact of acute myocardial infarction upon adipocyte function is unclear. Small extracellular vesicles (sEVs) critically contribute to organ-organ communication. Whether and how small extracellular vesicle mediate post-MI cardiomyocyte/adipocyte communication remain unknown. METHODS: Plasma sEVs were isolated from sham control (Pla-sEVSham) or 3 hours after myocardial ischemia/reperfusion (Pla-sEVMI/R) and incubated with adipocytes for 24 hours. Compared with Pla-sEVSham, Pla-sEVMI/R significantly altered expression of genes known to be important in adipocyte function, including a well-known metabolic regulatory/cardioprotective adipokine, APN (adiponectin). Pla-sEVMI/R activated 2 (PERK-CHOP and ATF6 [transcription factor 6]-EDEM [ER degradation enhancing alpha-mannosidase like protein 1] pathways) of the 3 endoplasmic reticulum (ER) stress pathways in adipocytes. These pathological alterations were also observed in adipocytes treated with sEVs isolated from adult cardiomyocytes subjected to in vivo myocardial ischemia/reperfusion (MI/R) (Myo-sEVMI/R). Bioinformatic/RT-qPCR analysis demonstrates that the members of miR-23-27-24 cluster are significantly increased in Pla-sEVMI/R, Myo-sEVMI/R, and adipose tissue of MI/R animals. Administration of cardiomyocyte-specific miR-23-27-24 sponges abolished adipocyte miR-23-27-24 elevation in MI/R animals, supporting the cardiomyocyte origin of adipocyte miR-23-27-24 cluster. In similar fashion to Myo-sEVMI/R, a miR-27a mimic activated PERK-CHOP and ATF6-EDEM-mediated ER stress. Conversely, a miR-27a inhibitor significantly attenuated Myo-sEVMI/R-induced ER stress and restored APN production. RESULTS: An unbiased approach identified EDEM3 (ER degradation enhancing alpha-mannosidase like protein 3) as a novel downstream target of miR-27a. Adipocyte EDEM3 deficiency phenocopied multiple pathological alterations caused by Myo-sEVMI/R, whereas EDEM3 overexpression attenuated Myo-sEVMI/R-resulted ER stress. Finally, administration of GW4869 or cardiomyocyte-specific miR-23-27-24 cluster sponges attenuated adipocyte ER stress, improved adipocyte endocrine function, and restored plasma APN levels in MI/R animals. CONCLUSIONS: We demonstrate for the first time that MI/R causes significant adipocyte ER stress and endocrine dysfunction by releasing miR-23-27-24 cluster-enriched small extracellular vesicle. Targeting small extracellular vesicle-mediated cardiomyocyte-adipocyte pathological communication may be of therapeutic potential to prevent metabolic dysfunction after MI/R.

Targeting Adiponectin Receptor 1 Phosphorylation Against Ischemic Heart Failure.

BACKGROUND: Despite significantly reduced acute myocardial infarction (MI) mortality in recent years, ischemic heart failure continues to escalate. Therapeutic interventions effectively reversing pathological remodeling are an urgent unmet medical need. We recently demonstrated that AdipoR1 (APN [adiponectin] receptor 1) phosphorylation by GRK2 (G-protein-coupled receptor kinase 2) contributes to maladaptive remodeling in the ischemic heart. The current study clarified the underlying mechanisms leading to AdipoR1 phosphorylative desensitization and investigated whether blocking AdipoR1 phosphorylation may restore its protective signaling, reversing post-MI remodeling. METHODS: Specific sites and underlying molecular mechanisms responsible for AdipoR1 phosphorylative desensitization were investigated in vitro (neonatal and adult cardiomyocytes). The effects of AdipoR1 phosphorylation inhibition upon APN post-MI remodeling and heart failure progression were investigated in vivo. RESULTS: Among 4 previously identified sites sensitive to GRK2 phosphorylation, alanine substitution of Ser205 (AdipoR1S205A), but not other 3 sites, rescued GRK2-suppressed AdipoR1 functions, restoring APN-induced cell salvage kinase activation and reducing oxidative cell death. The molecular investigation followed by functional determination demonstrated that AdipoR1 phosphorylation promoted clathrin-dependent (not caveolae) endocytosis and lysosomal-mediated (not proteasome) degradation, reducing AdipoR1 protein level and suppressing AdipoR1-mediated cytoprotective action. GRK2-induced AdipoR1 endocytosis and degradation were blocked by AdipoR1S205A overexpression. Moreover, AdipoR1S205E (pseudophosphorylation) phenocopied GRK2 effects, promoted AdipoR1 endocytosis and degradation, and inhibited AdipoR1 biological function. Most importantly, AdipoR1 function was preserved during heart failure development in AdipoR1-KO (AdipoR1 knockout) mice reexpressing hAdipoR1S205A. APN administration in the failing heart reversed post-MI remodeling and improved cardiac function. However, reexpressing hAdipoR1WT in AdipoR1-KO mice failed to restore APN cardioprotection. CONCLUSIONS: Ser205 is responsible for AdipoR1 phosphorylative desensitization in the failing heart. Blockade of AdipoR1 phosphorylation followed by pharmacological APN administration is a novel therapy effective in reversing post-MI remodeling and mitigating heart failure progression.

Adipokines as potential pharmacological targets for immune inflammatory rheumatic diseases: Focus on rheumatoid arthritis, osteoarthritis, and intervertebral disc degeneration.

Adipokines are a heterogeneous group of signalling molecules secreted prevalently by adipose tissue. Initially considered as regulators of energy metabolism and appetite, adipokines have been recognized for their substantial involvement in musculoskeletal disorders, including osteoarthritis, rheumatoid arthritis, and many others. Understanding the role of adipokines in rheumatic inflammatory and autoimmune diseases, as well as in other musculoskeletal diseases such as intervertebral disc degeneration, is crucial for the development of novel therapeutic strategies. Targeting adipokines, or their signalling pathways, may offer new opportunities for the treatment and management of these conditions. By modulating adipokines levels or activity, it may be possible to regulate inflammation, to maintain bone health, and preserve muscle mass, thereby improving the outcomes and quality of life for individuals affected by musculoskeletal diseases. The aim of this review article is to update the reader on the multifaceted role of adipokines in the main rheumatic diseases such as osteoarthritis and rheumatoid arthritis and to unravel the complex interplay among adipokines, cartilage metabolism, bone remodelling and muscles, which will pave the way for innovative therapeutic intervention in the future. For completeness, the role of adipokines in intervertebral disc degeneration will be also addressed.

Role of leptin and adiponectin in the pathogenesis of post-transplant diabetes mellitus.

Solid organ transplantation is a life-saving treatment for patients with end-stage organ failure, but it poses unique challenges due to metabolic and immunological changes in recipients. One significant complication is post-transplant diabetes mellitus (PTDM), which affects a variety of solid organ recipients. Leptin, a hormone produced by adipose tissue, regulates appetite and affects glucose metabolism. High leptin levels are associated with the development of PTDM, especially in kidney transplant recipients. Adiponectin, another adipokine, increases insulin sensitivity and has anti-diabetic properties. Low adiponectin levels are associated with insulin resistance and increase the risk of PTDM. As the incidence of PTDM increases due to the increased life expectancy among transplant patients, understanding the role of adipokines such as leptin and adiponectin becomes crucial for early detection and treatment. Additional studies on other adipokines may also provide valuable information on the pathogenesis of PTDM.

The role of adiposity, adipokines and polymorphisms of leptin and adiponectin in myelodysplastic syndromes.

The aim of the present study was to investigate the relationship between leptin and adiponectin gene polymorphisms, circulating levels of leptin and adiponectin, adiposity and clinical markers in patients with myelodysplastic syndrome (MDS). This cross-sectional study was conducted with 102 adults and elderly MDS patients and 102 age- and sex-matched controls. Clinical characteristics, co-morbidities, anthropometric data, laboratory evaluation and genetic analysis (polymorphisms -2548G > A/rs7799039 of the LEP gene and +276G > T/rs1501299 of the ADIPOQ gene) were investigated. Serum leptin was higher and adiponectin lower in MDS when compared with controls. There was a significant positive correlation between serum leptin levels and BMI (r = 0·264, P = 0·025), waist circumference (r = 0·235, P = 0·047), body fat percentage (BF %) (r = 0·373, P = 0·001) and the fat mass index (FMI) (r = 0·371, P < 0·001). A lower mean adiponectin was found among patients with high BF %, higher visceral adiposity index and metabolic syndrome. A significant association was found between the AA genotype (mutant) of the LEP polymorphism rs7799039 and male sex and blast excess (≥ 5 %). In addition, a significant association was observed between the TT genotype (mutant) of the ADIPOQ rs1501299 polymorphism and Fe overload. These results demonstrate the importance of a comprehensive and systematic evaluation in patients with MDS in order to identify and control negative factors not related to the disease at an early stage.

Predictive value of adipokines for the severity of acute pancreatitis: a meta-analysis.

BACKGROUND: Severe acute pancreatitis (SAP) is a dangerous condition with a high mortality rate. Many studies have found an association between adipokines and the development of SAP, but the results are controversial. Therefore, we performed a meta-analysis of the association of inflammatory adipokines with SAP. METHODS: We screened PubMed, EMBASE, Web of Science and Cochrane Library for articles on adipokines and SAP published before July 20, 2023. The quality of the literature was assessed using QUADAS criteria. Standardized mean differences (SMD) with 95% confidence intervals (CI) were calculated to assess the combined effect. Subgroup analysis, sensitivity analysis and publication bias tests were also performed on the information obtained. RESULT: Fifteen eligible studies included 1332 patients with acute pancreatitis (AP). Pooled analysis showed that patients with SAP had significantly higher serum levels of resistin (SMD = 0.78, 95% CI:0.37 to 1.19, z = 3.75, P = 0.000). The difference in leptin and adiponectin levels between SAP and mild acute pancreatitis (MAP) patients were not significant (SMD = 0.30, 95% CI: -0.08 to 0.68, z = 1.53, P = 0.127 and SMD = 0.11, 95% CI: -0.17 to 0.40, z = 0.80, P = 0.425, respectively). In patients with SAP, visfatin levels were not significantly different from that in patients with MAP (SMD = 1.20, 95% CI: -0.48 to 2.88, z = 1.40, P = 0.162). CONCLUSION: Elevated levels of resistin are associated with the development of SAP. Resistin may serve as biomarker for SAP and has promise as therapeutic target.

Impact of siRNA-Mediated Cofilin-1 Knockdown and Obesity Associated Microenvironment on the Motility of Natural Killer Cells.

The anti-tumor capacity of natural killer (NK) cells heavily relies on their ability to migrate towards their target cells. This process is based on dynamic actinrearrangement, so-called actin treadmilling, andis tightly regulated by proteins such as cofilin-1. The aim of the present study was to identify the role of cofilin-1 (CFL-1) in the migratory behavior of NK cells and to investigate a possible impact of an obesity-associated micromilieu on these cells, as it is known that obesity correlates with various impaired NK cell functions. CFL-1 was knocked-down via transfection of NK-92 cells with respective siRNAs. Obesity associated micromilieu was mimicked by incubation of NK-92 cells with adipocyte-conditioned medium from human preadipocyte SGBS cells or leptin. Effects on CFL-1 levels, the degree of phosphorylation to the inactive pCFL-1 as well as NK-92 cell motility were analyzed. Surprisingly, siRNA-mediated CFL-1 knockdown led to a significant increase of migration, as determined by enhanced velocity and accumulated distance of migration. No effect on CFL-1 nor pCFL-1 expression levels, proportion of phosphorylation and cell migratory behavior could be demonstrated under the influence of an obesity-associated microenvironment. In conclusion, the results indicate a significant effect of a CFL-1 knockdown on NK cell motility.

The effect of niacin on inflammatory markers and adipokines: a systematic review and meta-analysis of interventional studies.

PURPOSE: Niacin (nicotinic acid), known for its lipid-modifying effects, has been explored for its potential anti-inflammatory properties and potential to affect adipokines secretion from adipose tissue. The aim of this systematic review and meta-analysis was to assess the effects of niacin on inflammatory markers and adipokines. METHODS: A comprehensive search was conducted across five databases: PubMed, Scopus, Cochrane Library, Embase, and ISI Web of Science. Randomized controlled trials exploring the effects of niacin on inflammatory markers (CRP, IL-6, TNF-α) and adipokines (Adiponectin, Leptin) were included. Pooled effect sizes were analysed using a random-effects model, and additional procedures including subgroup analyses, sensitivity analysis and dose-response analysis were also performed. RESULTS: From an initial 1279 articles, fifteen randomized controlled trials (RCTs) were included. Niacin administration demonstrated a notable reduction in CRP levels (SMD: -0.88, 95% CI: -1.46 to -0.30, p = 0.003). Subgroup analyses confirmed CRP reductions in trials with intervention durations ≤ 24 weeks, doses ≤ 1000 mg/day, and elevated baseline CRP levels (> 3 mg/l). The meta-analysis of IL-6 and TNF-α revealed significant TNF-α reductions, while IL-6 reduction did not reach statistical significance. Niacin administration also substantially elevated Adiponectin (SMD: 3.52, 95% CI: 0.95 to 6.1, p = 0.007) and Leptin (SMD: 1.90, 95% CI: 0.03 to 3.77, p = 0.04) levels. CONCLUSION: Niacin treatment is associated with significant reductions in CRP and TNF-α levels, suggesting potential anti-inflammatory effects. Additionally, niacin positively influences adipokines, increasing Adiponectin and Leptin levels. These findings provide insights for future research and clinical applications targeting inflammation and metabolic dysregulation.

Longitudinal associations between vitamin D status and biomarkers of inflammation in a pan-European cohort of children and adolescents.

PURPOSE: To investigate longitudinal associations between the vitamin D status and inflammatory markers in children and adolescents. METHODS: Children from eight European countries from the IDEFICS/I.Family cohort with repeated measurements were included in this study. A linear mixed-effect model was used to model the association of serum 25(OH)D as independent variable and z-scores of inflammatory markers [CRP, cytokines, adipokines, combined inflammation score] as dependent variables, where one level accounts for differences between individuals and the other for changes over age within individuals. RESULTS: A total of 1,582 children were included in the study. In the adjusted model, 25(OH)D levels were positively associated with adiponectin (ß = 0.11 [95% CI 0.07; 0.16]) and negatively with the inflammation score (ß = - 0.24 [95% CI - 0.40; - 0.08]) indicating that the adiponectin z-score increased by 0.11 units and the inflammation score decreased by 0.24 units per 12.5 nmol/l increase in 25(OH)D. In children with overweight or obesity, only a positive association between 25(OH)D and IP-10 was observed while in children with normal weight adiponectin was positively and the inflammation score was negatively associated. Associations of vitamin D with adiponectin and the inflammation score were stronger in girls than in boys and a positive association with TNF-α was observed only in girls. CONCLUSION: Our results suggest that an increase in vitamin D concentrations may help to regulate inflammatory biomarkers. However, it seems to be no benefit of a better vitamin D status in children with overweight/obesity unless their weight is managed to achieve an improved inflammatory marker status.

Circulating leptin in patients with nonalcoholic fatty liver disease-related liver fibrosis: a systematic review and a meta-analysis.

BACKGROUND AND AIM: Clinical data on the association between leptin levels and nonalcoholic fatty liver disease (NAFLD)-related liver fibrosis are conflicting. This meta-analysis aimed to compare circulating leptin between NAFLD patients with versus without liver fibrosis or non-NAFLD controls. METHODS: A systematic search was conducted in PubMed, Scopus, and the Cochrane Library. Fifteen studies were included, reporting data from 964 individuals (422 NAFLD patients with fibrosis, 297 NAFLD patients without fibrosis, 245 no-NAFLD controls). RESULTS: Leptin standardized mean difference (SMD) was higher in NAFLD patients with fibrosis (F1-F4) than in controls (SMD: 2.27; 95% confidence interval [CI]: 0.81-3.73); however, this association did not remain robust after the exclusion of studies with morbidly obese individuals. No difference was observed in leptin SMD between NAFLD patients with fibrosis and those without fibrosis (F0), and NAFLD patients without fibrosis versus controls. Heterogeneity was high (I2: 66-98%) among studies. Meta-regression analysis revealed a positive association of leptin SMD with homeostasis model assessment-insulin resistance, when comparing NAFLD patients with fibrosis versus NAFLD patients without fibrosis (beta: 0.53; 95% CI: 0.04-1.03), and a negative association of leptin SMD with age, when comparing NAFLD patients with fibrosis versus controls (beta: -0.29; 95% CI: -0.53 to -0.05). CONCLUSION: Circulating leptin was higher in NAFLD patients with liver fibrosis than non-NAFLD controls, an association, however, attenuated after the exclusion of a study with morbidly obese individuals. Circulating leptin was not different between NAFLD patients with and without fibrosis, or NAFLD patients without fibrosis and controls.