Numerous studies have reported an association between neutrophils and type 2 diabetes mellitus (T2DM), although this relationship remains unclear.

To investigate the interaction of neutrophils and a dietary intervention on T2DM incidence after 60 months of follow-up.

A comprehensive analysis was conducted on the framework of the CORDIOPREV study, which included 462 patients without T2DM at the beginning of the study, randomly assigned to either a Mediterranean or a low-fat diet; 107 developed T2DM. Absolute neutrophil counts and neutrophil-related ratios were measured.

Kaplan-Meier curves showed that the lowest tertile of basal neutrophils was associated with a reduced likelihood of T2DM incidence when compared to the middle (hazard ratio [HR] = 0.499 [95% CI, 0.287-0.866]) and the highest tertiles (HR = 0.442 [95% CI, 0.255-0.768]) in the overall population, after adjusting for clinical variables. This association only remained significant in patients who followed a Mediterranean diet when comparing the lowest to the middle (HR = 0.423 [95% CI, 0.213-0.842]) and the highest tertiles (HR = 0.371 [95% CI, 0.182-0.762]). The predictive capacity yielded an AUC of 0.711 (95% CI, 0.652-0.769), with neutrophils being the most important variable in the in the model. Decrease in neutrophils over the 60 months was associated with increased insulin sensitivity index (R = -0.31; P = .019), particularly in patients who followed the Mediterranean diet.

These findings suggest that monitoring neutrophils can help prevent the development of T2DM, as a reduction in neutrophil counts could be associated with improved insulin sensitivity. Following a Mediterranean diet might be a potential strategy to reduce the incidence of T2DM by lowering neutrophil levels. Further research is necessary to gain a deeper understanding regarding this mechanism.

Adipose tissue (AT) is a complex connective tissue with a high relative proportion of adipocytes, which are specialized cells with the ability to store lipids in large droplets. AT is found in multiple discrete depots throughout the body, where it serves as the primary repository for excess calories. In addition, AT has an important role in functions as diverse as insulation, immunity and regulation of metabolic homeostasis. The Human Cell Atlas Adipose Bionetwork was established to support the generation of single-cell atlases of human AT as well as the development of unified approaches and consensus for cell annotation. Here, we provide a first roadmap from this bionetwork, including our suggested cell annotations for humans and mice, with the aim of describing the state of the field and providing guidelines for the production, analysis, interpretation and presentation of AT single-cell data.

Neutrophil dysregulation is implicated in a spectrum of inflammatory pathologies, suggesting the potential for targeting neutrophilic hyperactivation as a pharmacological strategy to manage inflammatory disorders. Building upon prior research where 2-thiolphenoxychromone derivatives were found to inhibit neutrophilic generation of superoxide anions, this study focused on exploring the structure-activity relationship (SAR) of different C2 bridging moieties and anti-inflammatory effects using bioisosteric replacements and scaffold-hopping approaches. Among various chemotypes, the N-(4-oxo-4H-chromen-2-yl)benzenesulfonamide derivatives emerged as robust inhibitors of both superoxide anion generation and elastase release from fMLF-activated human neutrophils, with IC50 values in the single-digit micromolar range. Leveraging a forward pharmacology approach through computational prediction, compound 15b, a representative within this active molecular class, was discovered to exert these anti-inflammatory functions by blocking the p38α mitogen-activated protein kinase (MAPK) signaling cascade. This responded to a significant reduction in p38α MAPK and its downstream MK2 phosphorylation in activated neutrophils treated with 15b, with no apparent impact on extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and protein kinase B (AKT) phosphorylation levels. Additionally, this molecule exhibited inhibitory potential on intracellular reactive oxygen species (ROS) production, granule exocytosis, and chemotactic responses. Collectively, this study provides a novel skeleton for the development of inhibitors targeting the p38α MAPK pathway to mitigate neutrophilic inflammation.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a series of obesity-related metabolic liver diseases, ranging from relatively benign hepatic steatosis to metabolic-associated steatohepatitis (MASH). With the changes in lifestyle, its incidence and prevalence have risen to epidemic proportions globally. In recent years, an increasing amount of evidence has indicated that the hepatic microenvironment is involved in the pathophysiological processes of MASH-induced liver fibrosis and the formation of hepatocellular carcinoma (HCC). The hepatic microenvironment is composed of various parenchymal and non-parenchymal cells, which communicate with each other through various factors. In this review, we focus on the changes in hepatocytes, cholangiocytes, liver sinusoidal endothelial cells (LSECs), hepatic stellate cells (HSCs), Kupffer cells (KC), dendritic cells (DC), neutrophils, monocytes, T and B lymphocytes, natural killer cells (NK), natural killer T cells (NKT), mucosal-associated invariant T cells (MAIT), γδT cells, and gut microbiota during the progression of MASLD. Furthermore, we discuss promising therapeutic strategies targeting the microenvironment of MASLD-MASH-HCC.

Chronic inflammatory diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), atherosclerosis, and inflammatory bowel disease (IBD), pose major global health concerns. These disorders are marked by persistent inflammation, immune system dysfunction, tissue injury, and fibrosis, ultimately leading to severe organ dysfunction and diminished quality of life. Osteopontin (OPN), a multifunctional extracellular matrix protein, plays a crucial role in immune regulation, inflammation, and tissue remodeling. It promotes immune cell recruitment, stimulates pro-inflammatory cytokine production, and contributes to fibrosis through interactions with integrins and CD44 receptors. Additionally, OPN activates key inflammatory pathways, including NF-κB, MAPK, and PI3K/Akt, further aggravating tissue damage in chronic inflammatory conditions. Our review highlights the role of OPN in chronic inflammation, its potential as a biomarker, and its therapeutic implications. We explore promising preclinical approaches, such as monoclonal antibodies, small molecule inhibitors, and natural compounds like curcumin, which have demonstrated potential in mitigating OPN-driven inflammation. However, challenges persist in selectively targeting OPN while maintaining its essential physiological roles, including bone remodeling and wound healing. Our review offers insights into therapeutic strategies and future research directions.

Background: Polycystic ovary syndrome (PCOS) is a leading cause of infertility but also a metabolic disorder, frequently associated with obesity, insulin resistance, and diabetes. However, its etiology remains inadequately understood. Recent studies have increasingly implicated neutrophil extracellular traps (NETs) in the pathogenesis of metabolic diseases. Methods: Serum and follicular fluid samples were collected from patients with PCOS and control populations to assess NETs levels. The effects of NETs were investigated using DNase I to reduce NETs in dehydroepiandrosterone sulfate (DHEAS)-induced PCOS rats. Metabolic differences were further analyzed by untargeted metabolomics, and in vitro studies were conducted using primary bone marrow-derived neutrophils and normal mouse liver cell lines. Results: Markers of NETs in both the serum and follicular fluid of patients with PCOS were significantly higher than those in the control group. PCOS rats treated with DNase I exhibited significant improvements in glucose metabolism. Untargeted metabolomics analysis of liver tissue from these rats revealed alterations in the glycolysis pathway. Subsequent in vitro experiments demonstrated that treatment with NETs-conditioned medium (NETs CM) led to reduced insulin sensitivity, glucose uptake, and glucose utilization in liver cells, accompanied by varying degrees of decline in the transcription, translation, and function of glycolysis pathway proteins. Conclusions: NETs may be involved in the regulation of insulin resistance pathogenesis in PCOS by downregulating glycolytic pathways in the liver. Our study offers a novel strategy for insulin resistance intervention in PCOS.

White adipose tissue (WAT) is highly flexible and was previously considered a passive location for energy storage. Its endocrine function has been established for several years, earning it the title of an "endocrine organ" due to its ability to secrete many adipokines that regulate metabolism. WAT is one of the core tissues that influence insulin sensitivity. Its dysfunction enhances insulin resistance and type 2 diabetes (T2D) progression. However, T2D may cause WAT dysfunction, including changes in distribution, metabolism, adipocyte hypertrophy, inflammation, aging, and adipokines and free fatty acid levels, which may exacerbate insulin resistance. This review used PubMed to search WAT dysfunction in T2D and the effects of these changes on insulin resistance. Additionally, we described and discussed the effects of antidiabetic drugs, including insulin therapy, sulfonylureas, metformin, glucose-like peptide-1 receptor agonists, thiazolidinediones, and sodium-dependent glucose transporters-2 inhibitors, on WAT parameters under T2D conditions.

Neutrophils interact with and activate fibroblasts through the release of neutrophil extracellular traps (NETs). We investigated the role of NETs-fibroblast crosstalk in the cutaneous wound healing of type 2 diabetes (T2D). Neutrophils/NETs, serum, and primary human skin fibroblasts (HSFs) were obtained from individuals with T2D and age/sex-matched controls. NET-stimulation studies were performed on neutrophils/HSFs, with and without specific inhibitors, while HSF healing capacity was assessed using a scratch wound healing assay. T2D HSFs display a profibrotic phenotype, showing increased CCN2/CTGF, α-smooth muscle actin, and collagen release, albeit with impaired healing capacity, elevated type I collagen C-terminal telopeptide, and collagen degradation associated with increased (∼3.5-fold) matrix metalloproteinase-9 (MMP-9) in T2D neutrophils/NETs. IL-8 induced the expression of MMP-9 in neutrophils/NETs. Moreover, T2D neutrophils/NETs exhibited increased IL-8 content, which acted in an autocrine/paracrine fashion to further augment its production by neutrophils/HSFs. The findings were validated in normoglycemic individuals during a hyperglycemic clamp with concomitant lipid infusion and further corroborated immunohistochemically in diabetic plantar ulcer biopsies. This novel, vicious circle of NETs/interleukin-8/MMP-9/HSFs was hindered by IL-8 or MMP-9 blockade via specific inhibitors or by dismantling the NET-scaffold with DNase I, suggesting candidate therapeutic targets in wound healing impairment of T2D.

The prevalence of obesity and metabolic diseases have risen significantly over the past decades. Chronic inflammation in obesity is a link between obesity and secondary disease. While macrophages and monocytes are known to contribute to metabolic disease risk during diet exposure, little is known about the contribution of neutrophils. We assessed the impact of obesity on neutrophils using a 16-week model of diet-induced obesity. Bone marrow (BM) neutrophils significantly expanded with chronic high-fat diet (HFD), significantly decreased TNFɑ protein release, and impaired neutrophil regenerative function compared to normal diet (ND) neutrophils. scRNAseq and flow cytometry demonstrated HFD neutrophil heterogeneity and validated that these cells do not have elevated expression of proinflammatory genes without secondary stimulation. HFD neutrophils showed elevated expression of genes associated with lipid metabolism-acyl-CoA thioesterase 1 (Acot1), carnitine palmitoyltransferase 1a (Cpt1a), and perilipin 2 (Plin2). Consistent with the importance of lipid metabolism in driving dysfunction, neutrophils from HFD-fed animals and neutrophils treated with palmitate had impaired bacterial phagocytosis and killing responses. These data shed light on the complex regulation of intracellular lipids and the role of metabolism on neutrophil function during homeostasis and disease.

Gut microbiota is reported to be related to the onset of insulin resistance (IR) and type 2 diabetes mellitus (T2DM). The dietary index for gut microbiota (DI-GM) is a novel index for reflecting gut microbiota diversity. We aimed to evaluate the association of DI-GM with T2DM and IR.

This cross-sectional research comprised 10,600 participants aged ≥20 from the National Health and Nutrition Examination Survey (NHANES) 2007-2018. We employed weighted multivariable linear and logistic regression models to examine the correlation of DI-GM with T2DM and IR. Linear or nonlinear relationships were examined by restricted cubic spline (RCS) regression. Additionally, subgroup and sensitivity analyses were performed to ensure the reliability of the results. Mediation analysis explored the roles of body mass index (BMI) and inflammatory factors in these associations.

Higher DI-GM were inversely associated with T2DM (OR = 0.93, 95%CI: 0.89-0.98) and IR (OR = 0.95, 95%CI: 0.91-0.99) after adjusting for confounders. DI-GM ≥ 6 group showed significantly lower risks of T2DM (OR = 0.74, 95%CI: 0.60-0.91) and IR (OR = 0.77, 95%CI: 0.62-0.95). RCS demonstrated a linear relationship between DI-GM and T2DM, as well as IR. DI-GM was also inversely correlated with the risk markers of T2DM. Mediation analysis showed that BMI and the systemic inflammation response index partly mediated the association of DI-GM with T2DM and IR, while the systemic immune-inflammation index mediated only the association with T2DM.

DI-GM is inversely associated with T2DM and IR, with BMI and inflammatory markers partly mediating this association.

The liver has critical digestive, metabolic, and immunosurveillance roles, which get disrupted during liver diseases such as viral hepatitis, fatty liver disease, and hepatocellular carcinoma. While previous research on the pathological development of these diseases has focused on liver-resident immune populations, such as Kupffer cells, infiltrating immune cells responding to pathogens and disease also play crucial roles. Neutrophils are one such key population contributing to hepatic inflammation and disease progression. Belonging to the initial waves of immune response to threats, neutrophils suppress bacterial and viral spread during acute infections and have homeostasis-restoring functions, whereas during chronic insults, they display their plastic nature by responding to the inflammatory environment and develop new phenotypes alongside longer life spans. This review summarizes the diversity in neutrophil function and subpopulations present at steady state, during liver disease, and during liver cancer.

The aim of this study is to evaluate and compare the suitability of routine blood neutrophil values as indicators of obesity-associated inflammation.

In this systematic review and meta-analysis, we assess absolute neutrophil counts (ANCs) and neutrophil-to-lymphocyte ratio (NLR) values in subjects with and without obesity and analyze the weight of both parameters on the disease. Additionally, correlation studies between ANC and NLR with BMI, a parameter internationally accepted to define obesity are performed.

Quantitative data from 12 (ANC) and 11 (NLR) studies were included, with a total of 4475 participants. The meta-analysis shows that while both parameters are increased in the obesity group, ANC values present higher differences with the control and less heterogeneity among studies. Additionally, unlike NLR, ANC demonstrates a positive and significant correlation with BMI.

Overall, this meta-analysis demonstrates that ANC is a more reliable and stable parameter than NLR for the assessment of obesity-related inflammation, which offers clinicians a novel tool to assist in preventing complications related to obesity.

Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) and its progressive form, Metabolic Dysfunction Associated Steatohepatitis (MASH), represent significant health concerns associated with the metabolic syndrome. These conditions are characterized by excessive hepatic fat accumulation, inflammation, and potential progression to cirrhosis and hepatocellular carcinoma. Neutrophils are innate immune cells that play a pivotal role in the development of MASLD and MASH. They can infiltrate the hepatic microenvironment in response to inflammatory cytokines and damage associated molecular patterns (DAMPs) derived from the liver and exacerbate tissue damage by releasing of reactive oxygen species (ROS), cytokines, and neutrophil extracellular traps (NETs). Moreover, neutrophils can disrupt the metabolism of hepatocytes through key factors such as neutrophil elastase (NE) and human neutrophil peptides-1 (HNP-1), leading to inflammation and fibrosis, while myeloperoxidase (MPO) and lipocalin (LCN2) are involved in inflammatory and fibrotic processes. In contrast, neutrophils contribute to liver protection and repair through mechanisms involving microRNA-223 and matrix metalloproteinase 9 (MMP9). This dual role of neutrophils highlights their significance in the pathogenesis of MASLD and MASH. This review summarizes current understanding from recent studies on the involvement of neutrophils in MASLD and MASH. Understanding complex roles of neutrophils within the liver's unique microenvironment offers insights into novel therapeutic strategies, emphasizing the need for further research to explore neutrophil-targeted interventions for managing MASLD and MASH. [BMB Reports 2025; 58(3): 116-123].

Chronodisruption, marked by circadian rhythm misalignment, is linked to inflammatory diseases like obesity. Chronotypes, reflecting individual circadian behavior, include morning, intermediate, and evening types, with evening chronotypes showing worse body composition and higher metabolic risk. This study evaluated the inflammatory profile of visceral adipose tissue (VAT) across chronotypes in individuals with obesity and examined clock gene expression.

Twenty-five participants with obesity (11/14 F/M, BMI 41.59 ± 7.69 kg/m², age 41.13 ± 11.08 years) candidates for bariatric surgery were classified using the Morningness-Eveningness Questionnaire (MEQ): morning (36%), intermediate (28%), or evening (36%) chronotypes. VAT biopsies were analyzed for cytokines, chemokines, and growth factors via multiplex ELISA, and clock genes (PER1, CLOCK, BMAL1) were assessed using qPCR.

Body composition and biochemical parameters were similar across groups, but evening chronotypes had higher triglyceride levels (p = 0.012) and lower phase angle (p = 0.035). VAT inflammatory markers, including IL-1β (p = 0.04), IL-8 (p = 0.03), bFGF (p = 0.01), MCP-1 (p = 0.01), and MIP-1β (p = 0.05), were highest in evening and lowest in morning chronotypes. Evening chronotypes had significantly elevated bFGF levels compared to other groups (p = 0.04). PER1 mRNA expression was also higher in evening chronotypes (p = 0.02) and correlated with VAT-released bFGF (p = 0.03) and IL-1β (p = 0.03). MEQ scores negatively correlated with VAT bFGF (p = 0.02), MCP-1 (p = 0.02), and PER1 expressions.

Despite similar metabolic profiles, evening chronotypes exhibit heightened VAT inflammation and altered clock gene expression, potentially worsening their metabolic risk.

Neutrophils, the most abundant circulating leukocytes, have long been recognized as key players in innate immunity and inflammation. However, recent discoveries unveil their remarkable heterogeneity and plasticity, challenging the traditional view of neutrophils as a homogeneous population with a limited functional repertoire. Advances in single-cell technologies and functional assays have revealed distinct neutrophil subsets with diverse phenotypes and functions and their ability to adapt to microenvironmental cues. This review provides a comprehensive overview of the multidimensional landscape of neutrophil heterogeneity, discussing the various axes along which diversity manifests, including maturation state, density, surface marker expression, and functional polarization. We highlight the molecular mechanisms underpinning neutrophil plasticity, focusing on the complex interplay of signaling pathways, transcriptional regulators, and epigenetic modifications that shape neutrophil responses. Furthermore, we explore the implications of neutrophil heterogeneity and plasticity in physiological processes and pathological conditions, including host defense, inflammation, tissue repair, and cancer. By integrating insights from cutting-edge research, this review aims to provide a framework for understanding the multifaceted roles of neutrophils and their potential as therapeutic targets in a wide range of diseases.

Current therapies for diabetes and atherosclerotic cardiovascular diseases (ACVDs) mainly target metabolic risk factors, but often fall short in addressing systemic inflammation, a key driver of disease onset and progression. Advances in our understanding of the biology of neutrophils, the cells that are principally involved in inflammatory situations, have highlighted their pivotal role in cardiometabolic diseases. Yet, neutrophils can reprogram their immune-metabolic functions based on the energetic substrates available, thus influencing both tissue homeostasis and the resolution of inflammation. In this review, we examine the effects of canonical therapies for cardiometabolic diseases on the key molecular pathways through which neutrophils respond to inflammatory stimuli. In addition, we explore potential synergies between these established therapeutic approaches and the anti-inflammatory therapies being evaluated for repurposing in the treatment of cardiometabolic diseases.

Brown adipose tissue (BAT) and thermogenic beige fat within white adipose tissue (WAT), collectively known as adaptive thermogenic fat, dissipate energy as heat, offering promising therapeutic potential to combat obesity and metabolic disorders. The specific biological functions of these fat depots are determined by their unique interaction with the microenvironments, composed of immune cells, endothelial cells, pericytes, and nerve fibers. Immune cells residing in these depots play a key role in regulating energy expenditure and systemic energy homeostasis. The dynamic microenvironment of thermogenic fat depots is essential for maintaining tissue health and function. Immune cells infiltrate both BAT and beige WAT, contributing to their homeostasis and activation through intricate cellular communications. Emerging evidence underscores the importance of various immune cell populations in regulating thermogenic adipose tissue, though many remain undercharacterized. This review provides a comprehensive overview of the immune cells that regulate adaptive thermogenesis and their complex interactions within the adipose niche, highlighting their potential to influence metabolic health and contribute to therapeutic interventions for obesity and metabolic syndrome.

Apical periodontitis (AP) is an inflammatory immune response in periapical tissues caused by microbial infections. Failure of root canal treatment or delayed healing is often due to intracanal or extra-radicular bacteria. However, beyond microbial factors, the patient's systemic health can significantly influence the progression and healing of AP. Metabolic syndrome is a risk factor and it is characterized by a cluster of interconnected metabolic risk factors, including abdominal obesity, hyperlipidemia, hypertension, and hyperglycemia.

A comprehensive literature review was conducted on apical periodontitis and metabolic syndrome, and their impact on the roles of different immune cell populations.

Both AP and metabolic syndrome are inflammatory diseases that involve complex and interwoven immune responses. The affected immune cells are categorized into the innate (neutrophils, macrophages, and dendritic cells) and adaptive immune systems (T cells and B cells).

Metabolic diseases and AP are closely correlated, possibly intertwined in a two-way relationship driven by a shared dysregulated immune response.

Understanding the pathophysiology and immune mechanisms underlying the two-way relationship between metabolic syndrome and AP can help improve treatment outcomes and enhance the overall well-being of patients with endodontic disease complicated by metabolic syndrome.

Non-alcoholic fatty liver disease (NAFLD) or metabolic dysfunction-associated steatotic liver disease (MASLD) is closely associated with chronic inflammation and lipid metabolism disorders. The neutrophil-to-high-density lipoprotein cholesterol ratio (NHR) is an integrative marker reflecting inflammatory responses and lipid metabolism disorders and is associated with various diseases. This cross-sectional study aimed to determine the association between NHR and NAFLD, MASLD, and liver fibrosis.

Data for this study were obtained from the 2017-2020 National Health and Nutrition Examination Survey (NHANES), we employed weighted multiple regression and restricted cubic spline (RCS) analysis to assess the relationship between NHR and NAFLD, MASLD, and liver fibrosis. Additionally, we performed stratified analyses based on gender, age, body mass index, diabetes, hypertension, smoking status, and history of cardiovascular disease to evaluate the consistency of these associations across different subgroups.

A total of 6,526 participants were included in the study. 2,839 (weighted 44.1%) participants were diagnosed with NAFLD and 2,813 (weighted 43.7%) participants were diagnosed with MASLD. After adjusting for confounders, NHR was positively associated with the risk of NAFLD/MASLD, and the correlation was particularly significant in the subgroups of females, those without hypertension, and those without diabetes (p < 0.05). By the NHR quartile, the risk of NAFLD/MASLD increased progressively with higher NHR levels (P for trend <0.001). In addition, RCS analysis showed a nonlinear association between NHR and NAFLD/MASLD and liver fibrosis (P-non-linear <0.05).

NHR may serve as a potential marker for NAFLD/MASLD and liver fibrosis, and lowering NHR levels could help reduce the incidence of these conditions.

The global pandemic of obesity poses a serious health, social, and economic burden. Patients living with obesity are at an increased risk of developing noncommunicable diseases or to die prematurely. Obesity is a state of chronic low-grade inflammation. Neutrophils are first to be recruited to sites of inflammation, where they contribute to host defense via phagocytosis, degranulation, and extrusion of neutrophil extracellular traps (NETs). NETs are web-like DNA structures of nuclear or mitochondrial DNA associated with cytosolic antimicrobial proteins. The primary function of NETosis is preventing the dissemination of pathogens. However, neutrophils may occasionally misidentify host molecules as danger-associated molecular patterns, triggering NET formation. This can lead to further recruitment of neutrophils, resulting in propagation and a vicious cycle of persistent systemic inflammation. This scenario may occur when neutrophils infiltrate expanded obese adipose tissue. Thus, NETosis is implicated in the pathophysiology of autoimmune and metabolic disorders, including obesity. This review explores the role of NETosis in obesity and two obesity-associated conditions-hypertension and liver steatosis. With the rising prevalence of obesity driving research into its pathophysiology, particularly through diet-induced obesity models in rodents, we discuss insights gained from both human and animal studies. Additionally, we highlight the potential offered by rodent models and the opportunities presented by genetically modified mouse strains for advancing our understanding of obesity-related inflammation.

Corticosteroid binding globulin (CBG; SERPINA6) binds >85% of circulating glucocorticoids but its influence on their metabolic actions is unproven. Targeted proteolytic cleavage of CBG by neutrophil elastase (NE; ELANE) significantly reduces CBG binding affinity, potentially increasing 'free' glucocorticoid levels at sites of inflammation. NE is inhibited by alpha-1-antitrypsin (AAT; SERPINA1). Using complementary approaches in mice and humans to manipulate NE or AAT, we show high-fat diet (HFD) increases the NE:AAT ratio specifically in murine visceral adipose tissue, an effect only observed in males. Notably, HFD-fed male mice lacking NE have reduced glucocorticoid levels and action specifically in visceral adipose tissue, with improved glucose tolerance and insulin sensitivity, independent of systemic changes in free glucocorticoids. The protective effect of NE deficiency is lost when the adrenals are removed. Moreover, human asymptomatic heterozygous carriers of deleterious mutations in SERPINA1 resulting in lower AAT levels have increased adipose tissue glucocorticoid levels and action. However, in contrast to mice, humans present with systemic increases in free circulating glucocorticoid levels, an effect independent of HPA axis activation. These findings show that NE and AAT regulate local tissue glucocorticoid bioavailability in vivo, providing crucial evidence of a mechanism linking inflammation and metabolism.

A slew of common metabolic disorders, including type 2 diabetes, metabolic dysfunction-associated steatotic liver disease and steatohepatitis, are exponentially increasing in our sedentary and overfed society. While macronutrients directly impact metabolism and bioenergetics, new evidence implicates immune cells as critical sensors of nutritional cues and important regulators of metabolic homeostasis. A deeper interrogation of the intricate and multipartite interactions between dietary components, immune cells and metabolically active tissues is needed for a better understanding of metabolic regulation and development of new treatments for common metabolic diseases. Responding to macronutrients and micronutrients, immune cells play pivotal roles in interorgan communication between the microbiota, small intestine, metabolically active cells including hepatocytes and adipocytes, and the brain, which controls feeding behavior and energy expenditure. This Review focuses on the response of myeloid cells and innate lymphocytes to dietary cues, their cross-regulatory interactions and roles in normal and aberrant metabolic control.

This study seeks to evaluate the prognostic significance of eGDR in predicting mortality outcomes within non-diabetic older adults.

8131 non-diabetic participants aged ≥60 years from the National Health and Nutrition Examination Survey (2001-2018) was included in this study. eGDR was calculated as: eGDR (mg/kg/min) = 21.158 - [0.09 × waist circumference (cm)] - [3.407 × Hypertension (Yes = 1/No = 0)] - [0.551 × HbA1c (%)]. Weighted Cox proportional hazards models, cumulative hazard curves, restricted cubic spline (RCS), and threshold effects analyses were performed to explore the relationship between eGDR and mortality outcomes. Subgroup analyses and mediation effects analyses were conducted.

2566 all-cause deaths and 689 cardiovascular deaths were recorded. Lower eGDR was associated with higher all-cause (HR = 0.76, 95 % CI: 0.63-0.91) and cardiovascular mortality (HR = 0.56, 95 % CI: 0.40-0.80). Inflection points were identified through RCS curve analyses, and the threshold effect was significant. The eGDR-mortality association remained consistent across subgroups. Mediation analyses showed that neutrophil to high-density lipoprotein cholesterol ratio mediated the association.

Lower eGDR levels are linked to higher risk of both all-cause and cardiovascular mortality in non-diabetic older adults, suggesting its potential utility for risk assessment among this population.

Obesity is a chronic, multifactorial disease characterized by persistent low-grade tissue and systemic inflammation. Fat accumulation in adipose tissue (AT) leads to stress and dysfunctional adipocytes, along with the infiltration of immune cells, which initiates and sustains inflammation. Neutrophils are the first immune cells to infiltrate AT during high-fat diet (HFD)-induced obesity. Emerging evidence suggests that the formation and release of neutrophil extracellular traps (NETs) play a significant role in the progression of obesity and related diseases. Additionally, obesity is associated with an imbalance in gut microbiota and increased intestinal barrier permeability, resulting in the translocation of live bacteria, bacterial deoxyribonucleic acid (DNA), lipopolysaccharides (LPS), and pro-inflammatory cytokines into the bloodstream and AT, thereby contributing to metabolic inflammation. Recent research has also shown that short-chain fatty acids (SCFAs), produced by gut microbiota, can influence various functions of neutrophils, including their activation, migration, and the generation of inflammatory mediators. This review comprehensively summarizes recent advancements in understanding the role of neutrophils and NET formation in the pathophysiology of obesity and related disorders while also focusing on updated potential therapeutic approaches targeting NETs based on studies conducted in humans and animal models.

Neutrophils, the most abundant type of granulocyte, are widely recognized as one of the pivotal contributors to the acute inflammatory response. Initially, neutrophils were considered the mobile infantry of the innate immune system, tasked with the immediate response to invading pathogens. However, recent studies have demonstrated that neutrophils are versatile cells, capable of regulating various biological processes and impacting both human health and disease. Cytokines and other active mediators regulate the functional activity of neutrophils by activating multiple receptors on these cells, thereby initiating downstream signal transduction pathways. Dysfunctions in neutrophils and disruptions in neutrophil homeostasis have been implicated in the pathogenesis of numerous diseases, including cancer and inflammatory disorders, often due to aberrant intracellular signaling. This review provides a comprehensive synthesis of neutrophil biological functions, integrating recent advancements in this field. Moreover, it examines the biological roles of receptors on neutrophils and downstream signaling pathways involved in the regulation of neutrophil activity. The pathophysiology of neutrophils in numerous human diseases and emerging therapeutic approaches targeting them are also elaborated. This review also addresses the current limitations within the field of neutrophil research, highlighting critical gaps in knowledge that warrant further investigation. In summary, this review seeks to establish a comprehensive and multidimensional model of neutrophil regulation, providing new perspectives for potential clinical applications and further research.

Circulating serpinB1 levels are increased in obese mice and have been shown to promote β-cell proliferation in several species. However, the data on serum serpinB1 levels in children with obesity are scarce. This study aimed to determine serum serpinB1 levels in children with overweight/obesity, and to study its association with obesity-related parameters.

A total of 54 children with overweight/obesity and 36 normal-weight healthy controls aged 6-14 were recruited in this study. Anthropometric parameters, glucolipid metabolic biochemical parameters, sex hormones, and serum serpinB1 levels were measured in all subjects. The association of serum serpinB1 levels with obesity-related parameters and the risk of overweight/obesity were analyzed using correlation analysis and binary regression analysis, respectively.

The serum serpinB1 level in overweight/obese children was notably greater than in normal-weight controls (2.03 ± 0.70 vs. 1.41 ± 0.58 ng/mL, p < 0.001). SerpinB1 levels were positively correlated with body mass index (BMI), BMI Z-score, triglyceride (TG), uric acid, fasting insulin, C-peptide, and homeostasis model assessment of insulin resistance (HOMA-IR) levels. Additionally, we found that elevated circulating serpinB1 levels were associated with the increased risk of childhood overweight/obesity even after adjustment for age, gender, and HOMA-IR (odds ratio, 4.132; 95% confidence interval, 1.315-12.983; p = 0.015).

Circulating serpinB1 level was significantly increased in children with overweight/obesity and positively associated with obesity-related glucolipid metabolic parameters. These results indicate a close association between serum serpinB1 concentrations and childhood overweight/obesity.

Obesity has emerged as a prominent global public health concern, leading to the development of numerous metabolic disorders such as cardiovascular diseases, type-2 diabetes mellitus (T2DM), sleep apnea and several system diseases. It is widely recognized that obesity is characterized by a state of inflammation, with immune cells-particularly macrophages-playing a significant role in its pathogenesis through the production of inflammatory cytokines and activation of corresponding pathways. In addition to their immune functions, macrophages have also been implicated in lipogenesis. Additionally, the mitochondrial disorders existed in macrophages commonly, leading to decreased heat production. Meantime, adipocytes have mitochondrial dysfunction and damage which affect thermogenesis and insulin resistance. Therefore, enhancing our comprehension of the role of macrophages and mitochondrial dysfunction in both macrophages and adipose tissue will facilitate the identification of potential therapeutic targets for addressing this condition.

Metabolic syndrome (MetS) is a cluster of conditions that increase the risk of cardiovascular disease and diabetes. This study aimed to investigate the association between Neutrophil-Percentage-to-Albumin Ratio (NPAR) and MetS in a large, nationally representative US population. We analyzed data from 28,178 participants in the National Health and Nutrition Examination Survey (NHANES) 2005-2018. Logistic regression models were used to evaluate the association between NPAR and MetS. Restricted cubic spline (RCS) models were employed to assess the dose-response relationship. Mediation analyses were conducted to explore potential mediating effects of serum uric acid and triglyceride-glucose (TyG) index. After adjusting for confounders, participants in the highest NPAR quartile had a 14% higher risk of MetS compared to those in the lowest quartile (OR 1.14, 95%CI 1.03-1.27, P = 0.010). RCS models revealed a monotonic increasing trend between NPAR and MetS risk (P for overall association = 0.002). Mediation analyses showed that serum uric acid and TyG index mediated 14.93% and 29.45% of the total effect of NPAR on MetS, respectively. Subgroup analyses indicated that the positive association between NPAR and MetS was more pronounced in Mexican Americans, individuals aged 20-65 years, those with lower income, males, current smokers, and moderate drinkers. Higher NPAR is associated with increased risk of MetS in the US adult population. This association is partially mediated by serum uric acid and TyG index. These findings suggest that NPAR may serve as a novel biomarker for MetS risk assessment and provide insights into potential mechanisms linking inflammation and metabolic disorders.

The inflammatory status of the kidneys, vasculature, and perivascular adipose tissue (PVAT) has a significant influence on blood pressure and hypertension. Numerous micronutrients play an influential role in hypertension-driving inflammatory processes, and recent reports have provided bases for potential targeted modulation of these micronutrients to reduce hypertension. Iron overload in adipose tissue macrophages and adipocytes engenders an inflammatory environment and may contribute to impaired anticontractile signalling, and thus a treatment such as chelation therapy may hold a key to reducing blood pressure. Similarly, magnesium intake has proven to greatly influence inflammatory signalling and concurrent hypertension in both healthy animals and in a model for chronic kidney disease, demonstrating its potential clinical utility. These findings highlight the importance of further research to determine the efficacy of micronutrient-targeted treatments for the amelioration of hypertension and their potential translation into clinical application.

The SWItch3-related gene (SRG3) is a core component of ATP-dependent SWI/SNF complexes, which are crucial for regulating immune cell development and function (e.g., macrophages and CD4+ T cells), embryonic development, and non-immune cell differentiation. Notably, SRG3 overexpression has been shown to polarize macrophages in the central nervous system toward an anti-inflammatory M2 phenotype, thereby protecting against the development of experimental autoimmune encephalomyelitis in mice. However, the effect of SRG3 on immune responses in adipose tissues remains unclear. To address this issue, we examined the cellularity and inflammatory status of adipose tissue in B10.PL mice overexpressing the SRG3 gene under the ubiquitous β-actin promoter (SRG3β-actin). Interestingly, SRG3 overexpression significantly reduced adipocyte size in both white and brown adipose tissues, without affecting the overall adipose tissue weight. Such phenotypic effects might be associated with the improved glucose tolerance observed in SRG3β-actin B10.PL mice. Moreover, we found that SRG3 overexpression down-regulates IL1β-expressing M1 macrophages, leading to a significant decrease in the M1/M2 macrophage ratio. Additionally, SRG3β-actin B10.PL mice showed a dramatic reduction in neutrophils as well as IL1β- and IL17-producing T cells in adipose tissues. Taken together, our results indicate that SRG3 plays a vital role in maintaining immune homeostasis within adipose tissues.

The mammalian immune system is constantly surveying our tissues to clear pathogens and maintain tissue homeostasis. In order to fulfill these tasks, immune cells take up nutrients to supply energy for survival and for directly regulating effector functions via their cellular metabolism, a process now known as immunometabolism. Neutrophilic granulocytes, the most abundant leukocytes in the human body, have a short half-life and are permanently needed in the defense against pathogens. According to a long-standing view, neutrophils were thought to primarily fuel their metabolic demands via glycolysis. Yet, this view has been challenged, as other metabolic pathways recently emerged to contribute to neutrophil homeostasis and effector functions. In particular during neutrophilic development, the pentose phosphate pathway, glycogen synthesis, oxidative phosphorylation, and fatty acid oxidation crucially promote neutrophil maturation. At steady state, both glucose and lipid metabolism sustain neutrophil survival and maintain the intracellular redox balance. This review aims to comprehensively discuss how neutrophilic metabolism adapts during development, which metabolic pathways fuel their functionality, and how these processes are reconfigured in case of various diseases. We provide several examples of hereditary diseases, in which mutations in metabolic enzymes validate their critical role for neutrophil function.

Metabolic diseases, notably obesity and type 2 diabetes (T2D), have reached alarming proportions and constitute a significant global health challenge, emphasizing the urgent need for effective preventive and therapeutic strategies. In contrast, exercise training emerges as a potent intervention, exerting numerous positive effects on metabolic health through adaptations to the metabolic tissues. Here, we reviewed the major features of our current understanding with respect to the intricate interplay between metabolic diseases and key metabolic tissues, including adipose tissue, skeletal muscle, and liver, describing some of the main underlying mechanisms driving pathogenesis, as well as the role of exercise to combat and treat obesity and metabolic disease.

Inflammation is an important causative factor of obesity. This study aimed to explore the possible association between the systemic immune-inflammatory index, a novel indicator of inflammation, and obesity.

Data were collected from 4395 participants of the National Health and Nutrition Examination Survey 2017-2018 aged ≥ 20 years. The systemic immune-inflammatory index was calculated by multiplying the platelet count by the neutrophil-to-lymphocyte ratio. Obesity was defined as a body mass index ≥ 30 kg/m2.

A significant positive correlation was observed between the systemic immune-inflammatory index and body mass index following multivariate linear regression analysis (β = 1.75; 95% confidence interval = 1.16-2.33), which was greatest in adults aged < 60 years without hypertension and diabetes. Smoothed curve fitting and threshold effect analysis were used to characterize the nonlinear association between the systemic immune-inflammatory index and body mass index, and the inflection point was found to be 729.3.

The systemic immune-inflammatory index is positively associated with body mass index among adults in the United States and has the potential to enhance efforts to prevent adult obesity.

Maintenance hemodialysis (MHD) patients suffer from enormous physical, mental stress and poor quality of life, so an increasing number of patients are in a long-term state of depression. A prominent feature of MHD patients is chronic persistent inflammation, which is also an important mechanism for the onset of depression. Therefore, finding economically convenient inflammatory markers to predict and diagnose the onset of depression in MHD patients is of great value. As a novel inflammatory marker, systemic immune inflammation index (SII) can more comprehensively reflect the inflammation and immunity level of patients. This study aims to explore the relationship between SII and depressive symptoms in MHD patients.

A cross-sectional study was conducted on 206 MHD patients from three dialysis centers. Based on the Hospital Anxiety and Depression Scale (HADS) scores, patients were divided into non-depression and depression groups. Inter group comparison and multivariate logistic regression analysis were performed to determine whether SII is an independent risk factor for depression in MHD patients. Receiver operating characteristic (ROC) curve was used to evaluate the predictive value of SII on depression symptoms in MHD patients.

According to the HADS scale score, 38.83% of the included patients were in a state of depression. After adjusting for all confounding factors, MHD patients with SII>963.93 had a 4.709 times higher risk of depression than those with SII ≤ 478.32 (OR=4.709, 95% CI 1.821-12.178, P<0.01). ROC analysis showed that SII>685.11 was the best cutoff value for MHD depression patients, and the area under the curve (AUC) was 0.681.

High SII is an independent risk factor for depressed MHD patients and an ideal inflammatory marker for predicting and identifying depression in MHD patients as assessed by the HADS scale.