Leptin, an adipokine related to obesity, is mainly known for its role in regulating energy homeostasis and appetite by working via the leptin receptor. Recently, different groups have demonstrated that apart from adipocytes, specific cell types associated with cancer and tumor microenvironments express leptin and leptin receptors. This tumor microenvironment-associated leptin-leptin receptor signaling contributes to the different hallmarks of cancer, ranging from inflammatory changes to metastasis. Eventually, it has also been reported that high serum level of leptin, a characteristic of obese people, is linked to enhanced tumor growth. On the other hand, leptin can influence both innate as well as adaptive immunity related to cancer. Overall, leptin's role in modulating cancer is controversial. So, in this review, we summarized the role of leptin in shaping different forms of cancer that are influenced by leptin-leptin receptor signaling with special emphasis on immunomodulation and inflammatory events and also discussed the possible therapeutic interventions to date. As this review work, with the collection of different updated knowledge, has summarized the role of leptin on cancer, it would be useful material to have on hand for both beginners as well as pioneers of these and related fields.

Nesfatin-1, a posttranslational product of the protein encoded by the nucleobindin 2 gene (NUCB2), was functionally identified as an appetite regulatory molecule in rat hypothalamic nuclei. In the years following the discovery, those findings have been corroborated and expanded upon, and we now know that nesfatin-1 is expressed throughout peripheral tissues and exerts physiological effects beyond feeding control. Literature indicates that adipose tissue is one of the peripheral sources of NUCB2/nesfatin-1, and in this setting, it has anti-inflammatory effects that have recently been implicated in regulating chronic inflammation associated with diet-induced obesity. Currently, there are gaps in our understanding of what cell types within the adipose tissue compartment respond to nesfatin-1, in addition to the cellular mechanism(s) of this peptide. In this study, we sought to determine a mechanism by which this peptide might directly interact with the immune system starting with a human B cell line, Raji. We show that nesfatin-1 inhibits lipopolysaccharide (LPS) and B cell receptor (BCR) dual stimulation-mediated B cell growth, stimulation-induced cell death, and secretion of inflammatory mediators. Specifically, there was a reduced fold-change in B cell growth during stimulation which is paired with a reduction in the formation of apoptotic (annexin V+) cells. In addition, nesfatin-1 significantly reduced IgM secretion and modestly reduced TNFα secretion by stimulated B cells. The anti-inflammatory effects of nesfatin-1 overall are likely due to attenuation of NF-κB signaling, via inhibition of IκB degradation, in stimulated B cells.NEW & NOTEWORTHY This study establishes an interaction of nesfatin-1 and a human B cell line, Raji. Nesfatin-1 was shown to limit the B cell response to receptor-mediated stimulation, an action that has potential implications within the immune system and the development of chronic inflammation associated with the obese state. This study, along with previously published works, highlights a need for further research on nesfatin-1's interactions with adipocytes and immune cells.

Immune cells and blood metabolites play essential roles in the development of polycystic ovary syndrome (PCOS); however, it remains unclear whether blood metabolites mediate the causal relationship between immune cells and PCOS. This study aimed to delineate the causal relationships among immune cells, PCOS and potential blood metabolites through Mendelian randomization (MR). A two-sample MR analysis was conducted using inverse variance weighting as the primary method to determine the causation between immune cells and PCOS risk. This was supplemented by a two-step MR analysis to assess the mediating role of blood metabolites between immune cells and PCOS. In addition, a series of sensitivity analysis methods were employed to test the robustness of the results. We also performed a reverse MR to evaluate the possibility of reverse causal relationships. Our findings identified 22 immune cell phenotypes causally linked to PCOS, with 12 acting as risk factors and 10 as protective factors for PCOS. Furthermore, 45 blood metabolites or ratios were causally related to PCOS. Mediation analysis revealed that X-25519 levels mediated 9.2% of the causal relationship between the absolute count of CD28-CD25++ CD8br and PCOS. In addition, N-acetylglucosamine/n-acetylgalactosamine levels and adenosine 5'-monophosphate levels mediated 6.7% and -11.1%, respectively, in the causation between naive DN(CD4- CD8-) %T cell and PCOS. The aspartate-to-citrate ratio mediated 8.6% of the causal relationship between CD20- CD38- %B cells and PCOS. Finally, reverse MR studies did not identify any reverse causation between the 22 immune cell phenotypes and PCOS. This study elucidates the causal links between immune cells and PCOS, highlighting the potential roles of four blood metabolites in mediating the interaction between immune cells and PCOS, thus providing new targets for research and therapeutic interventions.

Over the past few decades, obesity has transitioned from a localized health concern to a pressing global public health crisis affecting over 650 million adults globally, as documented by WHO epidemiological surveys. As a chronic metabolic disorder characterized by pathological adipose tissue expansion, chronic inflammation, and neuroendocrine dysregulation that disrupts systemic homeostasis and impairs physiological functions, obesity is rarely an isolated condition; rather, it is frequently complicated by severe comorbidities that collectively elevate mortality risks. Despite advances in nutritional science and public health initiatives, sustained weight management success rates and prevention in obesity remain limited, underscoring its recognition as a multifactorial disease influenced by genetic, environmental, and behavioral determinants. Notably, the escalating prevalence of obesity and its earlier onset in younger populations have intensified the urgency to develop novel therapeutic agents that simultaneously ensure efficacy and safety. This review aims to elucidate the pathophysiological mechanisms underlying obesity, analyze its major complications-including type 2 diabetes mellitus (T2DM), cardiovascular diseases (CVD), non-alcoholic fatty liver disease (NAFLD), obesity-related respiratory disorders, obesity-related nephropathy (ORN), musculoskeletal impairments, malignancies, and psychological comorbidities-and critically evaluate current anti-obesity strategies. Particular emphasis is placed on emerging pharmacological interventions, exemplified by plant-derived natural compounds such as berberine (BBR), with a focus on their molecular mechanisms, clinical efficacy, and therapeutic advantages. By integrating mechanistic insights with clinical evidence, this review seeks to provide innovative perspectives for developing safe, accessible, and effective obesity treatments.

Genome-wide association studies have linked millions of genetic variants to biomedical phenotypes, but their utility has been limited by lack of mechanistic understanding and widespread epistatic interactions. Recently, Transformer models have emerged as a powerful machine learning architecture with potential to address these and other challenges. Accordingly, here we introduce the Genotype-to-Phenotype Transformer (G2PT), a framework for modeling hierarchical information flow among variants, genes, multigenic systems, and phenotypes. As proof-of-concept, we use G2PT to model the genetics of TG/HDL (triglycerides to high-density lipoprotein cholesterol), an indicator of metabolic health. G2PT predicts this trait via attention to 1,395 variants underlying at least 20 systems, including immune response and cholesterol transport, with accuracy exceeding state-of-the-art. It implicates 40 epistatic interactions, including epistasis between APOA4 and CETP in phospholipid transfer, a target pathway for cholesterol modification. This work positions hierarchical graph transformers as a next-generation approach to polygenic risk.

Obesity is a worldwide health problem with a rapidly rising incidence. In organ transplantation, increasing numbers of patients with obesity accumulate on waiting lists and undergo surgery. Obesity is in general conceptualized as a chronic inflammatory disease, potentially impacting alloimmune response and graft function. Here, we summarize our current understanding of cellular and molecular mechanisms that control obesity-associated adipose tissue inflammation and provide insights into mechanisms affecting transplant outcomes, emphasizing on the beneficial effects of weight loss on alloimmune responses.

Perivascular adipose tissue (PVAT) expansion promotes inflammation and vascular dysfunction in metabolic syndrome (MetS), but the sexual dimorphisms of PVAT are poorly understood. Using a new mouse model of diet-induced MetS, we characterized the aorta and determined the influence of PVAT on vascular function in males and females. Six-week-old C57BL/6 mice were fed either a high-fat diet (43% kcal in food) with high sugar and salt in their drinking water (10% high fructose corn syrup and 0.9% NaCl; HFSS), or a normal chow diet (NCD) for 10 weeks. The aorta was characterized at endpoint using pin myography, flow cytometry, bulk RNA-sequencing, GSEA analysis, and histology. Compared to NCD-fed mice, HFSS-fed mice displayed higher weight gain, fasting blood glucose, systolic blood pressure, aortic fibrosis, and perivascular adipocyte cross-sectional area, regardless of sex (p < .05). Circulating adiponectin levels were also higher in HFSS-fed males compared to NCD males. PVAT enhanced U46619-mediated contraction in HFSS males only. HFSS increased the expression of immune regulation genes in female PVAT and ion transport genes in male PVAT but had no effect on total numbers of immune cells in the aorta in either sex. Despite having similar effects on metabolic parameters in males and females, HFSS caused contrasting effects on vascular function with and without PVAT. These data highlight the sexual dimorphisms of PVAT in regulating the vasculature in healthy and diseased states.

Background: Type 2 diabetes (T2D) is a global metabolic condition associated with complications of multiple organs, including the bone. However, the exact impact of T2D on bone along the disease progression, particularly in the early phase, remains largely unknown. Methods: Four-week and sixteen-week high-fat diet (HFD) feeding-induced T2D mouse models were established, and the glucose metabolic status was examined. Bone mass was evaluated by micro-computed tomography (micro-CT), and immunofluorescent (IF) staining was performed for bone histomorphometry with enzyme-linked immunosorbent assay (ELISA) determining serum markers. RNA sequencing analysis was performed to examine the transcriptome of bone, and single-cell RNA-sequencing (scRNA-seq) analysis was further applied. Bone marrow mesenchymal stem cells (BMMSCs) were isolated and analyzed for functional behaviors. Results: The occurrence of glucose metabolic disorders was confirmed at both four weeks and sixteen weeks of HFD feeding, showing increased blood glucose levels with impaired glucose tolerance and insulin sensitivity. Notably, early T2D osteoporosis symptoms were detected at four weeks, especially in the trabecular bone, demonstrating reduced bone mass and mineral density. Histological analysis confirmed that bone remodeling and immune-related inflammation were also altered in T2D mice, remarkably at the early phase, mainly reflected by suppressed bone formation, stimulated bone resorption, increased macrophages, and elevated tumor necrosis factor-alpha (TNF-α) levels. Transcriptomic sequencing further demonstrated significant yet distinct changes in the gene expression profile of bone during T2D progression, which confirmed the histological findings. Notably, overlapping genes with altered expression at four weeks and sixteen weeks of T2D compared to the respective control were identified, and bone marrow scRNA-seq analysis indicated many of them were expressed in BMMSCs, suggesting BMMSCs critically involved in T2D osteoporosis. Dysregulated molecular profiles and functional abnormalities of BMMSCs in T2D mice were validated by ex vivo assays, showing early and persistent occurrence of impaired colony-forming and proliferative capacities with biased differentiation potential. Conclusions: These findings elucidate the bone lesion phenotype in T2D, particularly at the early phase, uncover changes in gene expression profiles of bone during T2D progression, and clarify the functional alterations in bone stem cells, providing a basis for subsequent research and the development of treatment strategies.

Immunoglobulin G (IgG) is traditionally recognized as a plasma protein that neutralizes antigens for immune defense. However, our research demonstrates that IgG predominantly accumulates in adipose tissue during obesity development, triggering insulin resistance and macrophage infiltration. This accumulation is governed by neonatal Fc receptor (FcRn)-dependent recycling, orchestrated in adipose progenitor cells and macrophages during the early and late stages of diet-induced obesity (DIO), respectively. Targeting FcRn abolished IgG accumulation and rectified insulin resistance and metabolic degeneration in DIO. By integrating artificial intelligence (AI) modeling with in vivo and in vitro experimental models, we unexpectedly uncovered an interaction between IgG's Fc-CH3 domain and the insulin receptor's ectodomain. This interaction hinders insulin binding, consequently obstructing insulin signaling and adipocyte functions. These findings unveil adipose IgG accumulation as a driving force in obesity pathophysiology, providing a novel therapeutic strategy to tackle metabolic dysfunctions.

Membrane contact sites (MCS) are specialized regions where organelles are closely interconnected through membrane structures, facilitating the transfer and exchange of ions, lipids, and other molecules. This proximity enables a synergistic regulation of cellular homeostasis and functions. The formation and maintenance of these contact sites are governed by specific proteins that bring organelle membranes into close apposition, thereby enabling functional crosstalk between cellular compartments. In eukaryotic cells, lipids are primarily synthesized and metabolized within distinct organelles and must be transported through MCS to ensure proper cellular function. Consequently, MCS act as pivotal platforms for lipid synthesis and trafficking, particularly in cancer cells and immune cells within the tumor microenvironment, where dynamic alterations are critical for maintaining lipid homeostasis. This article provides a comprehensive analysis of how these cells exploit membrane contact sites to modulate lipid synthesis, metabolism, and transport, with a specific focus on how MCS-mediated lipid dynamics influence tumor progression. We also examine the differences in MCS and associated molecules across various cancer types, exploring novel therapeutic strategies targeting MCS-related lipid metabolism for the development of anticancer drugs, while also addressing the challenges involved.

Myeloid cell production of interleukin-1β (IL-1β) drives inflammaging in visceral white adipose tissue (vWAT) and contributes to the expansion of interleukin-1 receptor 1 (Il1r1)-positive aged adipose B cells (AABs). AABs promote metabolic dysfunction and inflammation under inflammatory challenges. However, whether IL-1β contributes to AAB-associated inflammation during aging is unclear. Using a B-cell-specific knockout of Il1r1 (BKO mice), we characterized old vWAT in the absence of IL-1β-B-cell signaling. In addition to sex-specific metabolic improvements in females, we identified a reduction in the proportion of B cells and a sex-specific increase in the B1/B2 B-cell ratio in BKO vWAT. Using single-cell RNA sequencing of vWAT immune cells, we observed that BKO differentially affected inflammatory signaling in vWAT immune cells. These data suggest that IL-1β-B-cell signaling supports the inflammatory response in multiple cell types and provides insight into the complex microenvironment in aged vWAT.

The population with cardiovascular-kidney-metabolic (CKM) syndrome has a higher risk of cardiovascular events. Chinese visceral adiposity index (CVAI), an index of both visceral obesity and surrogate insulin resistance, has been linked to cardiovascular events. However, the nature of this relationship remains unclear in individuals with CKM syndrome.

All data came from the China Health and Retirement Longitudinal Study (CHARLS). The association between CVAI and cardiovascular events risk was explored using Cox regression models, restricted cubic spline (RCS) curves, and multiple sensitivity analyses. To compare the predictive abilities of various indices, receiver operating characteristic (ROC) analyses were employed.

7744 participants were in final analysis. During 9 year follow-up, 1679 cases of cardiovascular disease (CVD), 1,255 cases of heart disease, and 604 cases of stroke were recorded. Cox regression analyses revealed that per-SD (standard deviation) increase in CVAI, the risk of CVD, heart disease, and stroke increased by 22% (95% CI 1.13-1.32), 22% (95% CI 1.13-1.32), and 32% (95% CI 1.19-1.47). In participants at CKM stage 3 with CVD, a J-shaped curve was observed in the RCS analyses (P non-linearity = 0.036). Subgroup analysis revealed an interaction between age and each 10-unit increase in CVAI in CVD (P interaction = 0.0173) and stroke risk (P interaction = 0.028). The AUC (area under curve) value for CVAI was highest compared to other indicators (all DeLong Test P values < 0.05).

This research demonstrates a higher CVAI was linked to increased cardiovascular risk in individuals with CKM syndrome stage 0-3. Monitoring CVAI can help identify high-risk individuals early and improve the effectiveness of disease management.

B cells have long been understood to be drivers of both humoral and cellular immunity. Recent advances underscore this importance but also indicate that in infection, inflammatory disease and cancer, B cells function directly at sites of inflammation and form tissue-resident memory populations. The spatial organization and cellular niches of tissue B cells have profound effects on their function and on disease outcome, as well as on patient response to therapy. Here we review the role of B cells in peripheral tissues in homeostasis and disease, and discuss the newly identified cellular and molecular signals that are involved in regulating their activity. We integrate emerging data from multi-omic human studies with experimental models to propose a framework for B cell function in tissue inflammation and homeostasis.

Age-related changes in the immune system, referred to as immunosenescence, appear to evolve with rather paradoxical manifestations, a diminished adaptive immune capacity, and an increased propensity for chronic inflammation often with autoimmunity, which may underlie the development of diverse disorders with age. Immunosenescent phenotypes are associated with the emergence of unique lymphocyte subpopulations of both T and B lineages. We report that a CD153+ programmed cell death protein 1 (PD-1)+ CD4+ T-cell subpopulation with severely attenuated T-cell receptor (TCR)-responsiveness, termed senescence-associated T (SAT) cells, co-evolve with potentially autoreactive CD30+ B cells, such as spontaneous germinal center B cells and age-associated B cells, in aging mice. SAT cells and CD30+ B cells are reciprocally activated with the aid of the interaction of CD153 with CD30 in trans and with the TCR complex in cis, resulting in the restoration of TCR-mediated proliferation and secretion of abundant pro-inflammatory cytokines in SAT cells and the activation and production of autoantibodies by CD30+ B cells. Besides normal aging, the development of SAT cells coupled with counterpart B cells may be robustly accelerated and accumulated in the relevant tissues of lymphoid or extra-lymphoid organs under chronic inflammatory conditions, including autoimmunity, and may contribute to the pathogenesis and aggravation of the disorders. This review summarizes and discusses recent advances in the understanding of SAT cells in the contexts of immunosenescent phenotypes, as well as autoimmune and chronic inflammatory diseases, and it provides a novel therapeutic clue.

To investigate the aberrant distribution and clinical relevance of regulatory B cells (Bregs) subsets in the peripheral blood of individuals with different levels of insulin resistance (IR).

A cohort of 124 subjects were divided into five groups according to their insulin resistance index (HOMA-IR) and diabetes diagnosis. The groups comprised Group 1 (IR- with good glycemic control) and Group 2 (IR- with poor glycemic control) at HOMA-IR < 3, Group 3 (IR+ without T2DM) and Group 4 (IR+ with T2DM), at 3 ≤ HOMA-IR < 6, and Group 5 (IR++ with T2DM) at HOMA-IR ≥ 6. Peripheral blood samples were collected from each group, the percentages of CD19+CD24+CD27+ and CD19+CD24+CD38+ Bregs and the levels of IL-2, IL-4, IL-6, IL-10, IL-17, TNF-α, IFN-γ were detected by flow cytometry and flow microsphere matrix method. Additionally, the cytokines levels were validated through ELISA. The activation of Bregs and the production of IL-10 among different groups were analyzed. Spearman correlation analysis was used to analyze the correlation between Bregs activation rate and IR degree.

The results showed that the levels of CD19+CD24+CD27+ and CD19+CD24+CD38+ cells were increased whether in IR+ without or with type 2 diabetes mellitus (T2DM) groups compared to the IR- groups, with the most significant increase observed in Group 5. Moreover, the plasma levels of IL-6, IL-10, IL-17, TNF-α and IFN-γ in the IR+ group were higher than those in the IR- group. The expression and activation level of Bregs were positively correlated with the severity of IR in T2DM.

These results suggest that the increase level of Bregs is closely related to the severity of IR, highlighting the potential significance of Bregs in the clinical progression of T2DM and its associated insulin resistance.

Obesity is an exceedingly prevalent and frequent health issue in today's society. Fat deposition is accompanied by low-grade inflammation in fat tissue and throughout the body, leading to metabolic disorders that ultimately promote the onset of obesity-related diseases. The development of obesity is accompanied by cell death events such as apoptosis as well as pyroptosis, however, the role of necroptosis in obesity has been widely reported in recent years. Necroptosis, a mode of cell death distinct from apoptosis and necrosis, is associated with developing many inflammatory conditions and their associated diseases. It also exhibits modulation of apoptosis and pyroptosis. It is morphologically similar to necroptosis, characterized by the inhibition of caspase-8, the formation of membrane pores, and the subsequent rupture of the plasma membrane. This paper focuses on the key pathways and molecules of necroptosis, exploring its connections with apoptosis and pyroptosis, and its implications in obesity. This paper posits that the modulation of necroptosis-related targets may represent a novel potential therapeutic avenue for the prevention and treatment of obesity-induced systemic inflammatory responses, and provides a synopsis of potential molecular targets that may prove beneficial in obesity-associated inflammatory diseases.

Immunometabolism is the interaction between immune system and nutrient metabolism. Severe obesity is considered a state of meta-inflammation associated with obesity that influences the development of chronic-degenerative diseases.

We aimed to establish the immunometabolic differences in bariatric patients and to determine whether cellular immunity is associated with metabolic changes.

We conducted an observational study in patients who underwent laparoscopic sleeve gastrectomy (LSG) or laparoscopic Roux-en-Y gastric bypass (LRYGB). We explored the differences in the immunometabolic profile before and after surgery in the study group, by surgical technique, and we evaluated the changes in immunological variables as a function of metabolic variables with correlation analysis.

The follow-up rate was 88.7%. After the intervention, there were changes in cellular immunity, with a decrease in effector T lymphocytes (CD8+CD28-) and an increase in B lymphocytes, memory helper T cells, and cytotoxic T lymphocytes. LSG resulted in a greater decrease in (CD4+CD62-) T lymphocytes compared with LRYGB. Patients who underwent surgery with LRYGB presented greater clinical and metabolic improvements, as well as improvement of obesity-associated medical problems. Women who underwent LRYGB showed a greater reduction in fat-free mass compared with women who underwent LSG.

Bariatric surgery, mainly LRYGB, leads to immunometabolic changes and improves associated medical problems.

Our previous work has shown that senescent B cells accumulate in the human adipose tissue (AT) of people with obesity, where they express transcripts for markers associated with the senescence-associated secretory phenotype (SASP) and secrete multiple inflammatory mediators. These functions of AT-derived B cells are metabolically supported.

To show that Metformin (MET), a widely used hypoglycemic and antidiabetic drug, is able at least in vitro to decrease frequencies, secretory profile, and metabolic requirements of senescent B cells isolated from the AT of people with obesity.

We recruited adult females with obesity (n = 8, age 40 ± 2 y, BMI range: 33-42) undergoing breast reduction surgery, who donated their discarded subcutaneous AT. B cells from stromal vascular fractions isolated after collagenase digestion of the AT were evaluated after in vitro incubation with MET (1 mM × 106 B cells) or with a control medium without MET for the following measures: expression of transcripts for SASP-associated markers (p16INK4a and p21CIP1/WAF1) measured by quantitative polymerase chain reaction (qPCR); secretion of inflammatory cytokines (TNF-α, IL-6, IFN-γ and IL-17A) measured by a Cytometric Bead Array); metabolic characteristics as identified by a glycolytic test and Seahorse technology, and by the expression of transcripts for glucose transporters and metabolic enzymes involved in glucose metabolic pathways, measured by qPCR. To examine differences between MET-treated compared with untreated groups, paired Student's t tests (two-tailed) were employed.

MET in vitro was able to reduce frequencies and numbers of senescent B cells, as identified by staining with β-galactosidase, as well as the secretion of inflammatory cytokines, the expression of transcripts for SASP, and metabolic markers that support intrinsic B cell inflammation.

Our results provide evidence to support the beneficial effects of MET in reducing AT-related inflammation through its effects on senescent B cells.

This narrative review article explores the complex interplay between obesity, osteoarthritis, and their associated inflammatory cascades, offering a deeper understanding of the underlying of mechanisms of inflammation and potential therapeutic interventions targeting both diseases. Through examination of the shared inflammatory pathway of obesity and osteoarthritis, our objective is to directly elucidate the relationship between these two conditions, highlighting the promising role of glucagon-like peptide-1 agonists in modulating inflammation and its therapeutic implications for patients with obesity and osteoarthritis.

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.

The prevalence of metabolic diseases, such as obesity, has been steadily increasing in recent years, posing a significant threat to public health. Therefore, early identification and intervention play a crucial role. With the deepening understanding of the etiology of metabolic diseases, novel therapeutic targets are emerging for the treatment of obesity, lipid metabolism disorders, cardiovascular and cerebrovascular diseases, glucose metabolism disorders, and other related metabolic conditions. IL-27, as a multi-potent cytokine, holds great promise as a potential candidate target in this regard. This article provides a comprehensive review of the latest findings on IL-27 expression and signal transduction in the regulation of immune inflammatory cells, as well as its implications in obesity and other related metabolic diseases. Furthermore, it explores the potential of IL-27 as a novel therapeutic target for the treatment of obesity and metabolic disorders. Finally, an overview is presented on both the opportunities and challenges associated with targeting IL-27 for therapeutic interventions.

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.

Type 2 Diabetes Mellitus (T2DM) represents a major global health challenge, marked by chronic hyperglycemia, insulin resistance, and immune system dysfunction. Immune cells, including T cells and monocytes, play a pivotal role in driving systemic inflammation in T2DM; however, the underlying single-cell mechanisms remain inadequately defined.

Single-cell RNA sequencing of peripheral blood mononuclear cells (PBMCs) from 37 patients with T2DM and 11 healthy controls (HC) was conducted. Immune cell types were identified through clustering analysis, followed by differential expression and pathway analysis. Metabolic heterogeneity within T cell subpopulations was evaluated using Gene Set Variation Analysis (GSVA). Machine learning models were constructed to classify T2DM subtypes based on metabolic signatures, and T-cell-monocyte interactions were explored to assess immune crosstalk. Transcription factor (TF) activity was analyzed, and drug enrichment analysis was performed to identify potential therapeutic targets.

In patients with T2DM, a marked increase in monocytes and a decrease in CD4+ T cells were observed, indicating immune dysregulation. Significant metabolic diversity within T cell subpopulations led to the classification of patients with T2DM into three distinct subtypes (A-C), with HC grouped as D. Enhanced intercellular communication, particularly through the MHC-I pathway, was evident in T2DM subtypes. Machine learning models effectively classified T2DM subtypes based on metabolic signatures, achieving an AUC > 0.84. Analysis of TF activity identified pivotal regulators, including NF-kB, STAT3, and FOXO1, associated with immune and metabolic disturbances in T2DM. Drug enrichment analysis highlighted potential therapeutic agents targeting these TFs and related pathways, including Suloctidil, Chlorpropamide, and other compounds modulating inflammatory and metabolic pathways.

This study underscores significant immunometabolic dysfunction in T2DM, characterized by alterations in immune cell composition, metabolic pathways, and intercellular communication. The identification of critical TFs and the development of drug enrichment profiles highlight the potential for personalized therapeutic strategies, emphasizing the need for integrated immunological and metabolic approaches in T2DM management.

Insulin resistance (IR) and metabolic syndrome (MetS) are significant global health challenges that increase the risk of various chronic diseases. The lymphocyte-to-high-density lipoprotein cholesterol ratio (LHR) has emerged as a novel inflammatory metabolic marker. The present study focused on evaluating the association between the LHR and both IR and MetS.

We analyzed data from 14,779 adults aged ≥ 20 years from the National Health and Nutrition Examination Survey (2007-2018). To investigate the relationship between LHR and both IR and MetS, we conducted multivariable logistic regression analyses. The reliability of the results was validated through both stratified and sensitivity analyses. Furthermore, we thoroughly examined possible nonlinear associations by implementing a restricted cubic spline in conjunction with a threshold effect analysis.

Compared to the lowest LHR quartile, individuals in the highest quartile indicated significantly increased prevalence of IR (odds ratio = 3.72, 95% confidence intervals: 3.01-4.59) and MetS (odds ratio = 11.38, 95% confidence intervals: 8.85-14.63) in fully adjusted models. Subgroup analyses demonstrated that the association between the LHR and IR remained consistent across all subgroups, with no significant interaction effect observed. However, the association between LHR and MetS was more pronounced in female participants. Restricted cubic spline analyses revealed nonlinear associations between LHR and both IR and MetS. The threshold effect analyses identified inflection points at 0.055 for these non-linear relationships.

An elevated LHR was positively associated with the prevalence of IR and MetS, indicating its promising role in early screening and disease prevention through biological monitoring.

Sarcopenia is defined as a muscle-wasting syndrome that occurs with accelerated aging, while cachexia is a severe wasting syndrome associated with conditions such as cancer and immunodeficiency disorders, which cannot be fully addressed through conventional nutritional supplementation. Sarcopenia can be considered a component of cachexia, with the bidirectional interplay between adipose tissue and skeletal muscle potentially serving as a molecular mechanism for both conditions. However, the underlying mechanisms differ. Recognizing the interplay and distinctions between these disorders is essential for advancing both basic and translational research in this area, enhancing diagnostic accuracy and ultimately achieving effective therapeutic solutions for affected patients. This review discusses the muscle microenvironment's changes contributing to these conditions, recent therapeutic approaches like lifestyle modifications, small molecules, and nutritional interventions, and emerging strategies such as gene editing, stem cell therapy, and gut microbiome modulation. We also address the challenges and opportunities of multimodal interventions, aiming to provide insights into the pathogenesis and molecular mechanisms of sarcopenia and cachexia, ultimately aiding in innovative strategy development and improved treatments.

Inflammation is an essential physiological defence mechanism, but prolonged or excessive inflammation can cause disease. Indeed, unresolved systemic and adipose tissue inflammation drives obesity-related cardiovascular disease and type 2 diabetes mellitus. Drugs targeting pro-inflammatory cytokine pathways or inflammasome activation have been approved for clinical use for the past two decades. However, potentially serious adverse effects, such as drug-induced weight gain and increased susceptibility to infections, prevented their wider clinical implementation. Furthermore, these drugs do not modulate the resolution phase of inflammation. This phase is an active process orchestrated by specialized pro-resolving mediators, such as lipoxins, and other endogenous resolution mechanisms. Pro-resolving mediators mitigate inflammation and development of obesity-related disease, for instance, alleviating insulin resistance and atherosclerosis in experimental disease models, so mechanisms to modulate their activity are, therefore, of great therapeutic interest. Here, we review current clinical attempts to either target pro-inflammatory mediators (IL-1β, NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome, tumour necrosis factor (TNF) and IL-6) or utilize endogenous resolution pathways to reduce obesity-related inflammation and improve cardiometabolic outcomes. A remaining challenge in the field is to establish more precise biomarkers that can differentiate between acute and chronic inflammation and to assess the functionality of individual leukocyte populations. Such advancements would improve the monitoring of drug effects and support personalized treatment strategies that battle obesity-related inflammation and cardiometabolic disease.

Polycystic ovary syndrome (PCOS) is a prevalent endocrine and metabolic disorder in premenopausal women. This investigation was to elucidate the underlying mechanism of endoplasmic reticulum stress (ERS) activation in granulosa cells, which has been implicated in the etiology of PCOS. Differentially expressed genes (DEGs) between PCOS and control groups were integrated with ERS gene lists from databases to identify DE-ERS genes, and functional analyses were performed. Univariate regression analysis and the LASSO method were used to select diagnostic factors, followed by establishing a DE-ERS gene-based diagnostic model. A nomogram model was further generated to predict the risk of PCOS. The correlation between ERS gene expression and immune cell proportion was assessed. A total of 14 DE-ERS genes associated with "protein processing in endoplasmic reticulum", "ferroptosis", and "glycerophospholipid metabolism" were selected as PCOS-related factors. An eight-DE-ERS genes-based diagnostic model was developed and displayed satisfactory performance in the training (Area under curve (AUC) = 0.983) and validation datasets (AUC = 0.802). High risk of PCOS can be accurately predicted, which might contribute to clinical decision-making. Moreover, EDEM1 expression was significantly positively correlated with naive B cell infiltration, while PDIA6 was negatively correlated with neutrophil proportion (P < 0.001). We identified eight novel molecules and developed an ERS gene-based diagnostic model in PCOS, which might provide novel insight for finding biomarkers and treatment methods.

The pathophysiology of diabetes is not fully understood; recent research indicates close relations with immunological alterations. Therefore, the aim of this study was to investigate the associations between markers of glucose metabolism and characteristics of blood lymphocytes in a population-based cohort.

The analysis was based on data from 219 non-diabetic participants of the MEGA study in Augsburg, Germany, who were recruited between 2018 and 2021. The majority of participants were examined two different times with a time lag of 9 months. Fasting venous blood samples were taken and oral glucose tolerance tests (OGTT) were performed at both visits. Immune cells were analyzed from fresh blood using flow cytometry. The associations between fasting blood glucose levels, glucose levels at 2 h after oral glucose bolus and glycated hemoglobin (HbA1c) concentrations and the quantity of different lymphocyte subsets were analyzed using linear mixed regression models with random intercept. P values were FDR-adjusted.

HbA1c was negatively associated with the marginal zone B cells (IgD + CD27+ B cells). Fasting glucose was positively associated with natural killer (NK) cells and 2-h OGTT glucose was positively associated with NKT cells. Finally, HbA1c showed significantly negative associations with the CD57-PD1-NKT cell subset.

Markers of glucose metabolism showed significant associations with B cell, NK cell and NKT cell subsets, which clearly indicates a relation between glucose metabolism and the adaptive immune system.

Nesfatin-1, derived from the nucleobindin 2 (NUCB2) precursor, is a potent anorexigenic peptide that was discovered in 2006. Since its identification in the hypothalamus, it has been shown to have wide ranging actions within and outside of the central nervous system. One of these actions is the regulation of inflammation, which could potentially be exploited therapeutically in the context of obesity-associated inflammation in adipose tissue. Here, we review recent advances in our knowledge about the ability of nesfatin-1 to control inflammation by regulating NFκB signaling, which likely attenuates pro-inflammatory cytokine production and inhibits apoptosis.

The aging population is increasing worldwide, and there is also an increase in the aging population living with overweight and obesity, due to changes in lifestyle and in dietary patterns that elderly individuals experience later in life. Both aging and obesity are conditions of accelerated metabolic dysfunction and dysregulated immune responses. In this review, we summarize published findings showing that obesity induces changes in humoral immunity similar to those induced by aging and that the age-associated B cell defects are mainly due to metabolic changes. We discuss the role of the obese adipose tissue in inducing dysfunctional humoral responses and autoimmune Ab secretion.

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.

Sarcopenia is a geriatric syndrome characterized by a functional decline in muscle. The prevalence of sarcopenia increases with natural aging, becoming a serious health problem among elderly individuals. Therefore, understanding the pathology of sarcopenia is critical for inhibiting age-related alterations and promoting health and longevity in elderly individuals. The development of sarcopenia may be influenced by interactions between visceral and subcutaneous adipose tissue and skeletal muscle, particularly under conditions of chronic low-grade inflammation and metabolic dysfunction. This hypothesis is supported by the following observations: (i) accumulation of senescent cells in both adipose tissue and skeletal muscle with age; (ii) gut dysbiosis, characterized by an imbalance in gut microbial communities as the main trigger for inflammation, sarcopenia, and aged adipose tissue; and (iii) microbial dysbiosis, which could impact the onset or progression of a senescent state. Moreover, adipose tissue acts as an endocrine organ, releasing molecules that participate in intricate communication networks between organs. Our discussion focuses on novel adipokines and their role in regulating adipose tissue and muscle, particularly those influenced by aging and obesity, emphasizing their contributions to disease development. On the basis of these findings, we propose that age-related adipose tissue and sarcopenia are disorders characterized by chronic inflammation and metabolic dysregulation. Finally, we explore new potential therapeutic strategies involving specialized proresolving mediator (SPM) G protein-coupled receptor (GPCR) agonists, non-SPM GPCR agonists, transient receptor potential (TRP) channels, antidiabetic drugs in conjunction with probiotics and prebiotics, and compounds designed to target senescent cells and mitigate their pro-inflammatory activity.

T cells play critical roles in adipose tissue (AT) inflammation. The role of CD20+T cell in AT dysfunction and their contributing to insulin resistance (IR) and type 2 diabetes progression, is not known. The aim was to characterize CD20+T cells in omental (OAT), subcutaneous (SAT) and peripheral blood (PB) from subjects with obesity (OB, n = 42), by flow cytometry. Eight subjects were evaluated before (T1) and 12 months post (T2) bariatric/metabolic surgery (BMS). PB from subjects without obesity (nOB, n = 12) was also collected. Higher percentage of CD20+T cells was observed in OAT, compared to PB or SAT, in OB-T1. CD20 expression by PB CD4+T cells was inversely correlated with adiposity markers, while follicular-like CD20+T cells were positively correlated with impaired glucose tolerance (increased HbA1c). Notably, among OB-T1, IR establishment was marked by a lower percentage and absolute number of PB CD20+T cells, compared nOB. Obesity was associated with higher percentage of activated CD20+T cells; however, OAT-infiltrated CD20+T cells from OB-T1 with diabetes displayed the lowest activation. CD20+T cells infiltrating OAT from OB-T1 displayed a phenotype towards IFN-γ-producing Th1 and Tc1 cells. After BMS, the percentage of PB CD4+CD20+T cells increased, with reduced Th1 and increased Th17 phenotype. Whereas in OAT the percentage of CD20+T cells with Th1/17 and Tc1/17 phenotypes increased. Interestingly, OAT from OB pre/post BMS maintained higher frequency of effector memory CD20+T cells. In conclusion, CD20+T cells may play a prominent role in obesity-related AT inflammation.

The intricate processes that govern the interactions between peripatetic immune cells and distal renal injury in obesity are not fully understood. Employing transcriptomic analysis of circulating extracellular vesicles (EVs), a marked amplification of small RNA (miR-3960) is discerned within CD3-CD19+ B cells. This RNA is found to be preferentially augmented in kidney tissues, contrasting with its subdued expression in other organs. By synthesizing dual-luciferase reporter assay with co-immunoprecipitation analysis, it is pinpointed that miR-3960 specifically targets the nuclear gene TRMT5, a pivotal actor in the methylation of mitochondrial tRNA. This liaison instigates aberrations in the post-transcriptional modifications of mitochondrial tRNA, engendering deficiencies within the electron respiratory chain, primarily attributable to the diminution of the mitochondrial bioenergetic compound (NDUFA7) complex I. Such perturbations lead to a compromised mitochondrial respiratory capacity in renal tubular cells, thereby exacerbating tubular injury. In contrast, EV blockade or miR-3960 depletion markedly alleviates renal tubular injury in obesity. This investigation unveils a hitherto unexplored pathway by which obesity-induced circulating immune cells remotely manipulate mitochondrial metabolism in target organs. The strategic targeting of obese EVs or infiltrative immune cells and their specifically secreted RNAs emerges as a promising therapeutic avenue to forestall obesity-related renal afflictions.

Obesity is associated with chronic low-grade inflammation, and adipose tissue inflammation is required for fatty tissue remodeling. Interestingly, immunosuppressed patients, as liver transplant recipients, often experience excessive weight gain. We investigated how liver recipients' inflammatory response affects body weight loss induced by dietary treatment.

Overweight liver recipients were paired with non-transplanted subjects to compare their peripheral immune profiles.

Transplanted patients had similar profiles of peripheral blood mononuclear cells compared to controls but lower CD8lowCD56+CD16+NK cells and higher B lymphocytes. Patients showed lower serum concentrations of IFN-γ, TNF, IL-4, IL-2, and IL-10 and lower inflammatory responsiveness of peripheral blood mononuclear cells under inflammatory stimuli. Liver recipients paired with non-transplanted subjects followed a weight loss dietary plan for 6 months to verify body composition changes. After 3 and 6 months of nutritional follow-up, the control group lost more body weight than the liver recipient group. The control group decreased fat mass and waist circumference, which was not observed in transplanted patients.

Therefore, liver recipients under immunosuppressant treatment responded less to different inflammatory stimuli. This impaired inflammatory milieu might be implicated in the lack of response to weight loss dietary intervention. Inflammation may be essential to trigger the weight loss induced by dietary prescription.

ClinicalTrials.gov identification number: NCT03103984.

The immune system plays a crucial role in protecting the body from invading pathogens and maintaining tissue homoeostasis. Maintaining homoeostatic lipid metabolism is an important aspect of efficient immune cell function and when disrupted immune cell function is impaired. There are numerous metabolic diseases whereby systemic lipid metabolism and cellular function is impaired. In the context of metabolic disorders, chronic inflammation is suggested to be a major contributor to disease progression. A major contributor to tissue dysfunction in metabolic disease is ectopic lipid deposition, which is generally caused by diet and genetic factors. Thus, we propose the idea, that similar to tissue and organ damage in metabolic disorders, excessive accumulation of lipid in immune cells promotes a dysfunctional immune system (beyond the classical foam cell) and contributes to disease pathology. Herein, we review the evidence that lipid accumulation through diet can modulate the production and function of immune cells by altering cellular lipid content. This can impact immune cell signalling, activation, migration, and death, ultimately affecting key aspects of the immune system such as neutralising pathogens, antigen presentation, effector cell activation and resolving inflammation.

Adipose tissue is composed of adipocytes, stromal vascular fraction, nerves, surrounding immune cells, and the extracellular matrix. Under various physiological or pathological conditions, adipose tissue shifts cellular composition, lipid storage, and organelle dynamics to respond to the stress; this remodeling is called "adipose tissue plasticity". Adipose tissue plasticity includes changes in the size, species, number, lipid storage capacity, and differentiation function of adipocytes, as well as alterations in the distribution and cellular composition of adipose tissue. This plasticity has a major role in growth, obesity, organismal protection, and internal environmental homeostasis. Moreover, certain thresholds exist for this plasticity with significant individualized differences. Here, we comprehensively elaborate on the specific connotation of adipose tissue plasticity and the relationship between this plasticity and the development of many diseases. Meanwhile, we summarize possible strategies for treating obesity in response to adipose tissue plasticity, intending to provide new insights into the dynamic changes in adipose tissue and contribute new ideas to relevant clinical problems.

Obesity, a complex condition that involves genetic, environmental, and behavioral factors, is a non-infectious pandemic that affects over 650 million adults worldwide with a rapidly growing prevalence. A major contributor is the consumption of high-fat diets, an increasingly common feature of modern diets. Maternal obesity results in an increased risk of offspring developing obesity and related health problems; however, the impact of maternal diet on the adipose tissue composition of offspring has not been evaluated. Here, we designed a generational diet-induced obesity study in female C57BL/6 mice that included maternal cohorts and their female offspring fed either a control diet (10% fat) or a high-fat diet (45% fat) and examined the visceral adipose proteome. Solubilizing proteins from adipose tissue is challenging due to the need for high concentrations of detergents; however, the use of a detergent-compatible sample preparation strategy based on suspension trapping (S-Trap) enabled label-free quantitative bottom-up analysis of the adipose proteome. We identified differentially expressed proteins related to lipid metabolism, inflammatory disease, immune response, and cancer, providing valuable molecular-level insight into how maternal obesity impacts the health of offspring. Data are available via ProteomeXchange with the identifier PXD042092.