Search Results (428)

This study explores the role of human visceral white adipocytes (hv-WAD) in latent tuberculosis infection (LTBI). While granulomas and macrophages are traditionally viewed as central to TB latency, emerging evidence highlights adipocytes as significant non-canonical host cells that may facilitate bacterial persistence by providing a protective niche. Unlike the immune-driven environment within granulomas, adipocytes can shield Mycobacterium tuberculosis (Mtb) from immune surveillance, promoting survival. In vitro experiments showed that Mtb invades approximately 39% of hv-WAD within 48–72 h post-infection (hpi). Both avirulent H37Ra and virulent H37Rv Mtb strains, when infecting adipocytes, expressed RNA for key virulence factors (19 kDa, 30 kDa, Ag85b, 5KST, CFP10, and ESAT6) and dormancy-associated genes (Icl1, LipY, WhiB3, SodA, and Tgs1) at 72 hpi. Infection stimulated the production of inflammatory cytokines, notably leading to a fivefold increase in TNF-α with H37Rv (p < 0.01). Additionally, we detected Mtb RNA transcripts (IS6110, 5KST, 30 kDa, CFP10, Ag85) in 68% of biopsies from TB asymptomatic patients. The transcripts suggest a metabolically heterogeneous state of mycobacteria. These findings position visceral fat as a potential reservoir for Mtb in latent TB infection and underscore the development of novel diagnostic strategies targeting adipose tissue. Full article

Lipedema is a chronic, progressive adipose tissue disorder that affects up to 10% of women and is characterized by disproportionate lower-limb fat accumulation, pain, edema, and resistance to conventional weight-loss approaches. Its pathophysiology involves a complex interplay of adipocyte hypertrophy, chronic inflammation, extracellular matrix fibrosis, mitochondrial dysfunction, and sex steroid imbalance, highlighting the need for disease-modifying therapies. This narrative review synthesizes mechanistic, translational, and clinical evidence linking metabolic, inflammatory, and fibrotic pathways to lipedema and tirzepatide’s potential therapeutic relevance. Tirzepatide, a dual GLP-1 (Glucagon-Like Peptide-1)/GIP (Glucose-Dependent Insulinotropic Polypeptide) receptor agonist, has demonstrated unprecedented efficacy in obesity and diabetes, alongside pleiotropic actions on inflammation, fibrosis, and adipose remodeling. Mechanistic studies reveal favorable effects on macrophage polarization, cytokine signaling, extracellular matrix turnover, and thermogenesis, suggesting potential relevance to lipedema biology. Translational evidence from related fibro-inflammatory conditions such as steatohepatitis and heart failure further supports its antifibrotic and immunomodulatory plausibility. Although direct clinical evidence in lipedema is lacking, the convergence of mechanistic pathways provides a strong rationale to investigate tirzepatide as a disease-modifying candidate. If future clinical studies confirm these mechanisms, tirzepatide could represent a novel metabolic–hormonal therapy capable of modifying the natural course of lipedema. Full article

Toxicant-associated steatohepatitis (TASH) is caused by environmental toxicants rather than metabolic factors; however, its pathogenic mechanisms remain poorly understood. Polychlorinated biphenyl 138 (PCB138), a persistent lipophilic contaminant that bioaccumulates in adipose tissue, may promote TASH through unclear mechanisms. In this study, we investigated whether PCB138 induces liver injury via hepatic iron dysregulation and adipose-liver inflammatory signaling. Male C57BL/6 mice received intraperitoneal PCB138 (1, 5, 10, or 50 mg/kg, four injections over six weeks). HepG2 hepatocytes were treated with PCB138 with or without ferric ammonium citrate (FAC), and PCB138-exposed 3T3-L1 adipocytes were co-cultured with HepG2 cells using a Transwell system. PCB138 dose-dependently increased serum transaminase and hepatic non-heme iron levels, with Hamp upregulation, macrophage infiltration, and fibrosis. In HepG2 cells, PCB138 synergized with FAC to elevate intracellular Fe²⁺, induced Hamp, suppressed Slc40a1, and upregulated inflammatory/profibrotic genes. In Transwell co-cultures, TNF-α, IL-6, and IL-1β from PCB138-exposed adipocytes amplified hepatic iron dysregulation and fibrotic responses. These findings demonstrated that PCB138 induced TASH through hepatic iron dysregulation and adipose-derived inflammatory signaling, independent of steatosis. These results highlighted the iron–adipose axis as a novel mechanistic link between PCB138 exposure and liver injury, offering potential therapeutic targets. Full article

Obesity, a global health crisis, is linked to chronic low-grade inflammation and an increased risk of developing various chronic diseases, including psoriasis. Probiotics, postbiotics, and fermented foods have shown promise in combating inflammation and obesity. This study aimed to develop and characterize a chicory extract fermented with Bacteroides fragilis (C-B. fragilis) and its supernatant (phyto-postbiotic supernatant, PPS) as potential treatments for obesity, inflammation, and psoriasis. Polyphenols, organic acids, and amino acids were identified in the metabolic profile of C-B. fragilis. PPS and C-B. fragilis extract both revealed potent anti-inflammatory, anti-obesity, and antioxidant activities. In vitro assays highlighted that PPS significantly reduced the production of reactive oxygen species (ROS), the expression of pro-inflammatory cytokines (TNF-α, IL-6, IL-8) in macrophages, and the secretion of IL-1β in LPS-stimulated PBMCs. Moreover, PPS decreased triglyceride content in human adipocytes and modulated the expression of leptin and adiponectin. Regarding psoriasis, PPS reduced pro-inflammatory cytokines (IL-6, IL-1β) in both psoriatic keratinocytes and a co-culture model mimicking the skin-adipose tissue interface. In addition, PPS lowered S100 calcium-binding protein A7 (S100A7) expression in the co-culture model, suggesting a potential role in restoring skin barrier function. In summary, our results highlight the potential of PPS extract (supernatant of chicory fermentation by Bacteroides fragilis) as a promising therapeutic strategy for the management of obesity-related inflammation and psoriasis. Full article

Obesity is characterized by chronic low-grade inflammation, largely driven by macrophage infiltration into adipose tissue, which contributes to the development of insulin resistance. All-trans retinoic acid (ATRA), a biologically active metabolite of vitamin A, has demonstrated anti-inflammatory properties. This study examined the effects of ATRA on inflammation and insulin resistance using a coculture model comprising hypertrophied 3T3-L1 adipocytes and RAW264.7 macrophages. Coculture markedly elevated the production of pro-inflammatory mediators—including nitric oxide, monocyte chemoattractant protein-1, tumor necrosis factor-alpha, and interleukin-6—and increased free fatty acid release while suppressing the secretion of anti-inflammatory adiponectin. Treatment with ATRA (0.1, 1, and 10 μM) significantly reversed these coculture-induced alterations (p < 0.001). ATRA also inhibited the nuclear translocation of NF-κB and downregulated the expression of retinol-binding protein 4 (RBP4). Moreover, ATRA improved insulin-stimulated glucose uptake in adipocytes rendered insulin-resistant by coculture (p < 0.01), an effect associated with the restoration of glucose transporter 4 (GLUT4) and insulin receptor substrate-2 (IRS-2) expression. These findings suggest that ATRA effectively mitigates inflammation and insulin resistance arising from adipocyte–macrophage interactions, highlighting its potential as a therapeutic agent for obesity-related metabolic disorders. Full article

Background: Immune dysregulation has emerged as a central mechanism in atrial fibrillation (AF), with accumulating evidence implicating T-cell subsets, cellular senescence, checkpoint dysfunction, and inflammatory signaling. Although individual studies have provided important insights, a comprehensive synthesis across histological, mechanistic, prognostic, and genetic domains has been lacking. Methods: We systematically reviewed 16 studies published between 2009 and 2025, encompassing histological investigations, translational and mechanistic analyses, interventional cohorts, prognostic studies, and Mendelian randomization. Data on immune cell subsets, cytokines, signaling pathways, and clinical outcomes were extracted. Risk of bias was assessed using ROBINS-I and RoB 2, while certainty of evidence was graded using the GRADE framework. Results: Histological studies consistently demonstrated infiltration of atrial tissue by T lymphocytes and macrophages, with greater intensity in persistent and permanent AF, causally linked to atrial dilatation and fibrosis. Epicardial adipose tissue emerged as a key reservoir of tissue-resident memory T cells that promote IL-17- and IFN-γ-mediated fibroinflammatory remodeling. Mechanistic analyses highlighted CD8⁺PAR1⁺ cytotoxic T cells, PD-1/PD-L1 checkpoint disruption, and adipose–myocardial crosstalk as pivotal drivers of AF. Prognostic studies indicated that immune biomarkers provide incremental predictive value beyond conventional risk scores, while genetic evidence supported a causal role for immune dysregulation in AF susceptibility and progression. Conclusions: Across multiple levels of evidence, immune dysregulation is a primary determinant of AF development, progression, and outcomes. Integration of immune biomarkers into clinical practice may enhance risk stratification and inform the design of immune-targeted therapies for atrial fibrillation. Full article

The tumor microenvironment (TME) comprises neoplastic and stromal cells, and extracellular matrix elements, all engaging in a complex interplay that ultimately dictates tumorigenesis, cancer progression, and therapeutic response. While extensive research on the TME has been conducted in human oncology, data on its veterinary counterpart, particularly in feline mammary tumors (FMTs), are still scarce. In this review, we explore current understanding of feline mammary carcinoma (FMC) microenvironment, focusing on tumor necrosis, fibrosis, angiogenesis, adipose tissue tumor-associated inflammation, extracellular vesicles, and epithelial–mesenchymal transition (EMT) and their prognostic implications. In FMC, remodeling of collagen fibers, cancer-associated fibroblasts (CAFs), regulatory T cells (Tregs) and elevated serum leptin have been associated with poor prognosis, whereas stromal cytotoxic T cells correlate with more favorable outcomes. By contrast, findings on necrosis and pro-angiogenic factors remain inconsistent, and research on extracellular vesicles (EVs) is still in its early stages. This review presents insights from human breast cancer (HBC) that further support and elucidate the potential relevance of these TME components. As FMCs are highly aggressive tumors, a deeper understanding of their microenvironment could not only improve prognostic accuracy but also uncover novel therapeutic targets. Furthermore, due to their similarities, FMCs offer a potential valuable spontaneous model for HBC, particularly for the aggressive triple-negative phenotypes. Full article

(1) Background: The present study investigated the effects of extracellular vesicles (EVs), derived from adipose tissue stem cells (ADSCs) and bone marrow mesenchymal stem cells (BMMSCs), on atherosclerosis-associated cardiac hypertrophy. (2) Methodology: The experiments were performed on hamsters divided into the following groups: control (C) fed with a standard diet; hypertensive–hyperlipidemic (HH) generated by combining a diet enriched with 3% cholesterol, 15% butter, and by gavage with 8% NaCl on a daily basis; HH groups injected with EVs (ADSCs) or EVs (BMMSCs), either transfected with Smad2/3 siRNAs or not (HH-EVs (ADSCs), HH-EVs (BMMSCs), HH-EVs (ADSCs) + Smad2/3siRNA, HH-EVs (BMMSCs) + Smad2/3siRNA); and HH group injected with Smad2/3 siRNAs (HH-Smad2/3siRNA). (3) Results: In comparison with the HH group, the findings demonstrated that treatment using EVs (ADSCs or BMMSCs), either with or without Smad2/3 siRNAs, resulted in several significant improvements in the following aspects: the plasma levels of cholesterol, LDL, triglycerides, TGF-β1, and Ang II were decreased; the left ventricular structure and function were recovered; inflammatory markers, ROS, COL1A, α-SMA, Cx43, MIF, ANF, and M1/M2 macrophages, were reduced; the level of key protein NF-κB p50 was diminished. (4) Conclusions: These findings underscore the therapeutic potential of mesenchymal stem cell-derived EVs in atherosclerosis-associated cardiac hypertrophy. Full article

Exposure to persistent organic pollutants such as 2,3,7,8-tetrachlorodibenzodioxin (TCDD) increases metabolic disorder risk. In this study, we show that a single intraperitoneal injection of TCDD (10 μg/kg) in C57BL/6J mice induced body weight gain, lipid accumulation in the liver and adipose tissue, macrophage infiltration, and elevated hepatic and serum triglyceride levels after 12 weeks. Despite serum aryl hydrocarbon receptor (AhR) ligand levels normalizing by 12 weeks, the persistent effects suggest TCDD sequestration in fat tissue. TCDD inhibited the expression of mitochondrial proteins (COX1, TOM20, TFAM, H2AX) and reduced mitochondrial oxygen consumption. Liver-specific AhR knockout ameliorated TCDD-induced mitochondrial dysfunction, lipid accumulation, and macrophage infiltration. Mechanistically, TCDD-induced hepatic plasminogen activator inhibitor-1 (PAI-1) promoted adipocyte hypertrophy. In the liver, PAI-1 disrupted the interaction between tissue-type plasminogen activator (tPA) and apolipoprotein B (ApoB), thereby enhancing very-low-density lipoprotein (VLDL) assembly. These findings reveal that hepatocyte-derived circulating PAI-1, upregulated via hepatic AhR activation, contributes to adipocyte hypertrophy and hepatosteatosis through the intracellular modulation of the tPA–PAI-1 axis. Thus, hepatic AhR activation drives mitochondrial dysfunction and obesity, even after a single TCDD exposure. Full article

Iron is essential for cellular respiration, oxidative defense, and host immunity, but its dysregulation is increasingly associated with metabolic disorders, such as obesity and type 2 diabetes. In these diseases, regional iron accumulation occurs in adipose tissue, independent of systemic overload. This process disrupts the mitochondrial redox balance, induces ferroptotic stress, and activates the innate immune pathways. Recent studies have highlighted the NLRP3 (nucleotide-binding domain, leucine-rich repeat, pyrin domain-containing protein 3) inflammasome and its effector cytokine interleukin-1β (IL-1β) as important mediators of the interface between iron and inflammation. In both adipocytes and macrophages, labile iron increased reactive oxygen species (ROS) production and promoted inflammasome formation. Simultaneously, metabolic stress factors upregulate hepcidin expression, suppress ferroportin activity and exacerbate intracellular iron retention. These molecular events converge to maintain low-grade inflammation and impair insulin signaling. Despite these compelling associations, direct mechanistic evidence remains limited, particularly with respect to depot-specific responses and cell type resolution. In this review, I examine the current evidence linking iron handling and inflammasome biology in adipose tissue, focusing on ferroptosis, thioredoxin-interacting protein (TXNIP) signaling, and spatial mapping of iron–cytokine networks. I also discuss novel therapeutic strategies targeting iron overload and inflammasome activation, including chelation, hepcidin modulation, and inflammasome inhibition in the context of metabolic diseases. Full article

Aims: Diabetes mellitus (DM) increases cardiovascular risk by inducing atherosclerotic plaque instability. StemBell therapy (i.e., adipose tissue-derived stem cells (ASCs) coupled to ultrasound-activated microbubbles) previously improved plaque stability in non-DM ApoE^−/− mice. Here, we investigated the effect of StemBell therapy on atherosclerotic plaque characteristics in a streptozotocin-induced DM mouse model. Methods: DM was induced in male C57BL/6 ApoE^−/− mice (n = 18) via intraperitoneal streptozotocin (STZ) injection (0.05 mg/g bodyweight) for 5 consecutive days. Eight weeks after the first STZ injection, the mice received either 5 × 10⁵ StemBells or vehicle intravenously. Due to unexpected mortality, the experiment was halted and restarted in week 9 with a final reduced dose of 1.25 × 10⁵ StemBells to avoid complications. The effect of StemBell therapy on plaque characteristics was determined 4 weeks post-treatment in five vehicle-treated and five StemBell-treated mice via (immuno)histochemical analyses. Furthermore, plasma monocyte subsets within 3 days pre- and 3 days post-treatment, and 3 weeks post-treatment, were studied via flow cytometry. Results: StemBell therapy did not significantly affect atherosclerotic plaque size or intra-plaque inflammation. StemBell-treated mice had less intra-plaque Ly6G+ neutrophils (0.4 ± 0.5%) and intra-plaque Mac3+ pan-macrophages (17.7 ± 3.4%), but more CD163+ anti-inflammatory M2 macrophages (p = 0.5) compared to vehicle-treated mice, although this was non-significant. Conclusions: StemBell therapy did not significantly affect atherosclerotic plaque size or intra-plaque inflammation in a streptozotocin-induced DM mouse model. Future research is essential to explore the potential and limitations of StemBell therapy in DM-related atherosclerosis. The higher mortality of StemBell therapy in diabetic mice compared to the previous non-diabetic mice also warrants further investigation. Full article

Interferon regulatory factor 5 (IRF5) plays a pivotal role in innate immune responses and macrophage polarization. Although its role in obesity-associated inflammation has been described, sex-specific differences in adipose IRF5 expression and its association with immune and metabolic markers remain poorly defined. To evaluate sex-specific associations between adipose tissue (AT) IRF5 expression and key inflammatory and metabolic markers in overweight and obese individuals. Subcutaneous AT samples from overweight/obese male and female subjects were analyzed for IRF5 expression using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Correlation and multiple linear regression analyses were performed to identify its associations with inflammatory gene expression and metabolic parameters including insulin, glucose, HOMA-IR, and adipokines. RF5 gene and protein levels were significantly elevated in the AT of overweight/obese females compared to males (p < 0.0001), with expression increasing progressively with BMI in females but not in males. Despite these sex-dependent expression levels, IRF5 demonstrated consistent, sex-independent positive correlations with several core immune and inflammatory markers, including CCR5, CD11c, CD16, CD163, FOXP3, RUNX1, and MyD88. However, distinct sex-specific patterns emerged: in males, IRF5 correlated positively with classical pro-inflammatory markers such as IL-2, IL-6, IL-8, TNF-α, and IRAK1; whereas in females, IRF5 was associated with a broader array of immune markers, including chemokines (CCL7, CXCL11), pattern recognition receptors (TLR2, TLR8, TLR9), and macrophage markers (CD68, CD86), along with anti-inflammatory mediators such as IL-10 and IRF4. Notably, IRF5 expression in overweight/obese males, but not females, was significantly associated with metabolic dysfunction, showing positive correlations with fasting blood glucose, HbA1c, insulin, and homeostatic model assessment for insulin resistance (HOMA-IR) levels. Multiple regression analyses revealed sex-specific predictors of IRF5 expression, with metabolic (HOMA-IR) and inflammatory (IRAK1, MyD88) markers emerging in males, while immune-related genes (RUNX1, CD68, CCL7, MyD88) predominated in females. These findings underscore a sex-divergent role of IRF5 in AT, with implications for differential regulation of immune-metabolic pathways in obesity and its complications. Full article

Obesity poses a serious threat to human health, with induced skeletal muscle dysfunction significantly increasing the risk of metabolic syndrome. In obesity, it is known that visceral adipose tissue (VAT) mediates the dysregulation of the adipose–muscle axis through exosome-delivered miRNAs, but the associated regulatory mechanisms remain incompletely elucidated. This study established an AAV-mediated miR-155 obese mouse model and a co-culture system (HFD VAD-evs/RAW264.7 cells/C2C12 cells) to demonstrate that high-fat diet-induced VA-derived extracellular vesicles (HFD VAD-evs) preferentially accumulate in skeletal muscle and induce developmental impairment. HFD VAD-evs disrupt skeletal muscle homeostasis through dual mechanisms: the direct suppression of myoblast development via exosomal miR-155 cargo and the indirect inhibition of myogenesis through macrophage-mediated inflammatory responses in skeletal muscle. Notably, miR-155 inhibition in HFD VAD-evs reversed obesity-associated myogenic deficits. These findings provide novel mechanistic insights into obesity-induced skeletal muscle dysregulation and facilitate potential therapeutic strategies targeting exosomal miRNA signaling. Full article

Kupffer cells (KCs) play a pivotal role in the progression of metabolic-associated steatohepatitis (MASH). This study evaluated the impact of short-term KC depletion induced by gadolinium chloride (GdCl₃) in a rat model of MASH. The intervention with GdCl₃ effectively reduced KC markers CD68 and Clec4f, together with pro-inflammatory cytokines (IL-1β, TNFα, NOS2), without affecting anti-inflammatory markers (IL-10, MRC1). Histologically, GdCl₃ reduced hepatocyte ballooning and NAS despite persistent steatosis. KC depletion was associated with decreased oxidative stress markers (TBARS, 3-nitrotyrosine) and antioxidant enzyme activity (SOD, catalase). Additionally, markers of endoplasmic reticulum stress (ATF4, GRP78, CHOP, P58^IPK) and apoptosis (BAX/BCL2 ratio, cleaved caspase-3) were diminished. Despite these improvements, GdCl₃ had no effect on lipid or glucose metabolism in the liver, associated with persistent elevation of PTP1B expression induced by SRD intake. KC depletion, however, increased FGF21 expression. GdCl₃ treatment improved systemic insulin sensitivity and reduced fasting glucose and NEFA serum levels. In white adipose tissue, the treatment decreased adipocyte size, restored insulin signaling, and inhibited lipolysis (ATGL expression) without altering macrophage infiltration (IBA) or thermogenic protein levels (UCP1) in SRD rats. These findings suggest that KC depletion modulates liver-to-adipose tissue crosstalk, potentially through FGF21 signaling, contributing to improved systemic metabolic homeostasis of SRD animals. Full article

Background: Sodium–glucose cotransporter-2 inhibitors (SGLT2is), initially developed as antihyperglycemic agents, have emerged as multifunctional therapeutics with profound cardiorenal and metabolic benefits. Their unique insulin-independent mechanism, targeting renal glucose reabsorption, distinguishes them from conventional antidiabetic drugs. Mechanisms and Clinical Evidence: SGLT2is induce glycosuria, reduce hyperglycemia, and promote weight loss through increased caloric excretion. Beyond glycemic control, they modulate tubuloglomerular feedback, attenuate glomerular hyperfiltration, and exert systemic effects via natriuresis, ketone utilization, and anti-inflammatory pathways. Landmark trials (DAPA-HF, EMPEROR-Reduced, CREDENCE, DAPA-CKD) demonstrate robust reductions in heart failure (HF) hospitalizations, cardiovascular mortality, and chronic kidney disease (CKD) progression, irrespective of diabetes status. Adipose Tissue and Metabolic Effects: SGLT2is mitigate obesity-associated adiposopathy by shifting macrophage polarization (M1 to M2), reducing proinflammatory cytokines (TNF-α, IL-6), and enhancing adipose tissue browning (UCP1 upregulation) and mitochondrial biogenesis (via PGC-1α/PPARα). Modest weight loss (~2–4 kg) occurs, though compensatory hyperphagia may limit long-term effects. Emerging Applications: Potential roles in non-alcoholic fatty liver disease (NAFLD), polycystic ovary syndrome (PCOS), and neurodegenerative disorders are under investigation, driven by pleiotropic effects on metabolism and inflammation. Conclusions: SGLT2is represent a paradigm shift in managing T2DM, HF, and CKD, with expanding implications for metabolic syndrome. Future research should address interindividual variability, combination therapies, and non-glycemic indications to optimize their therapeutic potential. Full article