Search Results (132)

Background: Epicardial adipose tissue (EAT) is a metabolically active organ implicated in coronary artery disease (CAD); however, its role in aortic stenosis (AS) remains unclear. Advanced glycation end products (AGEs) and their receptor (RAGE) promote cardiovascular tissue inflammation. This study aimed to investigate whether inflammatory activity within the EAT, particularly involving the AGEs-RAGE axis, is associated with AS. Methods: We studied 42 patients (isolated AS, n = 15; AS with CAD, n = 15; and CAD alone, n = 12) undergoing surgical intervention, along with 10 autopsy controls. EAT volume was assessed via computed tomography and indexed to body surface area. Furthermore, macrophage infiltration (CD68) and RAGE expression in EAT samples were analyzed using immunohistochemistry and immunofluorescence imaging. Results: EAT volume index was significantly higher in all surgical groups than in the controls (p < 0.001). These surgical groups also had markedly increased CD68- and RAGE-positive cells compared with the controls (p < 0.001), with colocalization detected by means of immunofluorescence imaging. Additionally, the EAT volume index independently and positively correlated with CD68-positive cell counts (p = 0.021), and causal mediation analysis suggested that it promotes CD68-positive macrophage activation through pathways mediated by RAGE-positive cells (p = 0.024). Inflammatory cells did not correlate with AS severity (maximum aortic jet velocity, mean pressure gradient, aortic valve area). Conclusions: EAT in AS exhibits increased macrophage infiltration and RAGE expression. Therefore, the AGEs-RAGE axis may contribute to local inflammatory activity, and EAT can be a potential biomarker and therapeutic target in AS. Full article

Macrophages accumulate in visceral adipose tissue (VAT) during hypertension and may contribute to hypertension-associated inflammation. Exercise has shown beneficial effects on hypertension; however, the exact mechanisms by which the activated immune cells lead to the protective effects remain unclear. Our study aimed to determine how exercise influences VAT inflammation by modulating the macrophage polarization in hypertensive mice. Renin transgenic (R+) mice were used as a hypertensive mouse model and subjected to exercise (8 weeks). The body weight and blood pressure were monitored, VAT morphology was assessed by H&E and Masson Trichrome staining, macrophage polarization was determined by immunostaining and flow cytometry, and macrophage phenotype-related proteins were analyzed within the VAT via Western Blots. Results showed that exercise reduced the adipocyte size and collagen content of VAT and increased cell infiltration in R+ mice. Immunostaining and flow cytometry data showed that the ratio of pro-inflammatory macrophages (M1) to anti-inflammatory macrophages (M2) was increased in the VAT of R+ mice, while exercise corrected the macrophage polarization, which was consistent with protein level changes in VAT. Together, our data suggest that exercise improves vascular remodeling and VAT function (reduced adipocyte size, loss of collagen) by modulating VAT inflammation (polarization of macrophages) in hypertensive mice. 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 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

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

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

Adipose tissue inflammation contributes to obesity-induced insulin resistance. However, increasing evidence shows that high BMI (obesity) is not an accurate predictor of poor metabolic health in individuals. The molecular mechanisms regulating the metabolically activated M1 macrophage phenotype in the adipose tissues leading to insulin resistance remain largely unknown. Although the Janus Kinase (Jak)/signal transducer and activator of transcription 3 (Stat3) signaling in myeloid cells are known to promote the M2 phenotype in tumors, we demonstrate here that the Jak2/Stat3 pathway amplifies M1-mediated adipose tissue inflammation and insulin resistance under metabolic challenges. Ablating Jak2 in the myeloid compartment reduces insulin resistance in obese mice, which is associated with a decrease in infiltration of adipose tissue macrophages (ATMs). We show that the adoptive transfer of Jak2-deficient myeloid cells improves insulin sensitivity in obese mice. Furthermore, the protection of obese mice with myeloid-specific Stat3 deficiency against insulin resistance is also associated with reduced tissue infiltration by macrophages. Jak2/Stat3 in the macrophage is required for the production of pro-inflammatory cytokines that promote M1 macrophage polarization in the adipose tissues of obese mice. Moreover, free fatty acids (FFAs) activate Stat3 in macrophages, leading to the induction of M1 cytokines. Silencing the myeloid cell Stat3 with an in vivo siRNA targeted delivery approach reduces metabolically activated pro-inflammatory ATMs, thereby alleviating obesity-induced insulin resistance. These results demonstrate Jak2/Stat3 in myeloid cells is required for obesity-induced insulin resistance and inflammation. Moreover, targeting Stat3 in myeloid cells may be a novel approach to ameliorate obesity-induced insulin resistance. Full article

The conversion of carbohydrates into fatty acids is central for energy storage and the development and functioning of organs. Our previous study revealed that Hacd2 deficiency alleviates the fatty liver and diabetes induced by HFD. This study aimed to explore the roles of Hacd2 in organ development and metabolic homeostasis under an LFHCD, which still need to be more deeply explored. We found that the germline deletion of Hacd2 impairs long-chain fatty acid synthesis, which caused embryonic abnormalities after 7.5 days and led to embryonic lethality, as confirmed via photograph and hematoxylin-eosin staining. We next constructed Hacd2LKO mice and found that Hacd2LKO mice were largely normal when fed a chow diet, except for reduced inguinal white adipose tissue formation and glucose metabolism. Meanwhile, under an LFHCD, Hacd2 deletion markedly controlled body weight and white adipose tissue formation, leading to lower cholesterol and triglycerides in serum; however, it unexpectedly resulted in enlarged liver volume, hepatocyte swelling and nuclear abnormalities, and infiltration of inflammatory cells, including macrophages, neutrophils and dendritic cells. Furthermore, inhibition of Hacd2 also reduced triglyceride levels and the expression of related lipogenic genes during adipocyte differentiation, as confirmed via RNA interference analysis. These findings highlight the critical roles of Hacd2 in embryonic development and metabolic diseases, revealing its protective function in maintaining liver homeostasis under an LFHCD. Therefore, targeted interventions involving Hacd2 for metabolic diseases must take into account dietary changes and the functioning of the liver. Full article

Obesity is characterized by excessive fat accumulation that triggers chronic low-grade inflammation and systemic immune dysregulation, significantly increasing the risk of metabolic disorders including insulin resistance, type 2 diabetes, and cardiovascular disease. This review examines the bidirectional relationship between obesity and immune dysfunction, focusing on how immune cell infiltration in adipose tissue drives inflammatory processes. We highlight the phenotypic shifts in key immune populations—macrophages polarized toward proinflammatory M1 phenotypes, T cell exhaustion occurrs, and alterations appear in B cells, natural killer (NK) cells, and dendritic cells—that collectively contribute to metabolic deterioration. The gut microbiome emerged as a critical mediator in this relationship, influencing both immune responses and metabolic regulation through gut–liver and gut–brain axes. We explore emerging immunomodulatory therapeutic strategies, including anti-inflammatory agents, microbiota interventions, and targeted immune therapies such as innovative nanomedicine approaches. The review also addresses the challenges of immunotherapy in obesity, particularly the paradoxical effects observed in cancer immunotherapy outcomes and the need for personalized treatment approaches. Artificial intelligence is highlighted as a potential tool to enhance patient stratification and treatment optimization in future immunomodulatory interventions. Understanding these immunometabolic interactions provides a foundation for developing more effective therapeutic strategies that could transform obesity management and reduce the burden of obesity-related metabolic diseases. Full article

Obesity, a global health concern of increasing significance, is characterized by chronic low-grade inflammation (LGCI) that significantly contributes to metabolic dysfunction. This narrative review explores the intricate pathophysiological mechanisms driving LGCI in obesity, emphasizing the role of adipose tissue, immune cell activation, and inflammatory signaling pathways. Hypertrophic adipocytes and infiltrating immune cells, particularly macrophages, release a cascade of pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1β, creating a self-perpetuating cycle of inflammation. These mediators disrupt insulin signaling through JNK and NF-κB pathway activation, leading to systemic insulin resistance, cardiovascular complications, gut dysbiosis and other metabolic disorders. The review further discusses therapeutic strategies to mitigate obesity-related LGCI, focusing on lifestyle interventions, nutritional approaches, and pharmacological agents. Physical activity, specific nutrients, and dietary patterns can modulate inflammatory responses, while anti-obesogenic medicines and bariatric procedures offer additional avenues for intervention. By understanding and addressing the root causes of inflammation in obesity, healthcare professionals can develop targeted strategies to improve metabolic health and overall well-being of individuals with obesity and, ultimately, prevent and manage the wide-ranging complications associated with this condition. Full article

Over the years, there has been a tendency for an increase in global obesity. The World Health Organization’s (WHO) 2024 report states that in 2019, more than one billion people were obese, and this condition was responsible for five million deaths, being that obesity is more prevalent among adults compared to adolescents and children. Obesity is a chronic disease characterized by alterations in adipose tissue. When excessive food is consumed and energy expenditure is low, adipose tissue undergoes hypertrophy and hyperplasia. This process activates B cells and induces the transition of anti-inflammatory M2-like macrophages into pro-inflammatory M1-like macrophages. B cells, acting as inflammatory mediators, stimulate pro-inflammatory CD8+ T cells, and promote macrophage infiltration into tissues. This condition triggers inflammation, increases oxidative stress, and ultimately leads to cellular death. During inflammation, an increase of pro-inflammatory cytokines occurs along with a decrease of anti-inflammatory cytokines. By contrast, the increase of oxidative stress is related to an increase of reactive oxygen species (ROS), oxidation of biomolecules, and a decrease in antioxidants. This mechanism for obesity can be mitigated through several healthy lifestyle changes, primarily including regular physical activity and healthy eating. These factors help reduce pro-inflammatory mediators and ROS, lowering inflammation and oxidative stress. Therefore, this review article focuses on studying the bioactive compounds present in the edible leaves of Annona cherimola Mill., Ipomoea batata (L.) Poir., Colocasia esculenta (L.) Schott, Eriobotrya japonica, Cymbopogon citratus, Psidium guajava (L.), and Smallanthus sonchifolius to evaluate their effects on the mechanisms involved in obesity. Full article

In obesity, recent research revealed that increased expression of the growth hormone secretagogue receptor (GHSR) in macrophages plays a pivotal role in the development of meta-inflammation, promoting macrophage infiltration and pro-inflammatory polarization. This study aimed to examine the association between GHSR-1a expression in atherosclerotic plaques and adjacent perivascular adipose tissue (PVAT) from 11 patients with obesity and peripheral artery disease (PAD) who underwent revascularization procedures. Immunohistochemistry was used to assess the expression of CD68, CD80, and CD14, while tissue homogenate levels of adiponectin, leptin, IL-6, and CRP were quantified via ELISA. Serum markers of inflammation were also measured. Among patients with GHSR-1a-positive (+) macrophages in atherosclerotic plaques, we observed significantly higher white blood cell counts and platelet-to-lymphocyte ratios in serum, a lower adiponectin-to-leptin ratio, and elevated IL-6 levels in both arterial and PVAT homogenates. Our findings suggest a link between GHSR-1a and macrophage/monocyte infiltration, macrophage polarization, and adipocytokine secretion in atherosclerotic plaques associated with obesity-induced PVAT dysfunction. Full article

Perivascular adipose tissue (PVAT) regulates vascular tone and is composed of adipocytes and several leukocyte subpopulations. Diet can modify PVAT function, as obesogenic diets cause morphological changes to adipocytes and skew the leukocyte phenotype, leading to PVAT dysregulation and impaired vasoregulation. Of note, platelets, the clot-forming cells, also modulate many facets of leukocyte activity, such as tissue infiltration and polarity. We aimed to determine whether platelets regulate the leukocyte populations residing within PVAT. Male C57Bl/6J mice were fed a Western diet (30% kcal sucrose, 40% kcal fat, 8.0% sodium) to develop obesogenic conditions for PVAT leukocyte remodeling. Diet was either administered acutely (2 weeks) or extended (8 weeks) to gauge the length of challenge necessary for remodeling. Additionally, platelet depletion allowed for the assessment of platelet relevance in PVAT leukocyte remodeling. Abdominal PVAT (aPVAT) and thoracic PVAT (tPVAT) were then isolated and leukocyte composition evaluated by flow cytometry. Compared to control, Western diet alone did not significantly impact PVAT leukocyte composition for either diet length. Platelet depletion, independent of diet, significantly disrupted PVAT leukocyte content with monocytes/macrophages most impacted. Furthermore, tPVAT appeared more sensitive to platelet depletion than aPVAT, providing novel evidence of platelet regulation of leukocyte composition within PVAT depots. Full article