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Obesity has become one of the main threats to health worldwide and therefore gained increasing clinical and economic significance as well as scientific attention. General adipose-tissue accumulation in obesity is associated with systemically increased pro-inflammatory mediators and humoral and cellular changes within this compartment. These adipose-tissue changes and their systemic consequences led to the concept of obesity as a chronic inflammatory state. A pathognomonic feature of Crohn's disease (CD) is creeping fat (CF), a locally restricted hyperplasia of the mesenteric fat adjacent to the inflamed segments of the intestine. The precise role of this adipose-tissue and its mediators remains controversial, and ongoing work will have to define whether this compartment is protecting from or contributing to disease activity. This review aims to outline specific cellular changes within the adipose-tissue, occurring in either obesity or CF. Hence the potential impact of adipocytes and resident immune cells from the innate and adaptive immune system will be discussed for both diseases. The second part focuses on the impact of generalized adipose-tissue accumulation in obesity, respectively on the locally restricted form in CD, on intestinal inflammation and on the closely related integrity of the mucosal barrier.

PAD4-mediated hypercitrullination of histone H4 arginine 3 (H4R3) has been previously found to promote the formation of Neutrophil Extracellular Traps in inflamed tissues and the resulting histone H4 citrulline 3 (H4Cit3) modification is thought to play a key role in extracellular trap (ET) formation by promoting chromatin decondensation. In addition to neutrophils, macrophages have also recently been found to generate functional extracellular traps (METs). However, a role for PADs in ET formation in macrophages has not been previously described. Transcripts for PAD2 and PAD4 are found in mature macrophages and these cells can be induced to citrullinate proteins, thus raising the possibility that PADs may play a direct role in ET formation in macrophages via histone hypercitrullination. In breast and visceral white adipose tissue from obese patients, infiltrating macrophages are often seen to surround dead adipocytes forming characteristic \"crown-like structures\" (CLS) and the presence of these lesions is associated with increased levels of inflammatory mediators. In light of these observations, we have initiated studies to test whether PADs are expressed in CLS macrophages and whether these macrophages might form METs. Our preliminary findings show that PAD2 (and to a lesser extent, PAD4) is expressed in both in the macrophage cell line (RAW 264.7) and in CLS lesions. Additionally, we provide evidence that macrophage-derived extracellular histones are seen around presumptive macrophages within CLS lesions and that these histones contain the H4Cit3 modification. These initial findings support our hypothesis that obesity-induced adipose tissue inflammation promotes the formation of METs within CLS lesions via PAD-mediated histone hypercitrullination. Subsequent studies are underway to further validate these findings and to investigate the role in PAD-mediated MET formation in CLS function in the mammary gland.

[This corrects the article DOI: 10.3389/fphar.2025.1576521.].

Abstract Context Metabolic disturbances and a pro-inflammatory state associated with aging and obesity may be mitigated by physical activity or nutrition interventions. Objective The aim of this study is to assess whether physical fitness/exercise training (ET) alleviates inflammation in adipose tissue (AT), particularly in combination with omega-3 supplementation, and whether changes in AT induced by ET can contribute to an improvement of insulin sensitivity and metabolic health in the elderly. Design, Participants, Main Outcome Measures The effect of physical fitness was determined in cross-sectional comparison of physically active/physically fit (trained) and sedentary/less physically fit (untrained) older women (71 ± 4 years, n = 48); and in double-blind randomized intervention by 4 months of ET with or without omega-3 (Calanus oil) supplementation (n = 55). Physical fitness was evaluated by spiroergometry (maximum graded exercise test) and senior fitness tests. Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp. Samples of subcutaneous AT were used to analyze mRNA gene expression, cytokine secretion, and immune cell populations. Results Trained women had lower mRNA levels of inflammation and oxidative stress markers, lower relative content of CD36+ macrophages, and higher relative content of γδT-cells in AT when compared with untrained women. Similar effects were recapitulated in response to a 4-month ET intervention. Content of CD36+ cells, γδT-cells, and mRNA expression of several inflammatory and oxidative stress markers correlated to insulin sensitivity and cardiorespiratory fitness. Conclusions In older women, physical fitness is associated with less inflammation in AT. This may contribute to beneficial metabolic outcomes achieved by ET. When combined with ET, omega-3 supplementation had no additional beneficial effects on AT inflammatory characteristics.

Background. Synovial collagen remodelling may mirror chronic inflammation and repair processes, potentially serving as a structural correlate of disease activity in arthritis. Based on this, the aim of this study was to investigate the relationship between synovial inflammatory histopathology and collagen remodelling in patients with active rheumatoid arthritis (RA) or psoriatic arthritis (PsA).   Methods. US-guided synovial biopsies were obtained from inflamed joints (knee/wrist) in 30 patients (18 RA, 12 PsA) with active arthritis, undergoing therapeutic re-evaluation.Synovial inflammation was evaluated considering Krenn Synovitis Score (KSS), immunohistochemical analysis (sublining CD68, CD3, CD20, CD138), pathotype classification, and evaluation of neutrophil infiltration.For 12 patients (RA, PsA),3-micrometer sections were stained with fresh Picrosirius red,then digitized via brightfield and polarized light microscopy for morphometry and collagen typing.Stained area and collagen maturation index were quantified using computer-aided image analysis.Clinical disease activity was recorded at baseline and at 3-month follow-up.   Results. The mean age of patients was 52 years and 64.5% were female;the mean disease duration was 5.6 years. Mean KSS was 4.5±0.5 in RA and 4.2±0.5 in PsA. 17 (56.7%) patients were classified as lympho-myeloid, 10(33.3%) as diffuse-myeloid,and 3(10%) as pauci-immune pathotype.Moreover, neutrophil infiltration of ST was present in 12(40%) of the overall cohort and was associated with higher KSS (p = 0.003).Higher KSS also tended to correlate with the number of previous bDMARDs, and pathotype distribution differed by prior biologic exposure (p = 0.029);notably, patients with a pauci-immune synovitis had received the highest number of previous bDMARDs. Considering collagen deposition,the mean collagen area was 39.48±7.52% in RA and 40.79±12.09% in PsA, while the mean collagen maturity index was 0.73±0.04 and 0.72±0.03, respectively.No associations were found between collagen parameters and sex, age, disease duration, or biopsy site. In RA, collagen area showed a trend toward inverse correlation with CD68+ macrophage infiltration (p = 0.057). In PsA, both collagen area and maturation index were inversely correlated with inflammatory infiltrate, B cells, and plasma cells (all p = 0.04). Additionally, disease duration in PsA was positively associated with both collagen area(p = 0.025) and collagen maturity index (p = 0.017), suggesting that long-standing disease may promote extracellular matrix stabilization. Importantly, a significant inverse correlation between collagen area and collagen maturity index was observed in RA (p = 0.047). At 3-month follow-up, histological pathotype was associated with DAS28 response: responders more frequently showed a diffuse-myeloid profile, while no responders were mostly observed among pauci-immune cases.   Conclusions. Synovial immune cell infiltration is associated with collagen remodelling in both RA and PsA, with distinct patterns linked to disease duration and tissue organization.The inverse correlation between collagen area and maturity in RA suggests matrix expansion during active synovitis.

Adipose tissue dysfunction and chronic inflammation contribute to atherosclerosis plaque development. Zhuriheng pills (ZRH) are an effective Mongolian herbal formula used in treating coronary heart disease in China, but their mechanisms of action have not been fully elucidated. To assess whether ZRH alleviates atherosclerosis (AS) and stabilizes plaque, this study investigates the modulatory effects of ZRH on AS and adipose tissue profiles in atherosclerotic model mice with vulnerable plaque to reveal the potential mechanisms and representative quality markers (Q-markers) of ZRH. the vulnerable atherosclerotic plaque model was induced in ApoE mice treated with intense co-stimulation. The anti-AS effect of ZRH was assessed by serum lipid profile, hematoxylin-eosin (HE), Oil O Red, Masson staining, immunohistochemistry (IHC), immunofluorescence, and plasma lipidomics. , a co-culture model was established with 3T3-L1 adipocytes treated with palmitic acid (PA) and RAW264.7 macrophages treated with lipopolysaccharide (LPS). The potential mechanism and Q-markers of ZRH were identified by lipid content test, inflammatory factors and adipocytokine analysis, flow cytometry for macrophage polarization, and Western blotting for PPAR and UCP-1 proteins. , ZRH stabilizes plaques by improving serum lipid profiles, lowering macrophage infiltration, and boosting collagen content in plaques. ZRH can counteract HFD-induced adipocyte hypertrophy, increase UCP-1 and PPARγ expression, enhance the \"browning\" of adipose tissue, and inhibit macrophage M1 polarization. Lipidomics results showed that ZRH treatment increased the abundance of lipid species with multiple unsaturated bonds and decreased harmful TAG, DAG, and HexCer. In addition, ZRH regulates inflammatory factors and adipokines in co-culture to inhibit macrophage M1 polarization and adipocyte abnormal lipid metabolism. In contrast, RDK and its monomers have a stronger anti-inflammatory effect, whereas GZ and its monomers regulate lipid metabolism better. ZRH was shown to be a PPARγ agonist for improving adipose tissue dysfunction and inflammation for anti-AS effects of ZRH. MIX, which comprises ellagic acid (G3), quercetin (G8), 3,3'-Di-O-methylellagic acid (G9), elemicin (R5), and safrole (R8) in equal proportions, is only one of ZRH's Q-markers. More research is needed on the roles of different ZRH metabolites. Our results demonstrated that ZRH stabilizes atherosclerotic plaques by ameliorating adipose tissue dysfunction and inflammation by regulating the PPARγ pathway.

Background Leptin-deficient ob/ob mice and leptin receptor-deficient db/db mice are commonly used mice models mimicking the conditions of obesity and type 2 diabetes development. However, although ob/ob and db/db mice are similarly gaining weight and developing massive obesity, db/db mice are more diabetic than ob/ob mice. It remains still unclear why targeting the same pathway—leptin signaling—leads to the development of two different phenotypes. Given that gut microbes dialogue with the host via different metabolites (e.g., short-chain fatty acids) but also contribute to the regulation of bile acids metabolism, we investigated whether inflammatory markers, bacterial components, bile acids, short-chain fatty acids, and gut microbes could contribute to explain the specific phenotype discriminating the onset of an obese and/or a diabetic state in ob/ob and db/db mice. Results Six-week-old ob/ob and db/db mice were followed for 7 weeks; they had comparable body weight, fat mass, and lean mass gain, confirming their severely obese status. However, as expected, the glucose metabolism and the glucose-induced insulin secretion were significantly different between ob/ob and db/db mice. Strikingly, the fat distribution was different, with db/db mice having more subcutaneous and ob/ob mice having more epididymal fat. In addition, liver steatosis was more pronounced in the ob/ob mice than in db/db mice. We also found very distinct inflammatory profiles between ob/ob and db/db mice, with a more pronounced inflammatory tone in the liver for ob/ob mice as compared to a higher inflammatory tone in the (subcutaneous) adipose tissue for db/db mice. When analyzing the gut microbiota composition, we found that the quantity of 19 microbial taxa was in some way affected by the genotype. Furthermore, we also show that serum LPS concentration, hepatic bile acid content, and cecal short-chain fatty acid profiles were differently affected by the two genotypes. Conclusion Taken together, our results elucidate potential mechanisms implicated in the development of an obese or a diabetic state in two genetic models characterized by an altered leptin signaling. We propose that these differences could be linked to specific inflammatory tones, serum LPS concentration, bile acid metabolism, short-chain fatty acid profile, and gut microbiota composition. DUGQcxDcUnuc9Bgg7Th-A2 Video abstract.

Immune cell infiltration in (white) adipose tissue (AT) during obesity is associated with the development of insulin resistance. In AT, the main population of leukocytes are macrophages. Macrophages can be classified into two major populations: M1, classically activated macrophages, and M2, alternatively activated macrophages, although recent studies have identified a broad range of macrophage subsets. During obesity, AT M1 macrophage numbers increase and correlate with AT inflammation and insulin resistance. Upon activation, pro-inflammatory M1 macrophages induce aerobic glycolysis. By contrast, in lean humans and mice, the number of M2 macrophages predominates. M2 macrophages secrete anti-inflammatory cytokines and utilize oxidative metabolism to maintain AT homeostasis. Here, we review the immunologic and metabolic functions of AT macrophages and their different facets in obesity and the metabolic syndrome.

Obesity is an endemic pathophysiological condition and a comorbidity associated with hypercholesterolemia, hypertension, cardiovascular disease, type 2 diabetes mellitus, and cancer. The adipose tissue of obese subjects shows hypertrophic adipocytes, adipocyte hyperplasia, and chronic low-grade inflammation. S100 proteins are Ca 2+ -binding proteins exclusively expressed in vertebrates in a cell-specific manner. They have been implicated in the regulation of a variety of functions acting as intracellular Ca 2+ sensors transducing the Ca 2+ signal and extracellular factors affecting cellular activity via ligation of a battery of membrane receptors. Certain S100 proteins, namely S100A4, the S100A8/S100A9 heterodimer and S100B, have been implicated in the pathophysiology of obesity-promoting macrophage-based inflammation via toll-like receptor 4 and/or receptor for advanced glycation end-products ligation. Also, serum levels of S100A4, S100A8/S100A9, S100A12, and S100B correlate with insulin resistance/type 2 diabetes, metabolic risk score, and fat cell size. Yet, secreted S100B appears to exert neurotrophic effects on sympathetic fibers in brown adipose tissue contributing to the larger sympathetic innervation of this latter relative to white adipose tissue. In the present review we first briefly introduce S100 proteins and then critically examine their role(s) in adipose tissue and obesity.

It has been established that ingestion of a high-fat diet increases the blood levels of lipopolysaccharides (LPS) from Gram-negative bacteria in the gut. Obesity is characterised by low-grade systemic and adipose tissue inflammation. This is suggested to be implicated in the metabolic syndrome and obesity. In the present review, we hypothesise that LPS directly and indirectly participates in the inflammatory reaction in adipose tissue during obesity. The experimental evidence shows that LPS is involved in the transition of macrophages from the M2 to the M1 phenotype. In addition, LPS inside adipocytes may activate caspase-4/5/11. This may induce a highly inflammatory type of programmed cell death (i.e. pyroptosis), which also occurs after infection with intracellular pathogens. Lipoproteins with or without LPS are taken up by adipocytes. Large adipocytes are more metabolically active and potentially more exposed to LPS than small adipocytes are. Thus, LPS might be involved in defining the adipocyte death size and the formation of crown-like structures. The adipocyte death size is reached when the intracellular concentration of LPS initiates pyroptosis. The mechanistic details remain to be elucidated, but the observations indicate that adipocytes are stimulated to cell death by processes that involve LPS from the gut microbiota. There is a complex interplay between the composition of the diet and microbiota. This influences the amount of LPS that is translocated from the gut. In particular, the lipid content of a meal may correlate with the amount of LPS built in to chylomicrons.