Visceral Adipose Tissue Inflammation Research Articles

1417-P: Gut Microbiome Translocation to Visceral Adipose Tissue Promotes Recruitment of Adipose-Specific Neutrophils in Human Obesity

Neutrophils protect against invading bacteria, and their unique role in adipose tissue inflammation and insulin resistance (IR) in obesity is increasingly recognized. We found that visceral adipose tissue (VAT) of obese (n=83) compared to lean (n=13) individuals had higher neutrophil abundance, correlating with IR. The obese subjects had elevated circulating plasma zonulin, a marker of intestinal permeability, and lipopolysaccharide-binding protein (LPSBP) , a marker of bacterial presence, consistent with evidence suggesting that changes in the microbiome and gut permeability in obesity permits the entry of gut bacteria and bacterial products into the circulation. Therefore, we tested for bacterial presence in VAT under sterile conditions. 16s rRNA analyses revealed that the family Streptococcaceae and an unnamed genus in the family Ruminococaceae were enriched in obese VAT contrary to order Bacilliales and genus Marvinobryantia in lean VAT, majorly originating from the GI tract. To confirm whether higher bacterial load is causal for VAT neutrophil abundance in obesity, we gavaged high-fat diet fed mice with fecal material from an obese human, which increased neutrophil, but not macrophage recruitment to VAT. As VAT is highly vascularized, we used RNA-seq to compare the gene expression signature of VAT neutrophils to peripheral blood neutrophils to eliminate the possibility that VAT neutrophils were circulating cells. Evidently, VAT neutrophils had a differential activation state compared to the circulating neutrophils, with a distinct gene expression pattern representing upregulated inflammatory, chemotactic, extracellular matrix, and ROS generation pathways. Overall, we find that that increased gut bacterial translocation enhances the recruitment of VAT specific neutrophils in obesity offering novel targets for managing VAT inflammation and comorbidities of obesity. Disclosure D.Shantaram: None. N.F.Williams: None. D.Spakowicz: None. W.Hsueh: None. A.M.Blaszczak: None. R.Hoyd: None. A.Smith: None. L.Antwi: None. J.Z.Liu: None. V.P.Wright: None. D.Bradley: None. Y.Liu: None.

Role of Biliverdin Reductase A in the Regulation of Insulin Signaling in Metabolic and Neurodegenerative Diseases: An Update.

Insulin signaling is a conserved pathway that orchestrates glucose and lipid metabolism, energy balance, and inflammation, and its dysregulation compromises the homeostasis of multiple systems. Insulin resistance is a shared hallmark of several metabolic diseases, including obesity, metabolic syndrome, and type 2 diabetes, and has been associated with cognitive decline during aging and dementia. Numerous mechanisms promoting the development of peripheral and central insulin resistance have been described, although most of them were not completely clarified. In the last decades, several studies have highlighted that biliverdin reductase-A (BVR-A), over its canonical role in the degradation of heme, acts as a regulator of insulin signaling. Evidence from human and animal studies show that BVR-A alterations are associated with the aberrant activation of insulin signaling, metabolic syndrome, liver steatosis, and visceral adipose tissue inflammation in obese and diabetic individuals. In addition, recent findings demonstrated that reduced BVR-A levels or impaired BVR-A activation contribute to the development of brain insulin resistance and metabolic alterations in Alzheimer’s disease. In this narrative review, we will provide an overview on the literature by focusing on the role of BVR-A in the regulation of insulin signaling and how BVR-A alterations impact on cell dysfunctions in both metabolic and neurodegenerative disorders.

Senescence and DNA Damage in Adipocytes and Fat Tissues and Its Potential Amelioration through Nutritional Interventions

Accumulating evidence demonstrates that senescence and the associated inflammatory phenotype (SASP) also occur in post-mitotic cells such as mature adipocytes. Visceral adipose tissue in humans is susceptible to inflammation due to nutritional imbalance and ageing. However, while adipose tissue has been well researched in the context of obesity, senescence of differentiated adipocytes has not been investigated thoroughly. Our group recently demonstrated that ageing and normal ad libitum (AL) nutrition in mice resulted in increased adipocyte size, DNA damage, p16INK4a expression and inflammation in visceral adipose tissue while some of these senescence markers could be alleviated by dietary restriction (DR). Moreover, another dietary restriction study described a “metabolic memory” as protection against AL-induced senescence after shifting mice from DR back to AL nutrition. Other recent DR studies on mice of different ages analysed the transcriptional profile of adipose tissue and described a metabolic memory for AL at high age. Finally, our group modelled nutritional imbalance in vitro through treatment of primary human subcutaneous and omental adipocytes with the saturated fatty acid (FA) palmitic acid (PA). This resulted in a significant increase in DNA damage as well as p16INK4a levels correlating with enhanced intracellular lipid accumulation. In contrast, DNA damage could be prevented with the unsaturated FA oleic acid (OA). With olive oil being an important part of the Mediterranean diet another study found also other oils such as argan oil to have similar effects of preventing DNA damage in vivo and in vitro. This review is focused on senescence, DNA damage and inflammation in WAT and adipocytes including nutritional interventions in vivo and in vitro. It also gives some basic background on these topics. However, it is not a systematic review but aims to highlight recent developments and nutritional interventions in the areas of senescence and DNA damage related to adipocyte tissues and cells.

Adipose invariant NKT cells interact with CD1d-expressing macrophages to regulate obesity-related inflammation.

Obesity is accompanied by and accelerated with chronic inflammation in adipose tissue, especially visceral adipose tissue (VAT). This low-level inflammation predisposes the host to the development of metabolic disease, most notably type 2 diabetes. We have focused on the capacity of glycolipid-reactive, CD1d-restricted natural killer T (NKT) cells to modulate obesity and its associated metabolic sequelae. We previously reported that CD1d knockout (KO) mice are partially protected against the development of obesity-associated insulin resistance, and these findings were recapitulated in mice with an adipocyte-specific CD1d deficiency, suggesting that NKT cell-adipocyte interactions play a critical role in exacerbating disease. However, many other CD1d-expressing cells contribute to the in vivo responses of NKT cells to lipid antigens. In the present study, we examined the role of CD1d expression by macrophages (Mϕ) in the development of obesity-associated metabolic inflammation using LysMcre-cd1d1f/f mice where the CD1d1gene is disrupted in a Mϕ-specific manner. Unexpectedly, these animals contained a higher frequency of T-bet+ CD4+ T cells in VAT with increased production of Th1 cytokines that aggravated VAT inflammation. Mϕ from mutant mice displayed increased production of IL-12p40, suggesting M1 polarization. These findings indicate that interactions of CD1d on Mϕ with NKT cells play a beneficial role in obesity-associated VAT inflammation and insulin resistance with a sharp contrast to an aggravating role of CD1d in another type of antigen-presenting cell, dendritic cells.

Visceral fat inflammation and fat embolism are associated with lung's lipidic hyaline membranes in subjects with COVID-19.

BackgroundPreliminary data suggested that fat embolism could explain the importance of visceral obesity as a critical determinant of coronavirus disease-2019 (COVID-19).MethodsWe performed a comprehensive histomorphologic analysis of autoptic visceral adipose tissue (VAT), lungs and livers of 19 subjects with COVID-19 (COVID-19+), and 23 people without COVID-19 (controls). Human adipocytes (hMADS) infected with SARS-CoV-2 were also studied.ResultsAlthough there were no between-group differences in body-mass-index and adipocytes size, a higher prevalence of CD68+ macrophages among COVID-19+ VAT was detected (p = 0.005) and accompanied by crown-like structures presence, signs of adipocytes stress and death. Consistently, human adipocytes were successfully infected by SARS-CoV-2 in vitro and displayed lower cell viability. Being VAT inflammation associated with lipids spill-over from dead adipocytes, we studied lipids distribution by ORO. Lipids were observed within lungs and livers interstitial spaces, macrophages, endothelial cells, and vessels lumen, features suggestive of fat embolism syndrome, more prevalent among COVID-19+ (p < 0.001). Notably, signs of fat embolism were more prevalent among people with obesity (p = 0.03) independently of COVID-19 diagnosis, suggesting that such condition may be an obesity complication exacerbated by SARS-CoV-2 infection. Importantly, all infected subjects’ lungs presented lipids-rich (ORO+) hyaline membranes, formations associated with COVID-19-related pneumonia, present only in one control patient with non-COVID-19-related pneumonia. Importantly, transition aspects between embolic fat and hyaline membranes were also observed.ConclusionsThis study confirms the lung fat embolism in COVID-19+ patients and describes for the first time novel COVID-19-related features possibly underlying the unfavorable prognosis in people with COVID-19 and obesity.

Electroacupuncture Stimulation Regulates Adipose Lipolysis via Catecholamine Signaling Mediated by NLRP3 Suppression in Obese Rats.

Chronic low-grade inflammation of visceral adipose tissue can cause obesity-associated insulin resistance, leading to metabolic syndrome. However, anti-inflammatory drugs and those for obesity management can lead to serious side effects such as abnormal heart rate and blood pressure. Consequently, this study aimed to explore the therapeutic potential of electroacupuncture stimulation (ES) for obesity and associated chronic inflammation. Sprague-Dawley male rats were fed a high-fat diet (HFD) for ten weeks to build an obesity model, and half of the diet-induced obesity (DIO) rats were received ES. The levels of inflammatory factors were detected by ELISA and qPCR analysis. The nerve-associated macrophages were marked with immunofluorescence staining. The molecular mechanism of NLRP3 inflammasome in ES was determined by the NLRP3 inflammasome activation model. Compared to HDF rats, ES showed decreased body weight and chronic inflammatory damage. Specifically, this occurred via a decrease in monoamine oxidase-A (MAOA) expression, which suppressed noradrenaline degradation. MAOA is expressed in nerve-associated macrophages (NAMs), and ES attenuated NAMs by suppressing the NLRP3 inflammasome. The NLRP3 agonist blocked the noradrenaline degradation-reducing effect of ES, and an increase in lipolysis via the inhibition of the NLRP3 inflammasome attenuated NAMs. Thus, our findings suggest that ES induced lipolysis via activation of the NLRP3 inflammasome in nerve-associated macrophages (NAMs), independently of sympathetic nervous system activity.

SP-1154, a novel synthetic TGF-β inhibitor, alleviates obesity and hepatic steatosis in high-fat diet-induced mice.

Obesity-induced inflamed visceral adipose tissue (VAT) secretes pro-inflammatory cytokines thereby promoting systemic inflammation and insulin resistance which further exacerbate obesity-associated nonalcoholic fatty liver disease (NAFLD). Transforming growth factor (TGF)-β /Smad3 signaling plays a crucial role in the inflammatory events within the VAT. Here, we investigate whether SP-1154, a novel synthetic verbenone derivative, can inhibit TGF-β/Smad3 signaling thereby exhibiting a therapeutic effect against obesity-induced inflamed VAT and subsequent NAFLD in high-fat diet-induced mice. NAFLD was induced by a high-fat diet (60% fat) for 20 weeks using the male C57BL/6 mice. SP-1154 (50mg/kg) was orally given daily for 20 weeks. In vivo VAT- and systemic inflammation were measured by using 18F-fluorodeoxyglucose positron emission tomography and C-reactive protein levels. Both insulin tolerance- and glucose tolerance test were performed to assess the status of insulin resistance and glucose intolerance. Histological and molecular analyses were performed on harvested liver and VAT. SP-1154 inhibited TGF-β/Smad3 signaling pathway and remarkably suppressed high-fat diet-induced VAT inflammation and its related systemic inflammation. Furthermore, SP-1154 significantly improved insulin sensitivity with glucose homeostasis and reduced hepatic steatosis. SP-1154 significantly improves VAT inflammation and obesity-related NAFLD. Our novel findings support the potential use of SP-1154 as a therapeutic drug for obesity and its related NAFLD by targeting the inflamed VAT.

Identification of Key Genes from the Visceral Adipose Tissues of Overweight/Obese Adults with Hypertension through Transcriptome Sequencing.

Overweight and obese (OW/OB) adults are at increased risk of hypertension due to visceral adipose tissue (VAT) inflammation. In this study, we explored gene level differences in the VAT of hypertensive and normotensive OW/OB patients. VAT samples obtained from six OW/OB adults (three hypertensive, three normotensive) were subjected to transcriptome sequencing analysis. Gene set enrichment analysis was conducted for all gene expression data to identify differentially expressed genes (DEGs) with |log2 (fold change)| ≥ 1 and q < 0.05. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional enrichment analyses were performed on the DEGs, and hub genes were identified by constructing a protein-protein interaction (PPI) network. The proposed hub genes were validated using quantitative real-time PCR in ten other samples from five hypertensive and five normotensive patients. In addition, we performed ROC analysis and Spearman correlation analysis. A total of 84 DEGs were identified between VAT samples from OW/OB patients with and without hypertension, among which 21 were significantly upregulated and 63 were significantly downregulated. Bioinformatics analysis revealed that spleen function was related to hypertension in OW/OB adults. Meanwhile, PPI network analysis identified the following top 10 hub genes: CD79A, CR2, SELL, CD22, IL7R, CCR7, TNFRSF13C, CXCR4, POU2AF1, and JAK3. Through qPCR verification, we found that CXCR4, CD22, and IL7R were statistically significant. qPCR verification suggested that RELA was statistically significant. However, qPCR verification indicated that NFKB1 and KLF2 were not statistically significant. These hub genes were mainly regulated by the transcription factor RELA. The AUC of ROC analysis for CXCR4, IL7R, and CD22 was 0.92. What is more, VAT CXCR4 and CD22 were positively related to RELA relative expression levels. Taken together, our research demonstrates that CXCR4, IL7R, and CD22 related to VAT in hypertensive OW/OB adults could serve as future therapeutic targets.

Metabolic Activity of Visceral Adipose Tissue Is Associated with Metastatic Status of Lymph Nodes in Endometrial Cancer: A 18F-FDG PET/CT Study.

Obesity contributes to increased cancer incidence and aggressiveness in patients with endometrial cancer. Inflamed metabolic activity of visceral adipose tissue (VAT) is regarded as a key underlying mechanism of adverse consequences of obesity. The aim of this study was to investigate the association between inflammatory metabolic activity of VAT evaluated by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) and metastatic status of lymph nodes (LN) in patients with endometrial cancer. In total, 161 women with newly diagnosed endometrial cancer, who received preoperative 18F-FDG PET/CT, were enrolled. VAT inflammatory metabolic activity was defined as V/S ratio and measured from the maximum standardized uptake value (SUVmax) of VAT normalized to the SUVmax of subcutaneous adipose tissue (SAT). The positive LN metastasis group exhibited a significantly higher V/S ratio than the negative LN metastasis group. Systemic inflammatory surrogate markers including high sensitivity C-reactive protein, spleen SUVmax, and bone marrow SUVmax were also higher in the LN metastasis group than in the negative LN metastasis group, showing significant correlations with V/S ratio. In multivariate logistic regression analysis, V/S ratio was independently associated with LN metastasis. V/S ratio is independently associated with the LN metastasis status in patients with endometrial cancer. This finding could be useful as a potential surrogate marker of obesity-induced VAT inflammation associated with tumor aggressiveness.

Inhibiting serotonin signaling through HTR2B in visceral adipose tissue improves obesity-related insulin resistance.

Insulin resistance is a cornerstone of obesity-related complications such as type 2 diabetes, metabolic syndrome, and nonalcoholic fatty liver disease. A high rate of lipolysis is known to be associated with insulin resistance, and inhibiting adipose tissue lipolysis improves obesity-related insulin resistance. Here, we demonstrate that inhibition of serotonin (5-hydroxytryptamine [5-HT]) signaling through serotonin receptor 2B (HTR2B) in adipose tissues ameliorates insulin resistance by reducing lipolysis in visceral adipocytes. Chronic high-fat diet (HFD) feeding increased Htr2b expression in epididymal white adipose tissue, resulting in increased HTR2B signaling in visceral white adipose tissue. Moreover, HTR2B expression in white adipose tissue was increased in obese humans and positively correlated with metabolic parameters. We further found that adipocyte-specific Htr2b-knockout mice are resistant to HFD-induced insulin resistance, visceral adipose tissue inflammation, and hepatic steatosis. Enhanced 5-HT signaling through HTR2B directly activated lipolysis through phosphorylation of hormone-sensitive lipase in visceral adipocytes. Moreover, treatment with a selective HTR2B antagonist attenuated HFD-induced insulin resistance, visceral adipose tissue inflammation, and hepatic steatosis. Thus, adipose HTR2B signaling could be a potential therapeutic target for treatment of obesity-related insulin resistance.

Some mechanisms of inflammation development in type 2 diabetes mellitus

Inflammation plays a key role in the development and progression of type 2 diabetes (T2DM), a disease characterized by peripheral insulin resistance and systemic glucolipotoxicity. The main source of inflammation in the early stages of the disease is visceral adipose tissue (VT). Macrophages are innate immune cells that are present in all peripheral tissues, including VT. Violation of the response of VT (MT) macrophages to changes in the microenvironment underlies aberrant inflammation and the development of local and systemic insulin resistance. The inflammatory activation of macrophages is regulated at several levels: stimulation of cell surface receptors, intracellular signaling, transcription, and metabolic levels. Which are activated by the transformation of macrophages along the pro-inflammatory or anti-inflammatory pathways. Such polarization of macrophages in modern immunology is divided into classical anti-inflammatory M1 polarization and alternative anti-inflammatory M2 polarization of macrophages. The M1 / M2 ratio of macrophages in the process of inflammation ensures the resolution of inflammation at different stages of its development. The review considers the main mechanisms involved in VT inflammation and the development of insulin resistance in T2DM, supported with the participation of immunocompetent cells, M1 / M2, as well as growth factors and humoral immunity factors secreted during this process.

Fructose Induces Visceral Adipose Tissue Inflammation and Insulin Resistance Even Without Development of Obesity in Adult Female but Not in Male Rats.

Introduction: Obesity and related metabolic disturbances are frequently related to modern lifestyle and are characterized by excessive fructose intake. Visceral adipose tissue (VAT) inflammation has a central role in the development of insulin resistance, type 2 diabetes (T2D), and metabolic syndrome. Since sex-related differences in susceptibility and progression of metabolic disorders are not yet fully understood, our aim was to examine inflammation and insulin signaling in VAT of fructose-fed female and male adult rats.Methods: We analyzed effects of 9-week 10% fructose-enriched diet on energy intake, VAT mass and histology, and systemic insulin sensitivity. VAT insulin signaling and markers of VAT inflammation, and antioxidative defense status were also evaluated.Results: The fructose diet had no effect on VAT mass and systemic insulin signaling in the female and male rats, while it raised plasma uric acid, increased PPARγ level in the VAT, and initiated the development of a distinctive population of small adipocytes in the females. Also, adipose tissue insulin resistance, evidenced by increased PTP1B and insulin receptor substrate 1 (IRS1) inhibitory phosphorylation and decreased Akt activity, was detected. In addition, fructose stimulated the nuclear accumulation of NFκB, increased expression of proinflammatory cytokines (IL-1β, IL-6, and TNFα), and protein level of macrophage marker F4/80, superoxide dismutase 1, and glutathione reductase. In contrast to the females, the fructose diet had no effect on plasma uric acid and VAT inflammation in the male rats, but less prominent alterations in VAT insulin signaling were observed.Conclusion: Even though dietary fructose did not elicit changes in energy intake and led to obesity in the females, it initiated the proliferation of small-sized adipocytes capable of storing fats further. In contrast to the males, this state of VAT was accompanied with enhanced inflammation, which most likely contributed to the development of insulin resistance. The observed distinction could possibly originate from sex-related differences in uric acid metabolism. Our results suggest that VAT inflammation could precede obesity and start even before the measurable increase in VAT mass, making it a silent risk factor for the development of T2D. Our results emphasize that adipose tissue dysfunction, rather than its simple enlargement, could significantly contribute to the onset and development of obesity and related metabolic disorders.

A nonhuman primate model of vertical sleeve gastrectomy facilitates mechanistic and translational research in human obesity

SummaryThe obesity epidemic significantly contributes to overall morbidity and mortality. Bariatric surgery is the gold standard treatment for obesity and metabolic dysfunction, yet the mechanisms by which it exerts metabolic benefit remain unclear. Here, we demonstrate a model of vertical sleeve gastrectomy (VSG) in nonhuman primates (NHP) that mimics the complexity and outcomes in humans. We also show that VSG confers weight loss and durable metabolic benefit, where equivalent caloric intake in shams resulted in significant weight gain following surgery. Furthermore, we show that VSG is associated with early, weight-independent increases in bile acids, short-chain fatty acids, and reduced visceral adipose tissue (VAT) inflammation with a polarization of VAT-resident immunocytes toward highly regulatory myeloid cells and Tregs. These data demonstrate that this strongly translational NHP model can be used to interrogate factors driving successful intervention to unravel the interplay between physiologic systems and improve therapies for obesity and metabolic syndrome.

Laparoscopic Vertical Sleeve Gastrectomy in Nonhuman Primates Modulates Visceral Adipose Tissue Inflammation with a Decrease in CD40-expressing Cells

Laparoscopic Vertical Sleeve Gastrectomy in Nonhuman Primates Modulates Visceral Adipose Tissue Inflammation with a Decrease in CD40-expressing Cells

Mechanism research on the interaction regulation of Escherichia and IFN-γ for the occurrence of T2DM.

Type 2 diabetes mellitus (T2DM) is a major social and public health problem which may be induced by intestinal flora imbalance through inflammatory response, and the specific mechanism remains unclear. In this study, we aim to explore the interaction network of intestinal flora and cell inflammation in T2DM. This a case-control study. Patients with T2DM was the case group and healthy people as control. The differences of cytokine expression levels between patients with T2DM and healthy controls were assessed by using flow cytometry. The diversity and abundance of intestinal flora were evaluated by using 16S rRNA three-generation full-length sequencing technology. A total of 29 patients with T2DM and 28 healthy controls were included for analysis. Compared with the healthy control group, the expression levels of plasma cytokine interleukin-2 (IL-2) (P=0.0000006), IL-6 (P=0.000193), tumor necrosis factor α (TNF-α) (P=0.016), interferon-γ (IFN-γ) (P=0.000036) and interleukin-17 (IL-17) (P=0.004) were significantly up-regulated in T2DM patients, and the abundance of Megamonas_funiformis (P=0.0016) and Escherichia (P=0.049) in the intestine were significantly increased. In contrast, the abundance of Bacteroides_stercoris (P=0.0068), Bacteroides_uniformis (P=0.033), and Phascolarctobacterium_faecium (P=0.033) were decreased in T2DM patients. Further, differentially expressed Escherichia had a positive correlation with IFN-γ (r=0.73) by Pearson correlation analysis. The interaction network between the intestinal bacteria Escherichia and the cytokine IFN-γ may drive inflammation in visceral adipose tissue (VAT), indicating insulin signal transduction can be inhibited in adipocytes to induce insulin resistance.

Leptin Receptor-Deficient db/db Mice Show Significant Heterogeneity in Response to High Non-heme Iron Diet

Recent studies have shown an association between iron homeostasis, obesity and diabetes. In this work, we investigated the differences in the metabolic status and inflammation in liver, pancreas and visceral adipose tissue of leptin receptor-deficient db/db mice dependent on high iron concentration diet. 3-month-old male BKS-Leprdb/db/JOrlRj (db/db) mice were divided into two groups, which were fed with different diets containing high iron (29 g/kg, n = 57) or standard iron (0.178 g/kg; n = 42) concentrations for 4 months. As anticipated, standard iron-fed db/db mice developed obesity and diabetes. However, high iron-fed mice exhibited a wide heterogeneity. By dividing into two subgroups at the diabetes level, non-diabetic subgroup 1 (<13.5 mmol/l, n = 30) significantly differed from diabetic subgroup two (>13.5 mmol/l, n = 27). Blood glucose concentration, HbA1c value, inflammation markers interleukin six and tumor necrosis factor α and heme oxygenase one in visceral adipose tissue were reduced in subgroup one compared to subgroup two. In contrast, body weight, C-peptide, serum insulin and serum iron concentrations, pancreatic islet and signal ratio as well as cholesterol, LDL and HDL levels were enhanced in subgroup one. While these significant differences require further studies and explanation, our results might also explain the often-contradictory results of the metabolic studies with db/db mice.

Fecal microbiota transplantation does not alter bacterial translocation and visceral adipose tissue inflammation in individuals with obesity.

AimsVisceral adipose tissue inflammation is a fundamental mechanism of insulin resistance in obesity and type 2 diabetes. Translocation of intestinal bacteria has been suggested as a driving factor for the inflammation. However, although bacterial DNA was detected in visceral adipose tissue of humans with obesity, it is unclear to what extent this is contamination or whether the gut microbiota is causally involved. Effects of fecal microbiota transplantation (FMT) on bacterial translocation and visceral adipose tissue inflammation in individuals with obesity and insulin resistance were assessed.Material and MethodsEight individuals with clinically severe obesity (body mass index [BMI] >35 kg/m2) and metabolic syndrome received lean donor FMT 4 weeks prior to elective bariatric surgery. The participants were age‐, sex‐, and BMI‐matched to 16 controls that underwent no fecal transplantation. Visceral adipose tissue was collected during surgery. Bacterial translocation was assessed by 16S rRNA gene sequencing of adipose tissue and feces. Pro‐inflammatory cytokine expression and histopathological analyses of visceral adipose tissue were performed to assess inflammation.ResultsFecal microbiota transplantation significantly altered gut microbiota composition. Visceral adipose tissue contained a very low quantity of bacterial DNA in both groups. No difference in visceral bacterial DNA content between groups was observed. Also, visceral expression of pro‐inflammatory cytokines and macrophage infiltration did not differ between groups. No correlation between inflammatory tone and bacterial translocation was observed.ConclusionsVisceral bacterial DNA content and level of inflammation were not altered upon FMT. Thus, bacterial translocation may not be the main driver of visceral adipose tissue inflammation in obesity.

Некоторые механизмы развития воспаления при сахарном диабете 2 типа

Inflammation plays a key role in the development and progression of type 2 diabetes (T2DM), a disease characterized by peripheral insulin resistance and systemic glucolipotoxicity. The main source of inflammation in the early stages of the disease is visceral adipose tissue (VT). Macrophages are innate immune cells that are present in all peripheral tissues, including VT. Violation of the response of VT (MT) macrophages to changes in the microenvironment underlies aberrant inflammation and the development of local and systemic insulin resistance. The inflammatory activation of macrophages is regulated at several levels: stimulation of cell surface receptors, intracellular signaling, transcription, and metabolic levels. Which are activated by the transformation of macrophages along the pro-inflammatory or anti-inflammatory pathways. Such polarization of macrophages in modern immunology is divided into classical anti-inflammatory M1 polarization and alternative anti-inflammatory M2 polarization of macrophages. The M1 / M2 ratio of macrophages in the process of inflammation ensures the resolution of inflammation at different stages of its development. The review considers the main mechanisms involved in VT inflammation and the development of insulin resistance in T2DM, supported with the participation of immunocompetent cells, M1 / M2, as well as growth factors and humoral immunity factors secreted during this process.

Innate Immune System Orchestrates Metabolic Homeostasis and Dysfunction in Visceral Adipose Tissue During Obesity.

Arising incidence of metabolic disorders and related diseases caused by obesity is a global health concern. Elucidating the role of the immune system in this process will help to understand the related mechanisms and develop treatment strategies. Here, we have focused on innate immune cells in visceral adipose tissue (VAT) and summarized the roles of these cells in maintaining the homeostasis of VAT. Furthermore, this review reveals the importance of quantitative and functional changes of innate immune cells when the metabolic microenvironment changes due to obesity or excess lipids, and confirms that these changes eventually lead to the occurrence of chronic inflammation and metabolic diseases of VAT. Two perspectives are reviewed, which include sequential changes in various innate immune cells in the steady state of VAT and its imbalance during obesity. Cross-sectional interactions between various innate immune cells at the same time point are also reviewed. Through delineation of a comprehensive perspective of VAT homeostasis in obesity-induced chronic inflammation, and ultimately metabolic dysfunction and disease, we expect to clarify the complex interactive networks among distinct cell populations and propose that these interactions should be taken into account in the development of biotherapeutic strategies.

Visceral Adipose Tissue: A New Target Organ in Virus-Induced Type 1 Diabetes.

Type 1 diabetes (T1D) is a proinflammatory pathology that leads to the specific destruction of insulin producing β-cells and hyperglycaemia. Much of the knowledge about type 1 diabetes (T1D) has focused on mechanisms of disease progression such as adaptive immune cells and the cytokines that control their function, whereas mechanisms linked with the initiation of the disease remain unknown. It has been hypothesized that in addition to genetics, environmental factors play a pivotal role in triggering β-cell autoimmunity. The BioBreeding Diabetes Resistant (BBDR) and LEW1.WR1 rats have been used to decipher the mechanisms that lead to virus-induced T1D. Both animals develop β-cell inflammation and hyperglycemia upon infection with the parvovirus Kilham Rat Virus (KRV). Our earlier in vitro and in vivo studies indicated that KRV-induced innate immune upregulation early in the disease course plays a causal role in triggering β-cell inflammation and destruction. Furthermore, we recently found for the first time that infection with KRV induces inflammation in visceral adipose tissue (VAT) detectable as early as day 1 post-infection prior to insulitis and hyperglycemia. The proinflammatory response in VAT is associated with macrophage recruitment, proinflammatory cytokine and chemokine upregulation, endoplasmic reticulum (ER) and oxidative stress responses, apoptosis, and downregulation of adipokines and molecules that mediate insulin signaling. Downregulation of inflammation suppresses VAT inflammation and T1D development. These observations are strikingly reminiscent of data from obesity and type 2 diabetes (T2D) in which VAT inflammation is believed to play a causal role in disease mechanisms. We propose that VAT inflammation and dysfunction may be linked with the mechanism of T1D progression.