Visceral Adipose Tissue Inflammation Research Articles

Changes in abdominal subcutaneous adipose tissue phenotype following menopause is associated with increased visceral fat mass

Menopause is associated with a redistribution of adipose tissue towards central adiposity, known to cause insulin resistance. In this cross-sectional study of 33 women between 45 and 60 years, we assessed adipose tissue inflammation and morphology in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) across menopause and related this to menopausal differences in adipose tissue distribution and insulin resistance. We collected paired SAT and VAT biopsies from all women and combined this with anthropometric measurements and estimated whole-body insulin sensitivity. We found that menopause was associated with changes in adipose tissue phenotype related to metabolic dysfunction. In SAT, postmenopausal women showed adipocyte hypertrophy, increased inflammation, hypoxia and fibrosis. The postmenopausal changes in SAT was associated with increased visceral fat accumulation. In VAT, menopause was associated with adipocyte hypertrophy, immune cell infiltration and fibrosis. The postmenopausal changes in VAT phenotype was associated with decreased insulin sensitivity. Based on these findings we suggest, that menopause is associated with changes in adipose tissue phenotype related to metabolic dysfunction in both SAT and VAT. Whereas increased SAT inflammation in the context of menopause is associated with VAT accumulation, VAT morphology is related to insulin resistance.

Visceral Adiposity Index, Triglyceride/High-Density Lipoprotein Ratio, and Lipid Accumulation Product Index to Discriminate Metabolic Syndrome Among Adult Type 1 Diabetes Patients.

Background: Obesity and metabolic syndrome (MetS) are growing problems in type 1 diabetic patients; these can influence clinical complications and also treatment regimens. Visceral adipose tissue inflammation plays an important role in cardiovascular complications. Visceral adiposity index (VAI), lipid accumulation product index (LAP), and triglyceride (TG)/high-density lipoprotein (HDL) ratio have been strongly correlated with insulin resistance and visceral adipose tissue amount in previous studies. Therefore, this study aimed to investigate and compare the usefulness of these indices to detect MetS in patients with type 1 diabetes mellitus (T1DM). Materials and Methods: Patients with T1DM and gender- and age-matched controls were included in this cross-sectional study. MetS was defined using both International Diabetes Federation (IDF), World Health Organization (WHO), and National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria. T1DM patients were divided into two groups according to the IDF criteria. VAI, LAP, and TG/HDL ratio were calculated for all patients. Groups were compared accordingly. Results: One hundred twenty-six patients with T1DM were included in the study. Increased VAI was observed in association with MetS. Patients with MetS (32.2%) had the highest VAI than healthy controls (8.21 ± 8.86; 3.49 ± 2.73, respectively, P < 0.01). For determining MetS in type 1 diabetes, the cutoff value of VAI was 2.65 [area under the curve (AUC) = 0.837, sensitivity 80.0%, specificity 72.8%], LAP was 27.57 (AUC = 0.842, sensitivity 80.0%, specificity74.0%), TG/HDL ratio was 2.18 (AUC = 0.826, sensitivity 75.0%, specificity 74.0%), each P < 0.001. Conclusions: MetS becomes increasingly common in T1DM. VAI, LAP, and TG/HDL ratio were useful for predicting MetS in patients with T1DM.

The Effects of Oxytocin on Appetite Regulation, Food Intake and Metabolism in Humans.

The hypothalamic peptide oxytocin and its receptor are involved in a range of physiological processes, including parturition, lactation, cell growth, wound healing, and social behavior. More recently, increasing evidence has established the effects of oxytocin on food intake, energy expenditure, and peripheral metabolism. In this review, we provide a comprehensive description of the central oxytocinergic system in which oxytocin acts to shape eating behavior and metabolism. Next, we discuss the peripheral beneficial effects oxytocin exerts on key metabolic organs, including suppression of visceral adipose tissue inflammation, skeletal muscle regeneration, and bone tissue mineralization. A brief summary of oxytocin actions learned from animal models is presented, showing that weight loss induced by chronic oxytocin treatment is related not only to its anorexigenic effects, but also to the resulting increase in energy expenditure and lipolysis. Following an in-depth discussion on the technical challenges related to endogenous oxytocin measurements in humans, we synthesize data related to the association between endogenous oxytocin levels, weight status, metabolic syndrome, and bone health. We then review clinical trials showing that in humans, acute oxytocin administration reduces food intake, attenuates fMRI activation of food motivation brain areas, and increases activation of self-control brain regions. Further strengthening the role of oxytocin in appetite regulation, we review conditions of hypothalamic insult and certain genetic pathologies associated with oxytocin depletion that present with hyperphagia, extreme weight gain, and poor metabolic profile. Intranasal oxytocin is currently being evaluated in human clinical trials to learn whether oxytocin-based therapeutics can be used to treat obesity and its associated sequela. At the end of this review, we address the fundamental challenges that remain in translating this line of research to clinical care.

CD8+ T Cells Involved in Metabolic Inflammation in Visceral Adipose Tissue and Liver of Transgenic Pigs.

Anti-inflammatory therapies have the potential to become an effective treatment for obesity-related diseases. However, the huge gap of immune system between human and rodent leads to limitations of drug discovery. This work aims at constructing a transgenic pig model with higher risk of metabolic diseases and outlining the immune responses at the early stage of metaflammation by transcriptomic strategy. We used CRISPR/Cas9 techniques to targeted knock-in three humanized disease risk genes, GIPRdn, hIAPP and PNPLA3I148M. Transgenic effect increased the risk of metabolic disorders. Triple-transgenic pigs with short-term diet intervention showed early symptoms of type 2 diabetes, including glucose intolerance, pancreatic lipid infiltration, islet hypertrophy, hepatic lobular inflammation and adipose tissue inflammation. Molecular pathways related to CD8+ T cell function were significantly activated in the liver and visceral adipose samples from triple-transgenic pigs, including antigen processing and presentation, T-cell receptor signaling, co-stimulation, cytotoxicity, and cytokine and chemokine secretion. The similar pro-inflammatory signaling in liver and visceral adipose tissue indicated that there might be a potential immune crosstalk between the two tissues. Moreover, genes that functionally related to liver antioxidant activity, mitochondrial function and extracellular matrix showed distinct expression between the two groups, indicating metabolic stress in transgenic pigs’ liver samples. We confirmed that triple-transgenic pigs had high coincidence with human metabolic diseases, especially in the scope of inflammatory signaling at early stage metaflammation. Taken together, this study provides a valuable large animal model for the clinical study of metaflammation and metabolic diseases.

N-carbamoylglutamate improves lipid metabolism, inflammation, and apoptosis responses in visceral adipocytes of Japanese seabass (Lateolabrax japonicus), invivo and invitro.

This study applied in vivo and in vitro methods to investigate the effect of dietary N-carbamoylglutamate (NCG) on lipid metabolism, inflammation and apoptosis related-gene expression in visceral adipose tissue and isolated adipocytes of Japanese seabass (Lateolabrax japonicus). A basal diet and a test diet supplemented with 720 mg/kg NCG were fed to the fish for 10 weeks. During the growth trial, no mortality and no significant differences in growth performance were observed in fish between the 2 groups (P > 0.05). Plasma Arg content and mRNA level of argininosuccinate synthetase (ASS) in adipose tissue were significantly increased, which indicated that NCG inclusion promoted endogenous Arg synthesis. Thereafter, the potential effects of NCG treatment on lipid metabolism-related genes expression were studied through in vivo and in vitro methods. In the present study, we successfully established a primary adipocytes culture system and isolated pre-adipocytes in vitro of Japanese seabass for the first time. Both the results in vivo and in vitro showed that NCG treatment decreased the mRNA levels of genes related to adipogenesis (fatty acid synthase, FASN), cholesterol synthesis (3-hydroxy-3-methylglutaryl-CoA reductase, HMGCR) and fat deposition (lipoprotein lipase [LPL] and leptin), which revealed the underlying mechanism of NCG on reducing fat deposition. The results of this study demonstrated that NCG inclusion reduced the expression of inflammatory and apoptosis cytokines markedly in vivo and in vitro. In conclusion, NCG did exert beneficial effects on ameliorating adipogenesis, inflammation and apoptosis via promoting Arg endogenous synthesis in Japanese seabass.

Chronic and Transient Hyperglycemia Induces Changes in the Expression Patterns of IL6 and ADIPOQ Genes and Their Associated Epigenetic Modifications in Differentiating Human Visceral Adipocytes.

Adipokines secreted by hypertrophic visceral adipose tissue (VAT) instigate low-grade inflammation, followed by hyperglycemia (HG)-related metabolic disorders. The latter may develop with the participation of epigenetic modifications. Our aim was to assess how HG influences selected epigenetic modifications and the expression of interleukin 6 (IL-6) and adiponectin (APN; gene symbol ADIPOQ) during the adipogenesis of human visceral preadipocytes (HPA-v). Adipocytes (Ads) were chronically or transiently HG-treated during three stages of adipogenesis (proliferation, differentiation, maturation). We measured adipokine mRNA, protein, proven or predicted microRNA expression (RT-qPCR and ELISA), and enrichment of H3K9/14ac, H3K4me3, and H3K9me3 at gene promoter regions (chromatin immunoprecipitation). In chronic HG, we detected different expression patterns of the studied adipokines at the mRNA and protein levels. Chronic and transient HG-induced changes in miRNA (miR-26a-5p, miR-26b-5p, let-7d-5p, let-7e-5p, miR-365a-3p, miR-146a-5p) were mostly convergent to altered IL-6 transcription. Alterations in histone marks at the IL6 promoter were also in agreement with IL-6 mRNA. The open chromatin marks at the ADIPOQ promoter mostly reflected the APN transcription during NG adipogenesis, while, in the differentiation stage, HG-induced changes in all studied marks were in line with APN mRNA levels. In summary, HG dysregulated adipokine expression, promoting inflammation. Epigenetic changes coexisted with altered expression of adipokines, especially for IL-6; therefore, epigenetic marks induced by transient HG may act as epi-memory in Ads. Such changes in the epigenome and expression of adipokines could be instrumental in the development of inflammation and metabolic deregulation of VAT.

Visceral Adipose Tissue Inflammation and Radiographic Visceral-to-Subcutaneous Adipose Tissue Ratio in Patients with Cirrhosis.

Accumulation of visceral adipose tissue is associated with hepatic inflammation and fibrosis, suggestive of its metabolic and inflammatory properties. We aimed to examine the histologic findings of visceral and subcutaneous adipose tissue and to associate these findings with clinical and radiologic characteristics in patients with cirrhosis. Included were 55 adults with cirrhosis who underwent liver transplantation from 3/2017-12/2018 and had an abdominal computed tomography (CT) scan within 6months prior to transplant. Visceral-to-subcutaneous adipose tissue ratio (VSR) was calculated using visceral (VATI) and subcutaneous adipose tissue index (SATI) quantified by CT at the L3-vertebral level and normalized for height (cm2/m2). VAT (greater omentum), SAT (abdominal wall), and skeletal muscle (rectus abdominis) biopsies were collected at transplant. Majority of patients had VAT inflammation (71%); only one patient (2%) had SAT inflammation. Patients with VAT inflammation had similar median VATI (42 vs 41 cm2/m2), lower median SATI (64 vs 97 cm2/m2), and higher median VSR (0.63 vs 0.37, p = 0.002) than patients without inflammation. In univariable logistic regression, VSR was associated with VAT inflammation (OR 1.47, 95%CI 1.11-1.96); this association remained significant even after adjusting for age, sex, BMI, HCC, or MELD-Na on bivariable analyses. In patients with cirrhosis undergoing liver transplantation, histologic VAT inflammation was common, but SAT inflammation was not. Increased VSR was independently associated with VAT inflammation. Given the emerging data demonstrating the prognostic value of VSR, our findings support the value of CT-quantified VSR as a prognostic marker for adverse outcomes in the liver transplant setting.

Dendrobium Officinale Polysaccharide Attenuates Insulin Resistance and Abnormal Lipid Metabolism in Obese Mice.

Objectives: Dendrobium officinale polysaccharide (DOP) is the main active ingredient in a valuable traditional Chinese medicine, which exerts several pharmacological activities including hepatoprotection and hypoglycemic effects. However, the effects of DOP on obesity-associated insulin resistance (IR) and lipid metabolism remain unknown. This study aimed to investigate the role of DOP in IR and abnormal lipid metabolism in obese mice. Methods: IR models were established using 3T3-L1 adipocytes, C2C12 myocytes, and primary cultured hepatocytes exposed to palmitate acid. After treatment with DOP, insulin-stimulated glucose uptake, glucose release, and AKT phosphorylation was detected. Fasting blood glucose, fasting serum insulin, the glucose tolerance test (GTT), and the insulin tolerance test (ITT) were measured to evaluate IR of obese mice. Lipid analysis was conducted to evaluate the effects of DOP on lipid metabolism in obese mice. Results: In vitro, DOP treatment ameliorated palmitic acid-induced IR in adipocytes, myocytes, and hepatocytes. DOP regulated cellular insulin sensitivity via the peroxisome proliferator-activated receptor-γ (PPAR-γ). Furthermore, administration of DOP significantly reduced the IR and visceral adipose tissue (VAT) inflammation of diet-induced obese (DIO) and the genetically-induced obesity mice (ob/ob) mouse models. In addition, DOP treatment attenuated the high-fat diet (HFD)-induced liver lipid accumulation by reducing liver triglycerides (TG), plasma free fatty acid (FFA), serum cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) levels, while increasing HDL-C levels. Conclusion: DOP could improve obesity-associated IR and abnormal lipid metabolism through its activities on PPAR-γ, and may serve as a potential therapeutic agent for obesity-associated insulin resistance and lipid metabolism disorder.

Adipocyte calcium sensing receptor is not involved in visceral adipose tissue inflammation or atherosclerosis development in hyperlipidemic Apoe\u2212/\u2212 mice

The calcium sensing receptor (CaSR) is a G-protein coupled receptor that especially plays an important role in the sensing of extracellular calcium to maintain its homeostasis. Several in-vitro studies demonstrated that CaSR plays a role in adipose tissue metabolism and inflammation, resulting in systemic inflammation and contributing to atherosclerosis development. The aim of this study was to investigate whether adipocyte CaSR plays a role in adipose tissue inflammation in-vivo and atherosclerosis development. By using a newly established conditional mature adipocyte specific CaSR deficient mouse on a hyperlipidemic and atherosclerosis prone Apoe−/− background it could be shown that CaSR deficiency in adipocytes does neither contribute to initiation nor to progression of atherosclerotic plaques as judged by the unchanged lesion size or composition. Additionally, CaSR deficiency did not influence gonadal visceral adipose tissue (vAT) inflammation in-vivo, although a small decrease in gonadal visceral adipose cholesterol content could be observed. In conclusion, adipocyte CaSR seems not to be involved in vAT inflammation in-vivo and does not influence atherosclerosis development in hyperlipidemic Apoe−/− mice.

Human Visceral Adipose Tissue (VAT) Inflammation Is Not Associated With Perforin Deficiency in Type 2 Diabetes Mellitus (DM) Subjects as Compared to Health Controls

Abstract Introduction: Role of T cells in VAT inflammation is poorly characterised. Perforin deficiency is associated with autoimmune inflammatory diseases like Hemophagocytosis Lymphohistiocytosis,as also in context of type 1 DM pathogenesis. Data from animal models suggest that perforin deficiency leads to VAT inflammation1Objective: We hypothesized CD8+/perf+ and CD56+/perf+ cells to be decreased in type 2 DM as compared to healthy controls. The present study also explored the difference in activation of T/NK cells between two groups Methods: 2×2 cm omental tissue was obtained from subjects undergoing elective abdominal surgery. The sample was transported in RPMI solution and stored in -80 ℃. Processing involved thawing, incubation at 37.6 ℃ for 24 hours with type IV Collagenase (1 mg/ml, Sigma Aldrich) 1ml/g of tissue,centrifuge (32g for 10 min at 10℃). The resultant Stromal Vascular fraction (SVF) was suspended in phosphate buffer saline (PBS), passed through cell strainer to make single cell suspension. It was again centrifuged and tagged with CD markers of interest. Fc block was added and single cell solution with FACS fluid prepared. It was run in BD CANTO-2 flow cytometer as described2Results: Of seventeen samples analysed, twelve samples of type 2 diabetes subjects were compared with five healthy controls. All results are presented in median. The diabetics had higher HbA1c (8.1 % vs 6%), higher BMI (28 kg/m2 vs 24 kg/m2), hsCRP(2.1 mg/dl Vs 0.9 mg/dl) but there was no difference in HOMA-Ir (5 vs 5.2 mU/L/mg/dl). The percentage of CD4+ + CD8+ cells/g of VAT was similar in both cases and control (20 × 103 Vs 23× 103). CD8+/CD45+/perf+ and CD56+/CD45+/perf+ could not be identified in any of the samples. Although CD8+/CD45+/perf-- and CD56+/CD45+/perf-- cells were identified. Next, we analysed the same cells for cytotoxic activation by 107a. The percentage of 107a positivity was low in CD 8+ (7% and 4 % respectively in cases and control) and CD 56+ cells (10% and 9 % respectively in cases and control),Although clinically type 2 DM subjects were obese and had inflammation (i.e higher hsCRP), there was no difference in VAT activation of immune cells studied. Also, we could not delineate perforin in any of the samples. Conclusion: Taken together this work suggests VAT T cell immune milieu in human Type 2 DM is different from mouse model. It is neither characterised by perforin deficiency nor activation of T cell/NK cell. This study points towards the probability that, the role of T cell/NK cells in human VAT infiltration could be fundamentally different from mice models. Further studies should be focussed on functional characteristics of these cells and interaction with VAT macrophages.

Lineage‐tracing Reveals Multiple Roles of Tcf21 Lineage Cells in the Development and Expansion of Visceral Adipose Tissue

The specific correlation between visceral adipose tissue (VAT) and insulin resistance makes VAT a potential target for treating type 2 diabetes. Recent studies have shown that Tcf21, a basic helix-loop-helix transcription factor, is expressed in VAT but not in subcutaneous AT (SAT). Thus, we hypothesized that cells expressing Tcf21 played a critical role in VAT. Using tamoxifen-inducible Tcf21 lineage-tracing mouse lines, we identified that Tcf21 was exclusively expressed in progenitor cells in VAT but not those in SAT. Lineage-tracing showed that most Tcf21 lineage progenitor cells also express Pdgfra, a marker of mesenchymal stem cell. Tcf21 expression was abolished upon adipogenic differentiation. Tcf21 lineage-tracing induced at embryonic day 11.2 (E11.5) revealed that progenitor cells of Tcf21 lineage give rise to all visceral adipocytes. Tamoxifen treatment during postnatal days 2-4 (P2-4) lineage-traced ~40% adipocytes in epididymal VAT (eVAT) at weaning, indicating high adipogenic activity in VAT during the neonatal stage. EdU assay showed that Tcf21 lineage-traced cells actively proliferated during the first 2 weeks after birth followed by a phase of robust adipogenic differentiation between P14 and P21. Tcf21 lineage-tracing induced at 6 weeks of age only labeled less than 1% of adipocytes in eVAT of mice after 12 weeks of high-fat diet (HFD) treatment regardless of a significant expansion of Tcf21 lineage-traced cells, indicating that Tcf21 lineage cells in adult mice were less adipogenic in vivo. In addition, it was found Tcf21 lineage cells also gave rise to a small portion of vascular smooth muscle cells (VSMCs). However, these cells lacked the expression of PDGFRα. RNA-seq analysis of Tcf21 lineage-traced PDGFRα+ cells isolated from mice at different developmental and growth stages showed distinct gene expression profiles. Proliferation genes were highly active in Tcf21 lineage cells at P12, while genes associated with adipogenic differentiation were more active at P12 and P21. Interestingly, some inflammatory genes that are commonly expressed in inflammatory cells were highly enriched in Tcf21 lineage cells isolated from mice after long-term HFD treatment. Single-cell RNA-seq of Tcf21 lineage-traced cells isolated from mice of different ages showed that the gene expression of individual cells became increasingly diverse as the age of the mice increased. Single-cell RNA-seq analysis confirmed the presence of a small subpopulation of Tcf21 lineage-traced VSMCs as well as a Tcf21 lineage-traced inflammatory cell subpopulation that was exclusive to HFD-treated mice. IHC staining showed that Tcf21 lineage-traced inflammatory cells were located in crown-like structures and might play a role in inflammation and phagocytosis. Several additional subpopulations of Tcf21 lineage-traced cells were also identified and are currently being investigated. Our study clearly showed the critical roles of Tcf21 lineage cells in the growth and development of VAT as well as in the development of VAT inflammation in obese mice.

Sex differences in markers of metabolic syndrome and adipose tissue inflammation in obesity-prone, Osborne-Mendel and obesity-resistant, S5B/Pl rats

The current study examined the role of sex differences in the development of risk factors associated with obesity and its comorbidities using models that differ in their susceptibility to develop obesity, obesity-resistant S5B/Pl (S5B) and obesity-prone Osborne-Mendel (OM) rats. Male and female rats were fed a low fat or high fat diet (HFD) and markers of metabolic syndrome (MetSyn) and expression of inflammatory cytokines/chemokines in visceral and subcutaneous adipose depots were measured. We hypothesized that male and female OM and S5B rats would exhibit differential responses to the consumption of HFD and that females, regardless of susceptibility to develop obesity, would display decreased obesity-related risk factors. Results suggested that consumption of HFD increased adiposity and fasting glucose levels in male OM and S5B rats, decreased circulating adiponectin levels in male S5B rats, and increased body weight and triglyceride levels in male OM rats. The consumption of HFD increased body weight and adiposity in female OM rats, not female S5B rats. Overall, female rats did not meet criteria for MetSyn, while male rats consuming HFD met criteria for MetSyn. Visceral and subcutaneous adipose tissue inflammation was higher in male rats. In visceral adipose tissue, HFD consumption differentially altered expression of cytokines in male and female S5B and OM rats. These findings suggest that resistance to obesity in males may be overridden by chronic consumption of HFD and lead to increased risk for development of obesity-related comorbidities, while female rats appear to be protected from the adverse effects of HFD consumption.

Vascular Adhesion Protein 1 Mediates Gut Microbial Flagellin-Induced Inflammation, Leukocyte Infiltration, and Hepatic Steatosis

Toll-like receptor 5 ligand, flagellin, and vascular adhesion protein 1 (VAP-1) are involved in non-alcoholic fatty liver disease. This study aimed to determine whether VAP-1 mediates flagellin-induced hepatic fat accumulation. The effects of flagellin on adipocyte VAP-1 expression were first studied in vitro. Then, flagellin (100 ng/mouse) or saline was intraperitoneally injected into C57BL/6J (WT) and C57BL/6-Aoc3-/- (VAP-1 KO) mice on a high-fat diet twice a week every 2 weeks for 10 weeks. After that, the effects on inflammation, insulin signaling, and metabolism were studied in liver and adipose tissues. Hepatic fat was quantified histologically and biochemically. Because flagellin challenge increased VAP-1 expression in human adipocytes, we used VAP-1 KO mice to determine whether VAP-1 regulates the inflammatory and metabolic effects of flagellin in vivo. In mice, VAP-1 mediated flagellin-induced inflammation, leukocyte infiltration, and lipolysis in visceral adipose tissue. Consequently, an increased release of glycerol led to hepatic steatosis in WT, but not in KO mice. Flagellin-induced hepatic fibrosis was not mediated by VAP-1. VAP-1 KO mice harbored more inflammation-related microbes than WT mice, while flagellin did not affect the gut microbiota. Our results suggest that by acting on visceral adipose tissue, flagellin increased leukocyte infiltration that induced lipolysis. Further, the released glycerol participated in hepatic fat accumulation. In conclusion, the results describe that gut microbial flagellin through VAP-1 induced hepatic steatosis.

Visceral Adipose Tissue of Prediabetic and Diabetic Females Shares a Set of Similarly Upregulated microRNAs Functionally Annotated to Inflammation, Oxidative Stress and Insulin Signaling.

Hypertrophic and hypoxic visceral adipose tissue (VAT) secretes proinflammatory cytokines promoting insulin resistance (IR), prediabetes and type 2 diabetes (T2DM) microRNAs (miRNAs) are markers of metabolic disorders regulating genes critical for e.g., inflammation, glucose metabolism, and antioxidant defense, with raising diagnostic value. The aim of the current study was to evaluate whether hyperglycemia is able to affect the expression of selected miRNAs in VAT of prediabetic (IFG) and diabetic (T2DM) patients vs. normoglycemic (NG) subjects using qPCR. Statistical analyses suggested that miRNAs expression could be sex-dependent. Thus, we determined 15 miRNAs as differentially expressed (DE) among NG, T2DM, IFG females (miR-10a-5p, let-7d-5p, miR-532-5p, miR-127-3p, miR-125b-5p, let-7a-5p, let-7e-5p, miR-199a-3p, miR-365a-3p, miR-99a-5p, miR-100-5p, miR-342-3p, miR-146b-5p, miR-204-5p, miR-409-3p). Majority of significantly changed miRNAs was similarly upregulated in VAT of female T2DM and IFG patients in comparison to NG subjects, positively correlated with FPG and HbA1c, yet, uncorrelated with WHR/BMI. Enrichment analyses indicated involvement of 11 top DE miRNAs in oxidative stress, inflammation and insulin signaling. Those miRNAs expression changes could be possibly associated with low-grade chronic inflammation and oxidative stress in VAT of hyperglycemic subjects.

Surgical ablation of whitened interscapular brown fat ameliorates cardiac pathology in salt-loaded metabolic syndrome rats.

Brown adipose tissue (BAT) is an endocrine organ that contributes to thermogenesis and energy consumption. We investigated the effects of salt loading and surgical removal of whitened interscapular BAT (iBAT) on cardiac and adipose tissue pathology in DahlS.Z-Leprfa /Leprfa (DS/obese) rats, an animal model of metabolic syndrome (MetS). DS/obese rats were subjected to surgical removal of iBAT or sham surgery at 8 weeks of age and were provided with drinking water containing or not containing 0.3% NaCl for 4 weeks beginning at 9 weeks of age. Removal of iBAT suppressed the salt-induced exacerbation of left ventricular inflammation, fibrosis, and diastolic dysfunction, but not that of hypertension development, in DS/obese rats. Salt loading attenuated adipocyte hypertrophy but enhanced inflammation in both visceral white adipose tissue (WAT) and iBAT. Although iBAT removal did not affect visceral WAT pathology in salt-loaded DS/obese rats, it attenuated the elevation of circulating interleukin-6 levels in these animals. Downregulation of uncoupling protein-1 expression in iBAT of DS/obese rats was not affected by salt loading. Our results suggest that the conversion of iBAT to WAT-like tissue contributes to a salt-induced elevation of circulating proinflammatory cytokine levels that leads to exacerbation of cardiac pathology in this model of MetS.

Reduced Biliverdin Reductase-A Expression in Visceral Adipose Tissue is Associated with Adipocyte Dysfunction and NAFLD in Human Obesity

Biliverdin reductase A (BVR-A) is an enzyme involved in the regulation of insulin signalling. Knockout (KO) mice for hepatic BVR-A, on a high-fat diet, develop more severe glucose impairment and hepato-steatosis than the wild type, whereas loss of adipocyte BVR-A is associated with increased visceral adipose tissue (VAT) inflammation and adipocyte size. However, BVR-A expression in human VAT has not been investigated. We evaluated BVR-A mRNA expression levels by real-time PCR in the intra-operative omental biopsy of 38 obese subjects and investigated the association with metabolic impairment, VAT dysfunction, and biopsy-proven non-alcoholic fatty liver disease (NAFLD). Individuals with lower VAT BVR-A mRNA levels had significantly greater VAT IL-8 and Caspase 3 expression than those with higher BVR-A. Lower VAT BVR-A mRNA levels were associated with an increased adipocytes’ size. An association between lower VAT BVR-A expression and higher plasma gamma-glutamyl transpeptidase was also observed. Reduced VAT BVR-A was associated with NAFLD with an odds ratio of 1.38 (95% confidence interval: 1.02–1.9; χ2 test) and with AUROC = 0.89 (p = 0.002, 95% CI = 0.76–1.0). In conclusion, reduced BVR-A expression in omental adipose tissue is associated with VAT dysfunction and NAFLD, suggesting a possible involvement of BVR-A in the regulation of VAT homeostasis in presence of obesity.

Multinucleated Giant Cells in Adipose Tissue Are Specialized in Adipocyte Degradation.

Obesity is associated with chronic low-grade inflammation of visceral adipose tissue (AT) characterized by an increasing number of AT macrophages (ATMs) and linked to type 2 diabetes. AT inflammation is histologically indicated by the formation of so-called crown-like structures, as ATMs accumulate around dying adipocytes, and the occurrence of multinucleated giant cells (MGCs). However, to date, the function of MGCs in obesity is unknown. Therefore, the aim of this study was to characterize MGCs in AT and unravel the function of these cells. We demonstrated that MGCs occurred in obese patients and after 24 weeks of a high-fat diet in mice, accompanying signs of AT inflammation and then representing ∼3% of ATMs in mice. Mechanistically, we found evidence that adipocyte death triggered MGC formation. Most importantly, MGCs in obese AT had a higher capacity to phagocytize oversized particles, such as adipocytes, as shown by live imaging of AT, 45-µm bead uptake ex vivo, and higher lipid content in vivo. Finally, we showed that interleukin-4 treatment was sufficient to increase the number of MGCs in AT, whereas other factors may be more important for endogenous MGC formation in vivo. Most importantly, our data suggest that MGCs are specialized for clearance of dead adipocytes in obesity.

Coronary plaque instability is associated with inflammatory activity of visceral adipose tissue and carotid artery: a prospective pilot F-18 FDG PET/CT study

Abstract Background Dysfunctional Visceral adipose tissue (VAT) secretes pro-inflammatory cytokines and promotes inflammatory cell infiltration into VAT thereby boosting insulin resistance and systemic inflammation which eventually lead to increased risk of cardiovascular disease (CVD). F-18 FDG PET/CT is well known to reflect the inflammatory activity of classically activated (M1) macrophage. Purpose We hypothesized that F-18 FDG PET/CT could reflect the inflammatory activity of dysfunctional VAT and carotid artery which were associated with coronary plaque instability. Methods A total of 90 participants were enrolled in this prospective study. F-18 FDG PET/CT was performed in 32 participants with acute myocardial infarction (AMI) within a week of disease onset, 33 participants with stable coronary artery disease (CAD), and 25 control subjects. Maximum standardized uptake value (SUVmax) was calculated in VAT, subcutaneous adipose tissue (SAT), spleen, and bone marrow (BM). Target-to-background ratio (TBR) was calculated in right carotid artery and right jugular vein. Results The SUVmax of VAT and the TBR of right carotid artery were highest in patients with AMI, intermediate in patient with stable CAD, and lowest in control subjects. Systemic inflammation surrogate markers such as high-sensitivity C-reactive protein, spleen SUVmax were also showed similar pattern like the SUVmax of VAT and the TBR of right carotid artery. Furthermore, multiple linear regression analysis showed that the SUVmax of VAT and spleen SUVmax were independently associated with the TBR of right carotid artery. Conclusions F-18 FDG PET/CT could reflect the synchronized systemic inflammation in VAT and carotid artery which could affect the coronary artery instability. Furthermore, our findings offer clinical insights into risk stratification, monitoring of therapy, and physiological changes in the development of CAD. Funding Acknowledgement Type of funding source: None

Angiopoietin-Like Protein 4 Overexpression in Visceral Adipose Tissue from Obese Subjects with Impaired Glucose Metabolism and Relationship with Lipoprotein Lipase.

Angiopoietin-like protein 4 (ANGPTL4) regulates lipid partitioning by inhibiting circulating and tissue lipoprotein lipase (LPL); ANGPTL4 loss-of-function variants improve insulin sensitivity and reduce type 2 diabetes (T2D) risk with mechanisms partially unknown. This study was designed to explore metabolic implications of differential ANGPTL4 and LPL expression in human adipose tissue (AT). We recruited eighty-eight obese individuals, with and without abnormal glucose metabolism (AGM), undergoing bariatric surgery; visceral AT (VAT) fragments were obtained intra-operatively and analyzed by immunohistochemistry and mRNA by rt-PCR. Data on hepatic ANGPTL4 mRNA were available for 40 participants. VAT ANGPTL4 expression was higher in AGM individuals than in those with normal glucose tolerance (NGT) and associated with VAT inflammation, insulin resistance, and presence of adipocyte size heterogeneity. Increased ANGPTL4 was associated with AGM with OR = 5.1 (95% C.I.: 1.2–23; p = 0.02) and AUROC = 0.76 (95% C.I.: 1.2–23; p < 0.001). High LPL was associated with the detection of homogeneous adipocyte size, reduced microvessel density, and higher HIF-1α levels and inversely correlated to blood transaminases. In conclusion, in obese individuals, VAT ANGPTL4 levels are increased in the presence of local inflammation and AGM. Conversely, higher LPL expression describes a condition of increased lipid storage in adipocytes, which may serve as a protective mechanism against ectopic fat accumulation and related metabolic disease in obesity.

Adrenomedullin AttenuatesInflammation inWhite Adipose Tissueof Obese Rats Through Receptor-Mediated PKA Pathway.

ObjectiveAdrenomedullin (ADM) possesses therapeutic potential for inflammatory diseases. Consequently, the effects of ADM on inflammation in visceral white adipose tissue (vWAT) of obese rats or in adipocytes were explored in this study.MethodsMale rats were fed a high‐fat diet for 12 weeks to induce obesity, and obese rats were implanted with osmotic minipumps providing constant infusion of ADM (300 ng/kg per hour) and continued to be fed a high‐fat diet for 4 weeks.ResultsWhen compared with the control group, endogenous protein expression of ADM and ADM receptors in vWAT and in lipopolysaccharide (LPS)‐treated adipocytes was markedly increased. ADM significantly decreased the protein expression of the inflammatory mediators TNFα, IL‐1β, cyclooxygenase‐2, and inducible nitric oxide synthase in vWAT of obese rats and in adipocytes stimulated by LPS. It also inhibited the activation of the inflammatory signaling pathways MAPK and NF‐κB induced by LPS in adipocytes. These effects of ADM in adipocytes were inhibited by the administration of ADM receptor antagonist and cAMP‐dependent protein kinase (PKA) activation inhibitor.ConclusionsADM can inhibit inflammation in WAT in obesity, which may be mediated by the activation of ADM receptors and PKA.