Adipose Tissue Of Patients Research Articles

Impact of systolic blood pressure on epicardial adipose tissue in patients with chronic coronary artery disease

Abstract Objectives The current study aimed to investigate the impact of systolic blood pressure (SBP) on epicardial adipose tissue (EAT) volume in a large, multi-center cohort of patients with chronic coronary artery disease (CAD). Methods We included 879 patients with CAD (mean age: 58±11 years; 294 females; 72% Chinese, 20% Indian/Malay, 8% Others) in the APOLLO study. The EAT volume was measured using non-contrast computed tomography (CT) imaging. The contour of the pericardium was traced from the pulmonary artery bifurcation to the apex of the heart. CT attenuation between -190 and -30 Hounsfield units (HU) was used to select the EAT on every axial slice. The EAT volumes were automatically calculated from 3-dimensional fat voxels at each axial slice, which were then summed to obtain the total EAT volume (Figure 1). Results EAT volume was positively correlated with age (r=0.261, P<0.0001). With a one-year increase in age, the EAT volume was found to increase by 1.5 cm3, adjusting for other confounders. The mean EAT volume for males was 8.3 cm3 higher than for females (P=0.015). Patients with hypertension had significantly higher EAT volume (134±51 vs. 114±48 cm3, P<0.0001) compared to those without hypertension. Multivariable analysis adjusted for age, gender and other cardiac risk factors showed that the presence of hypertension (P=0.043) was independently associated with EAT volume. Compared to the highest SBP tertile (≥148 mmHg), those in the lowest SBP tertile (≤132 mmHg) had lower EAT volume (117±52 vs. 128±51 cm3, P=0.007). When examined as a continuous variable, higher SBP was significantly associated with higher EAT volume: for every 10mmHg increase in SBP, EAT volume increased by 2.6 cm3. Conclusion The study found a significant association between hypertension and increased EAT volume, emphasizing the importance of managing hypertension to reduce cardiovascular risk.

Dapagliflozin reduces epicardial adipose tissue in patients with heart failure with reduced ejection fraction and type 2 diabetes

Abstract Introduction Epicardial adipose tissue (EAT) accumulation is associated with adverse outcome in heart failure with preserved ejection fraction, however its role in HF with reduced ejection fraction (HFrEF) is less clear. The relationship between EAT thickness and their impact on patients who have diabetes and heart failure remains unclear. SGLT2 inhibitors such as dapagliflozin improve outcomes in heart failure and diabetes, however their mechanism of benefit is not well understood. The aim of our study was to assess whether dapagliflozin reduced EAT in patients with type 2 diabetes and HFrEF. Methods We performed an analysis of individuals with type 2 diabetes and HFrEF who were randomised to receive either dapagliflozin or a placebo for 12 months as part of the REFORM trial. Participants had cardiac magnetic resonance (CMR) scans at baseline and at 12 months. Epicardial fat was measured utilizing 4-chamber cine images to quantify adipose tissue between the myocardium and the visceral layer of the pericardium. This assessment was carried out using the single end-diastolic image, with measurements conducted by evaluators blinded to the randomisation status of participants. Results 47 participants completed the stud. At baseline, not only EAT thickness and BMI level (placebo: 33, dapagliflozin 32, p=0.49) but also heart rate (74.39 bpm vs. 77.61 bpm, p=0.35), systolic blood pressure (132.75 mmHg vs. 135.00 mmHg, p=0.63), diastolic blood pressure (71.39 mmHg vs. 74.04 mmHg, p=0.33) and age (67 vs. 66, p=0.79) were comparable between the two groups. 23 randomised to placebo and 24 to dapagliflozin. Baseline EAT was similar in both groups (placebo: 11.54 cm², dapagliflozin 11.74 cm², p=0.414). After 12 months of treatment dapagliflozin caused a significant reduction in EAT compared to placebo (1.21 cm² vs. 0.09 cm², p=0.007). Conclusion Dapagliflozin significantly reduced epicardial adipose tissue compared to placebo in patients with type 2 diabetes and HFrEF. The reduction in EAT may play a role in the beneficial effects of dapagliflozin in heart failure patients.4 Ch CMRBox plot

Characteristics of gene expression in epicardial adipose tissue and subcutaneous adipose tissue in patients at risk for heart failure undergoing coronary artery bypass grafting

BackgroundEpicardial adipose tissue (EAT) surrounds the heart and is hypothesised to play a role in the development of heart failure (HF). In this study, we first investigated the differences in gene expression between epicardial adipose tissue (EAT) and subcutaneous adipose tissue (SAT) in patients undergoing elective coronary artery bypass graft (CABG) surgery (n = 21; 95% male). Secondly, we examined the association between EAT and SAT in patients at risk for HF stage A (n = 12) and in pre-HF patients, who show signs but not symptoms of HF, stage B (n = 9).ResultsThe study confirmed a distinct separation between EAT and SAT. In EAT 17 clusters of genes were present, of which several novel gene modules are associated with characteristics of HF. Notably, seven gene modules showed significant correlation to measures of HF, such as end diastolic left ventricular posterior wall thickness, e’mean, deceleration time and BMI. One module was particularly distinct in EAT when compared to SAT, featuring key genes such as FLT4, SEMA3A, and PTX3, which are implicated in angiogenesis, inflammation regulation, and tissue repair, suggesting a unique role in EAT linked to left ventricular dysfunction. Genetic expression was compared in EAT across all pre-HF and normal phenotypes, revealing small genetic changes in the form of 18 differentially expressed genes in ACC/AHA Stage A vs. Stage B.ConclusionsThe roles of subcutaneous and epicardial fat are clearly different. We highlight the gene expression difference in search of potential modifiers of HF progress. The true implications of our findings should be corroborated in other studies since HF ACC/AHA stage B patients are common and carry a considerable risk for progression to symptomatic HF.

Adipocytes Size of the Epicardial Adipose Tissue in Patients With Coronary Artery Disease and Coronary Atherosclerosis: Relationship With Parameters of Blood Lipid Transport Function, Carbohydrate Metabolism and Inflammatory Markers

Aim. To assess the potential relationship between morphometric characteristics of adipocytes in epicardial and subcutaneous adipose tissue (EAT, SAT) and the lipid transport function of the blood, glucose e metabolism, and inflammatory biomarkers in patients with ischemic heart disease (IHD) after coronary artery bypass grafting.Material and methods. The study included 47 patients (33 men and 14 women) aged 53-72 years with chronic IHD. The study material was EAT and SAT adipocytes obtained from intraoperative explants. The size of EAT and SAT adipocytes and the proportion of EAT and SAT adipocytes with ≥100 μm and ≤50 μm sizes were determined. Carbohydrate metabolism parameters, blood lipid transport function, and inflammatory biomarkers were assessed. Surrogate indices of insulin resistance (IR) were calculated.Results. The mean size of EAT adipocytes, in contrast to SAT adipocytes, correlated (p<0.05) with serum concentrations of tumor necrosis factor alpha (TNF-α) (rs=0.43), triglycerides (TG) (rs=0.36), interleukin (IL)-1β (rs=0.29), basal C-peptide (rs=0.40) and TyG index (rs=0.32). Male gender and blood concentrations of basal C-peptide and TG in combination were identified as statistically significant determinants of an increase in the mean size of EAT adipocytes. The threshold values of TG and non-high-density lipoprotein cholesterol (nHDL-C) associated with an increase in the mean size of EAT adipocytes ≥87.61 μm were 1.4 and 2.63 mM, respectively. Patients with TG concentrations ≥1.4 mM had a greater size and proportion of hypertrophied EAT adipocytes, IR indices, and higher blood concentrations of basal glucose, high-sensitivity C-reactive protein, TNF-α, and IL-1β. TG concentrations of 1.2-1.4 mM, compared with concentrations <1.2 mM, were associated with a greater mean size of EAT adipocytes and higher serum IL-10 concentrations. Patients with non-HDL-C ≥2.63 mM, compared with its lower concentrations, had more pronounced hypertrophy of EAT adipocytes.Conclusion. Disorders in the morphometric characteristics of EAT adipocytes, in contrast to SAT adipocytes, are associated with increased blood concentrations of TG, non-HDL-C, inflammatory markers, and increased IR indices. It was shown for the first time that a combination of three factors, male gender, blood concentrations of basal C-peptide, and TG, independently of other indicators describe the variability of the mean size of EAT adipocytes. Increases in TG from 1.2 to 1.4 mM are associated with a larger size of EAT adipocytes and cytokine imbalance. Our data confirm the validity of identifying optimal blood concentrations of TG and non-HDL-C in patients with IHD and coronary atherosclerosis.

Computer tomography-based assessment of perivascular adipose tissue in patients with abdominal aortic aneurysms

This retrospective study investigates perivascular adipose tissue (PVAT) alterations in CT as a marker of inflammation in patients with abdominal aortic aneurysms (AAA). 100 abdominal CT scans of patients with abdominal aortic aneurysms and 100 age and sex matched controls without underlying aortic disease were included. Artificial Intelligence (AI) assisted segmentation of the aorta and the surrounding adipose tissue was performed. Adipose tissue density was measured in Hounsfield units (HU) close (2-5mm, HUclose) and distant (10-12mm, HUdistant) to the aortic wall. To investigate alterations in adipose tissue density close to the aorta (HUclose) as a potential marker of inflammation, we calculated the difference HUΔ = HUclose-HUdistant and the fat attenuation ratio HUratio = HUclose/HUdistant as normalized attenuation measures. These two markers were compared i) inter-individually between AAA patients and controls and ii) intra-individually between the aneurysmal and non-aneurysmal segments in AAA patients. Since most AAAs are generally observed infrarenal, the aneurysmal section of the AAA patients was compared with the infrarenal section of the aorta of the control patients. In inter-individual comparisons, higher HUΔ and a lower HUratio were observed (aneurysmal: 8.9 ± 5.1 HU vs. control: 6.9 ± 4.8 HU, p-value = 0.006; aneurysmal: 89.8 ± 5.7% vs. control: 92.1 ± 5.5% p-value = 0.004). In intra-individual comparisons, higher HUΔ and lower HUratio were observed (aneurysmal: 8.9 ± 5.1 HU vs. non-aneurysmal: 5.5 ± 4.1 HU, p-value < 0.001; aneurysmal: 89.8 ± 5.7% vs. non-aneurysmal 93.3 ± 4.9%, p-value < 0.001). The results indicate PVAT density alterations in AAA patients. This motivates further research to establish non-invasive imaging markers for vascular and perivascular inflammation in AAA.

Expression profile of IL2RA, FOXP3, PPARG, IL6, IL10, LRRC32 AND GATA3 genes in adipose tissue of patients with obesity and type 2 diabetes mellitus

Expression profile of IL2RA, FOXP3, PPARG, IL6, IL10, LRRC32 AND GATA3 genes in adipose tissue of patients with obesity and type 2 diabetes mellitus

Comparison of adipokines expression in adipose tissues of patients with coronary artery disease - Role of chemerin

Comparison of adipokines expression in adipose tissues of patients with coronary artery disease - Role of chemerin

Differential Lipidomic Profiles in Epicardial Versus Subcutaneous Adipose Tissue in Patients With Coronary Artery Disease

Differential Lipidomic Profiles in Epicardial Versus Subcutaneous Adipose Tissue in Patients With Coronary Artery Disease

Hypoxic Preconditioning Promotes Survival of Human Adipose Derived Mesenchymal Stem Cell

Background: Contributing factors for improved survival of human adipocytes mesenchymal stem cells (h-AMSCs) cultured through hypoxia preconditioning, in example apoptosis inhibition involving BCL2 and HSP27 expression, trigger signal expression (VEGF), SCF expression, OCT-4 expression, and CD44+ expression. The objective if this study was to explain the mechanism and role of hypoxic preconditioning and the optimal duration of hypoxic preconditioning exposure to improve survival of h-AMSCs. Methods: An experimental laboratory explorative study (in vitro) with hypoxic preconditioning in h-AMSCs cultures. This research was conducted through four stages. First, isolation of h-AMSCs culture from adipose tissue of patients. Second, the characterization of h-AMSCs from adipose tissue by phenotype (flowcytometry) through CD44+, CD90+ and CD45-expression before being pre-conditioned for hypoxic treatment. Third, the hypoxic preconditioning in h-AMSCs culture (in vitro) was performed with an oxygen concentration of 1% for 24, 48 and 72 hours. Fourth, observation of survival from h-AMSCs culture was tested on the role of CD44+, VEGF, SCF, OCT-4, BCL2, HSP27 with Flowcytometry and apoptotic inhibition by Tunnel Assay method. Results: The result of regression test showed that time difference had an effect on VEGF expression (p&lt;0.001;β=-0.482) and hypoxia condition also influenced VEGF expression (p&lt;0.001;β=0.774). The result of path analysis showed that SCF had effect on OCT-4 expression (p&lt;0.001; β=0.985). The regression test results showed that time effects on HSP27 expression (p&lt;0.001; β=0.398) and hypoxia precondition also affects HSP27 expression (p&lt;0.001; β=0.847). Pathway analysis showed that BCL2 expression inhibited apoptosis (p=0.030; β=-0.442) and HSP27 expression also inhibited apoptosis (p&lt;0,001;β=-0.487). Conclusion: Hypoxic preconditioning of h-AMSC culture has proven to increase the expression of VEGF, SCF, OCT-4, and BCL2 and HSP27. This study demonstrated and explained the existence of a new mechanism of increased h-AMSC survival in cultures with hypoxic preconditioning (O2 1%) via VEGF, SCF, OCT-4, BCL2, and HSP 27.

Excessive palmitic acid disturbs macrophage α-ketoglutarate/succinate metabolism and causes adipose tissue insulin resistance associated with gestational diabetes mellitus

Abnormal polarization of adipose tissue macrophages (ATMs) results in low-grade systemic inflammation and insulin resistance (IR), potentially contributing to the development of diabetes. However, the underlying mechanisms that regulate the polarization of ATMs associated with gestational diabetes mellitus (GDM) remain unclear. Thus, we aimed to determine the effects of abnormal fatty acids on macrophage polarization and development of insulin resistance in GDM. Levels of fatty acids and inflammation were assessed in the serum samples and adipose tissues of patients with GDM. An in vitro cell model treated with palmitic acid was established, and the mechanisms of palmitic acid in regulating macrophage polarization was clarified. The effects of excessive palmitic acid on the regulation of histone methylations and IR were also explored in the high-fat diet induced GDM mice model. We found that pregnancies with GDM were associated with increased levels of serum fatty acids, and inflammation and IR in adipose tissues. Increased palmitic acid could induce mitochondrial dysfunction and excessive ROS levels in macrophages, leading to abnormal cytoplasmic and nuclear metabolism of succinate and α-ketoglutarate (αKG). Specifically, a decreased nuclear αKG/succinate ratio could attenuate the enrichment of H3K27me3 at the promoters of pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α, leading to cytokine secretion. Importantly, GDM mice treated with GSK-J4, an inhibitor of histone lysine demethylase, were protected from abnormal pro-inflammatory macrophage polarization and excessive production of pro-inflammatory cytokines. Our findings highlight the importance of the metabolism of αKG and succinate as transcriptional modulators in regulating the polarization of ATMs and the insulin sensitivity of adipose tissue, ensuring a normal pregnancy. This novel insight sheds new light on gestational fatty acid metabolism and epigenetic alterations associated with GDM.

Hypoxic Preconditioning Promotes Survival of Human Adipose Derived Mesenchymal Stem Cell.

Background: Contributing factors for improved survival of human adipocytes mesenchymal stem cells (h-AMSCs) cultured through hypoxia preconditioning, in example apoptosis inhibition involving BCL2 and HSP27 expression, trigger signal expression (VEGF), SCF expression, OCT-4 expression, and CD44+ expression. The objective if this study was to explain the mechanism and role of hypoxic preconditioning and the optimal duration of hypoxic preconditioning exposure to improve survival of h-AMSCs. Methods: An experimental laboratory explorative study ( in vitro) with hypoxic preconditioning in h-AMSCs cultures. This research was conducted through four stages. First, isolation of h-AMSCs culture from adipose tissue of patients. Second, the characterization of h-AMSCs from adipose tissue by phenotype (flowcytometry) through CD44+, CD90+ and CD45-expression before being pre-conditioned for hypoxic treatment. Third, the hypoxic preconditioning in h-AMSCs culture ( in vitro) was performed with an oxygen concentration of 1% for 24, 48 and 72 hours. Fourth, observation of survival from h-AMSCs culture was tested on the role of CD44+, VEGF, SCF, OCT-4, BCL2, HSP27 with Flowcytometry and apoptotic inhibition by Tunnel Assay method. Results: The result of regression test showed that time difference had an effect on VEGF expression ( p<0.001; β=-0.482) and hypoxia condition also influenced VEGF expression ( p<0.001; β=0.774). The result of path analysis showed that SCF had effect on OCT-4 expression ( p<0.001; β=0.985). The regression test results showed that time effects on HSP27 expression ( p<0.001; β=0.398) and hypoxia precondition also affects HSP27 expression ( p<0.001; β=0.847). Pathway analysis showed that BCL2 expression inhibited apoptosis ( p=0.030; β=-0.442) and HSP27 expression also inhibited apoptosis ( p<0,001; β=-0.487). Conclusion: Hypoxic preconditioning of h-AMSC culture has proven to increase the expression of VEGF, SCF, OCT-4, and BCL2 and HSP27. This study demonstrated and explained the existence of a new mechanism of increased h-AMSC survival in cultures with hypoxic preconditioning (O2 1%) via VEGF, SCF, OCT-4, BCL2, and HSP 27.

Evaluation of the cushion effect in blunt abdominal trauma patients: A computerized analysis

BackgroundObesity may serve as a protective factor in blunt abdominal trauma (BAT) patients due to a "cushion effect". In this study, we aim to use computed tomography (CT) scans to measure abdominal adiposity and its correlation with injury severity in BAT patients. MethodsWe conducted a retrospective analysis of male BAT patients who had undergone CT scans. Subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) were manually measured and height-normalized for analysis at lumbar levels L2 and L3. Statistical methods were used to compare differences in adiposity between patients with and without severe abdominal injuries. For controls, we also compared adipose tissue in patients with and without severe trauma to the chest, where less fat typically accumulates. ResultsWe included 361 male participants and conducted a comparative analysis of their demographic and injury characteristics. Patients without severe abdominal injuries had significantly higher SAT and VAT indices at both L2 and L3 (p < 0.05). However, these measures showed no significant differences between patients with and without severe chest trauma. Solid organ injuries, particularly liver injuries, were associated with decreased SAT and VAT. ConclusionIncrease abdominal adiposity was linked to lower abdominal injury severity and solid organ injuries, particularly liver injuries. In addition to conventional BMI for evaluating obesity, either subcutaneous or visceral adipose tissue over lumbar levels L2 and L3 can be used to assess the "cushion effect."

The role of fibroblast growth factor 21 in metabolic processes in patients with gastrointestinal diseases

Background. Recently, the number of patients with obesity and metabolic syndrome has increased. Numerous studies to find new regulators of metabolic processes have led to the disco­very of a new fibroblast growth factor 21 (FGF21). The purpose of the study was to determine the correlation between FGF21 and meta­bolic processes among patients with gastrointestinal pathology. Materials and methods. The study was conducted in 80 patients with gastrointestinal diseases aged 18 to 66 years, the average age was (39.04 ± 1.03) years. Among the subjects, there were 56 men (70.0 %) and 24 women (30.0 %). Body composition was assessed using the Tanita MC-780MA apparatus (Japan). Serum leptin, FGF21, insulin levels were measured by enzyme-linked immunosorbent assay, and the HOMA-IR was calculated. Free fatty acids in the serum of patients were evaluated on Chromateс Crystal-5000, a gas chromatograph with a flame ionization detector. Results. The study found positive correlations between FGF21 levels and indicators of bioimpedance analysis: body mass index (r = 0.24; p = 0.004), fat mass (r = 0.26; p = 0.01) and visceral fat (r = 0.29; p = 0.01). In addition, a relationship was detected between FGF21 levels and laboratory data: insulin (r = 0.32; p = 0.001), HOMA-IR (r = 0.31; p = 0.001), leptin (r = 0.32; p = 0.001), triglyceride/high-density lipoprotein ratio (r = 0.48; p = 0.0001), and the content of certain free fatty acids. This indicates that FGF21 affects the development of obesity and metabolic disorders. It was found that FGF21 is associated with visceral obesity in patients with digestive diseases (odds ratio = 1.28, p = 0.0022). FGF21 levels above 1,317.5 pg/mL (sensitivity of 71.0 %, specificity of 53.1 %) indicate the presence of visceral obesity in patients with gastrointestinal di­seases. Conclusions. As a result of a comprehensive study, new data were obtained on the role of FGF21 as a key regulator of metabolic disorders, which is confirmed by the established relationships of this indicator with the components of lipid and carbohydrate metabolism disorders, cytokine imbalance, and hormonal activity of adipose tissue in patients with pathology of the digestive system.

Obesity-dependent molecular alterations in fatal COVID-19: A retrospective postmortem study of metabolomic profile of adipose tissue.

We investigated the effects of obesity on metabolic, inflammatory, and oxidative stress parameters in the adipose tissue of patients with fatal COVID-19. Postmortem biopsies of subcutaneous adipose tissue were obtained from 25 unvaccinated inpatients who passed from COVID-19, stratified as nonobese (N-OB; body mass index [BMI],26.5 ± 2.3 kg m-2) or obese (OBBMI 34.2 ± 5.1 kg m-2). Univariate and multivariate analyses revealed that body composition was responsible for most of the variations detected in the metabolome, with greater dispersion observed in the OB group. Fifteen metabolites were major segregation factors. Results from the OB group showed higher levels of creatinine, myo-inositol, O-acetylcholine, and succinate, and lower levels of sarcosine. The N-OBgroup showed lower levels of glutathione peroxidase activity, as well as higher content of IL-6and adiponectin. We revealed significant changes in the metabolomic profile of the adipose tissue in fatal COVID-19 cases, with high adiposity playing a key role in these observed variations. These findings highlight the potential involvement of metabolic and inflammatory pathways, possibly dependent on hypoxia, shedding light on the impact of obesity on disease pathogenesis and suggesting avenues for further research and possible therapeutic targets.

Whole-body deletion of Endospanin 1 protects from obesity-associated deleterious metabolic alterations.

The importance of the proper localization of most receptors at the cell surface is often underestimated, although this feature is essential for optimal receptor response. Endospanin 1 (Endo1) (also known as OBRGRP or LEPROT) is a protein generated from the same gene as the human leptin receptor and regulates the trafficking of proteins to the surface, including the leptin receptor. The systemic role of Endo1 on whole-body metabolism has not been studied so far. Here, we report that general Endo1-KO mice fed a high-fat diet develop metabolically healthy obesity with lipid repartitioning in organs and preferential accumulation of fat in adipose tissue, limited systematic inflammation, and better controlled glucose homeostasis. Mechanistically, Endo1 interacts with the lipid translocase CD36, thus regulating its surface abundance and lipid uptake in adipocytes. In humans, the level of Endo1 transcripts is increased in the adipose tissue of patients with obesity, but low levels rather correlate with a profile of metabolically healthy obesity. We suggest here that Endo1, most likely by controlling CD36 cell surface abundance and lipid uptake in adipocytes, dissociates obesity from diabetes and that its absence participates in metabolically healthy obesity.

Potential Clinical Implications of Senotherapies for Cardiovascular Disease.

Aging is a major risk factor for cardiovascular diseases (CVDs) and accumulating evidence indicates that biological aging has a significant effect on the onset and progression of CVDs. In recent years, therapies targeting senescent cells (senotherapies), particularly senolytics that selectively eliminate senescent cells, have been developed and show promise for treating geriatric syndromes and age-associated diseases, including CVDs. In 2 pilot studies published in 2019 the senolytic combination, dasatinib plus quercetin, improved physical function in patients with idiopathic pulmonary fibrosis and eliminated senescent cells from adipose tissue in patients with diabetic kidney disease. More than 30 clinical trials using senolytics are currently underway or planned. In preclinical CVD models, senolytics appear to improve heart failure, ischemic heart disease, valvular heart disease, atherosclerosis, aortic aneurysm, vascular dysfunction, dialysis arteriovenous fistula patency, and pre-eclampsia. Because senotherapies are completely different strategies from existing treatment paradigms, they might alleviate diseases for which there are no current effective treatments or they could be used in addition to current therapies to enhance efficacy. Moreover, senotherapies might delay, prevent, alleviate or treat multiple diseases in the elderly and reduce polypharmacy, because senotherapies target fundamental aging mechanisms. We comprehensively summarize the preclinical evidence about senotherapies for CVDs and discuss future prospects for their clinical application.

P1193 NOD2 and Beyond: Unmasking Tobacco-Induced Epigenetic Changes in Crohn's Disease

Abstract Background Smoking has been shown to have a very negative impact on Crohn's disease (CD). Indeed, this harmful habit induces the early onset of the disease and doubles the risk of postoperative recurrence. This research project involves a thorough analysis of omics data, with a primary focus on DNA methylation, one of the most prevalent epigenetic modifications. Our hypothesis is that tobacco-induced alterations in gene methylation pattern of subcutaneous adipose tissue (SAT), particularly within key pathways, contribute to a more adverse disease profile in smokers. Methods A comprehensive epigenome-wide analysis was conducted using the Illumina EPIC/450k array to investigate subcutaneous adipose tissue in patients with CD, encompassing both smokers and non-smokers. Utilizing tools such as dmpfinder and Bumphunter (minfi), differentially methylated positions (DMPs) and regions (DMRs) were identified. Additionally, gene expression analysis for key genes was performed to establish correlations between methylation and subsequent gene expression, not only in SAT but also in other fat depots such as visceral adipose tissue (VAT) or peripheral blood mononuclear cells (PBMCs). Results A distinctive DNA methylation pattern in the SAT of smokers compared to non-smoker CD patients was identified (Fig. 1A). Over 27,270 DMPs associated with significant biological processes related to DNA damage, inflammation, or immunity were uncovered (Fig. 1B-C). Additionally, more than 13,000 DMRs located in the promoter region were identified (Fig. 1C). The relationship between methylation levels in the promoter regions and subsequent gene expression on SAT was validated for selected genes. Specifically, NOD2 exhibited higher DNA methylation in the promoter region among smokers compared to non-smokers CD patients (p value=0.04), resulting in reduced NOD2 gene expression on SAT (p value=0.04) (Fig.1D). Consistent results were observed in other tissues such as VAT and PBMCs (Fig. 1E). Finally, we observe the implication of NOD2 in pathways related to immune response, inflammation or apoptosis and a trend indicating that lower NOD2 expression is associated with higher levels of C-reactive protein (CRP)(Fig. 1F). Conclusion Our study reveals that smoking produces DNA methylation changes on SAT of CD patients and affects the expression of several key genes involved in the pathogeny of CD. Particularly, our results unveil a new link between tobacco-smoking and lower NOD2 expression and associate this to an elevated levels of PCR, paving the way for a fresh perspective in exploring disease prognosis.

Clinical and molecular profiling of human visceral adipose tissue reveals impairment of vascular architecture and remodeling as an early hallmark of dysfunction

Adipose tissue dysfunction is more related to insulin resistance than body mass index itself and an alteration in adipose tissue function is thought to underlie the shift from metabolically healthy to unhealthy obesity. Herein, we performed a clustering analysis that revealed distinct visceral adipose tissue gene expression patterns in patients with obesity at distinct stages of metabolic dysregulation. We have built a cross-sectional cohort that aims at reflecting the evolution of the metabolic sequelae of obesity with the main objective to map the sequential events that play a role in adipose tissue dysfunction from the metabolically healthy (insulin-sensitive) state to several incremental degrees of metabolic dysregulation, encompassing insulin resistance establishment, pre-diabetes, and type 2 diabetes. We found that insulin resistance is mainly marked by the downregulation of adipose tissue vasculature remodeling-associated gene expression, suggesting that processes like angiogenesis and adaptative expansion/retraction ability suffer early dysregulation. Prediabetes was characterized by compensatory growth factor-dependent signaling and increased response to hypoxia, while type 2 diabetes was associated with loss of cellular response to insulin and hypoxia and concomitant upregulation of inflammatory markers. Our findings suggest a putative sequence of dysregulation of biological processes that is not linear and has multiple distinct phases across the metabolic dysregulation process, ultimately culminating in the climax of adipose tissue dysfunction in type 2 diabetes. Several studies have addressed the transcriptomic changes in adipose tissue of patients with obesity. However, to the best of our knowledge, this is the first study unraveling the potential molecular mechanisms associated with the multi-step evolution of adipose tissue dysfunction along the metabolic sequelae of obesity.

Assessment of lipolysis biomarkers in adipose tissue of patients with gastrointestinal cancer

BackgroundAdipose tissue metabolism may be impaired in patients with cancer. In particular, increased lipolysis was described in cancer-promoting adipose tissue atrophy.For this reason, we assessed the expression of the lipolysis-associated genes and proteins in subcutaneous adipose tissue (SAT) of gastrointestinal (GI) cancer patients compared to controls to verify their involvement in cancer, among different types of GI cancers, and in cachexia.MethodsWe considered patients with GI cancer (gastric, pancreatic, and colorectal) at their first diagnosis, with/without cachexia, and controls with benign diseases.We collected SAT and total RNA was extracted and ATGL, HSL, PPARα, and MCP1 were analyzed by qRT-PCR. Western blot was performed to evaluate CGI-58, PLIN1 and PLIN5.ResultsWe found higher expression of ATGL and HSL in GI cancer patients with respect to controls (p ≤ 0.008) and a trend of increase for PPARα (p = 0.055). We found an upregulation of ATGL in GI cancer patients with cachexia (p = 0.033) and without cachexia (p = 0.017) vs controls. HSL was higher in patients with cachexia (p = 0.020) and without cachexia (p = 0.021), compared to controls. ATGL was upregulated in gastric cancer vs controls (p = 0.014) and higher HSL was found in gastric (p = 0.008) and in pancreatic cancer (p = 0.033) vs controls. At the protein level, we found higher CGI-58 in cancer vs controls (p = 0.019) and in cachectic vs controls (p = 0.029), as well as in gastric cancer vs controls (p = 0.027).ConclusionIn our cohort of GI cancer patients, we found a modulation in the expression of genes and proteins involved in lipolysis, and differences were interestingly detected according to cancer type.

Epigenetic alterations of 11beta-hydroxysteroid dehydrogenase 1 gene in the adipose tissue of patients with primary aldosteronism.

11Beta-hydroxysteroid dehydrogenase 1 (11β-HSD1) is a key enzyme involved in metabolic syndrome. Transcript-specific epigenetic regulation of the gene encoding 11β-HSD1 (HSD11B1) has been reported. We examined the mRNA level and methylation status of the HSD11B1 promoter region in the adipose tissue of patients with primary aldosteronism (PA). We compared 10 tissue specimens from patients with PA caused by aldosterone-producing adenoma (APA) with 8 adipose tissue specimens from patients with subclinical Cushing's syndrome (SCS) caused by cortisol-producing adenomas, 4 tissue specimens from patients with Cushing's adenoma (Cu), or 7 tissue specimens from patients with non-functioning adrenal adenoma (NFA). PA, SCS, and Cu were diagnosed according to the guideline of the Japan Endocrine Society. The mRNA level of HSD11B1 was quantified using real-time PCR. Isolated DNA was treated with bisulfite and amplified using primers specific to the human HSD11B1 promoter region. The glycohemoglobin level was significantly higher in patients with APA, SCS, or Cu than in those with NFA (p < 0.05). Blood pressure was significantly higher in patients with APA than in those with SCS, Cu, or NFA (p < 0.01). The HSD11B1 mRNA level was significantly increased in the adipose tissues of APA or SCS patients compared with Cu or NFA patients (p < 0.05). The methylation ratio was significantly lower in SCS patients than in APA, Cu, or NFA patients (p < 0.05). HSD11B1 expression is partly controlled by an epigenetic mechanism in human tissues. The pathophysiological role of epigenetic regulation of HSD11B1 expression in adipose tissue requires further study.