Adipose Tissue Of Obese Patients Research Articles

Does a higher body mass index influence additional presence of low voltage areas in the left atrium in patients with persistent atrial fibrillation?

Abstract Introduction Pulmonary vein isolation (PVI) is recommended during all atrial fibrillation (AF) catheter ablation procedures. In nearly half of patients with persistent AF, low voltage areas (LVAs), commonly defined as areas in left atrium (LA) with a bipolar electrogram amplitude of < 0.5 mV, could be documented during electrophysiological study (EP). The remaining presence of these areas in LA after a PVI-only catheter ablation procedure is identified as a risk factor for recurrence of AF. Targeting and ablating (substrate modification) these areas reduces recurrency of AF. Pre-procedural identification of patients with additional LVAs is thus very important, until date very challenging and not established. Many markers are evaluated but it remains elusive. Extensive adipose tissue in obese patients leads to LA enlargement and remodeling via different mechanisms, leading to higher incidence of AF. The link between obesity and presence of LVAs in LA other than of pulmonary veins (PV) is to our knowledge not yet evaluated. Aim of the study Is to evaluate role of body mass index (BMI) in the presence of low voltage areas in left atrium besides pulmonary vein by comparing the BMI in patients with persistent AF with and without LVAs in LA, thus eventually identifying BMI as a possible pre-procedural marker of the presence of these areas. Methodology We analyzed data from 91 consecutive patients with persistent AF undergoing first time LA catheter ablation from 09/2021 until 10/2023 inside of the Jen-PACE study. In all patients a high-density 3D endocardial voltage mapping was carried out using EnSite Precision™/ Ensite X™ and the Advisor™ HD-Grid Mapping Catheter. Results The mean BMI was 29.6 ± 4.8, mean LV-EF was 53,4% ± 9.7, 24 patients (27%) were females, average age was 67 years. Depending on the presence of low voltage areas, the patients underwent either PVI only when no such areas were documented (61 patients, 67%) or PVI and substrate modification (30 patients, 33%) with documentation of LVAs. There was no statistical difference in the BMI between the two groups (29.9 ± 4.9 in patients with PVI only vs 29.0 ± 4.8 in patients with PVI + substrate modification; p=0.37). Furthermore, in a subgroup analysis of only adipose patients with a BMI higher than 30 (44 patients; 48%; mean BMI 33.8 ± 3.0), there was no significant difference in BMI between the two groups (34.2 ± 3.3 in PVI only vs 33.2 ± 2.4 in patients with PVI and substrate modification; p=0.2) Discussion and conclusion Even though a high BMI is generally related to a higher incidence of AF, a higher BMI was not observed in patients having additional low-voltage areas in LA compared to patients in whom such areas could not be identified. Electric remodeling caused by obesity could be rather diffuse than localized in specific areas in LA. BMI is not a pre-procedural marker for the presence of additional low voltage areas in LA.

Perindopril decreases angiotensin-converting enzyme 2 (ACE2) expression in human adipocytes exposed to SARS-CoV-2 S1 spike protein.

The expression of angiotensin-converting enzyme 2 (ACE2) in the adipose tissues of obese patients needs further study, as it may aid infection and serve as a viral reservoir. There has been controversy over whether to use ACE inhibitors to prevent coronavirus disease 2019 (COVID-19) severity. Perindopril, an ACE2 inhibitor, has been proposed; however, its relationship with COVID-19 has not yet been clear. The aim of this study was to investigate the effect of perindopril to reduce the expression of ACE2 and pro-inflammatory cytokine in adipocytes exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Enzymatic isolation of adipose tissues was performed from obese male donor patients aged 30-50 years, then exposed it with SARS-CoV-2 S1 spike protein. This study also included human recombinant ACE2 (hrsACE2) as a comparison to perindopril. The expression of ACE2 was evaluated using ELISA. Our data indicated that SARS-CoV-2 Spike protein exposure increased ACE2 expression significantly. Administration of perindopril decreased ACE2 expression (43.37 μg/mL) significantly compared to the positive group (80.31 μg/mL) (p<0.001). Perindopril administration also decreased IL-6 levels significantly compared to positive group (p<0.001). This study highlights that perindopril could reduce the ACE2 expression and pro-inflammatory cytokine levels in adipocytes exposed to SARS-CoV-2 S1 spike protein.

High-resolution genomic profiling and locus-specific FISH in subcutaneous and visceral adipose tissue of obese patients.

Obesity is known as a heterogeneous and multifactorial disease. The distribution of body fat is crucial for the development of metabolic complications. Comprehensive genetic analyses on different fat tissues are rare but necessary to provide more detailed information. Therefore, we performed genetic analyses of three patients with obesity using high resolution genome wide SNP array (blood, visceral fat tissue) and fluorescence in situ hybridization (FISH) analyses (visceral and subcutaneous fat tissue). Altogether, we identified 31 small Copy Number Variations (losses: 1p31.1, 1p22.2, 1q21.3, 2q34, 2q37.1, 3q28, 6p25.3, 7q31.33, 7q33, 8p23.3, 10q22.3, 11p15.4, 11p15.1, 11p14.2, 11p12, 13q12.3, 15q11.2-q13.1, 15q13.3, 20q13.2, 22q11.21; gains: 2q22.1-q22.2, 3p14.3, 4p16.3, 4q32.2, 6q27, 7p14.3, 7q34, 11p12, 12p11.21, 16p11.2-p11.1, 17q21.31) and 289 small copy-neutral Loss of Heterozygosity (cn-LOH). For the chromosomal region 15q11.2-q13.1, we detected a microdeletion (Prader-Willi-Syndrome) in one patient. Interestingly, we identified chromosomal SNP differences between EDTA-blood and visceral fat tissue (deletion and gain). Small losses of 7q31.33, 7q33, 11p14.2, 11p12, 13q12.3 as well as small gain of 7q34 were detected only in fat tissue and not in blood. Furthermore, FISH analyses on 7q31.33, 7q33 and 11p12 revealed differences between subcutaneous and visceral fat tissue. Generally, the deletions were detected more frequent in visceral fat tissue. Predominantly detected cn-LOH vs. CNV suggests a meaning of these cn-LOH for the pathogenesis of obesity. We conclude that the SNP array and FISH analyses used is applicable to generate more information for basic research on difficult cell subpopulations (e.g., visceral adipose tissue) and could opens up new diagnostic aspects in the field of obesity. Altogether, the significance of these mostly not yet described genetic aberrations in different fat tissues needs to confirmed in a larger series.

Subclinical Hypothyroidism in Patients with Obesity and Metabolic Syndrome: A Narrative Review.

The literature on the connection between obesity, metabolic syndrome, and subclinical hypothyroidism is critically analyzed in this narrative review. These conditions are frequently observed among adult populations and various studies and meta-analyses have assessed their association. The prevalence of subclinical hypothyroidism in obese individuals is higher than in non-obese subjects and this trend is more pronounced in unhealthy obesity phenotypes. However, the diagnosis and treatment of subclinical hypothyroidism can be difficult in obese patients. Exaggerated body fat is linked to thyroid hypoechogenicity as evident through ultrasonography and euthyroid obese people have greater TSH, FT3, and FT3/FT4 ratios than non-obese individuals in a euthyroid condition. Moreover, a reduced expression of the TSH receptor and altered function of deiodinases has been found in the adipose tissue of obese patients. Current data do not support the necessity of a pharmacological correction of the isolated hyperthyrotropinemia in euthyroid obese patients because treatment with thyroid hormone does not significantly improve weight loss and the increase in serum TSH can be reversible after hypocaloric diet or bariatric surgery. On the other hand, obesity is linked to elevated leptin levels. Inflammation can raise the risk of Hashimoto thyroiditis, which increases the likelihood that obese patients will experience overt or subclinical hypothyroidism. Both metabolic syndrome and subclinical hypothyroidism are associated with atherosclerosis, liver and kidney disease. Hence, the association of these two illnesses may potentiate the adverse effects noted in each of them. Subclinical hypothyroidism should be identified in patients with obesity and treated with appropriate doses of L-thyroxine according to the lean body mass and body weight. Randomized controlled trials are necessary to verify whether treatment of thyroid deficiency could counteract the expected risks.

Relationship Between Obesity and Allergies with Olfactory Disorders in Covid-19 Patients

Background: The prevalence of olfactory disorders is around 68% - 85% which occurs in COVID-19 patients with obesity and allergies as risk factors. The abnormalities olfactory pathways can cause by inflammatory response in adipose tissue in obese patients and excessive inflammation due to hyperreactivity of the immune system to allergens in allergic patients. This study aims to analyze the relationship between obesity and allergies to the occurrence of olfactory disorders in COVID-19. Method: It was an observational study during pandemic. Subjects were adult COVID-19 patients in the dr. Kariadi Hospital from June to July 2021. Patient with complete medical record ask for olfactory and allergic questionnaire. Patient with nasal tumor were excluded. Result: We found 100 subjects who meet the criteria. There was a significant difference in smell disturbances between obese and non-obese subjects. (p = 0.019, OR 4.99). There was a significant difference (p=0.001) in complaints of olfactory disorders between allergic and non-allergic subjects, whereas all allergic subjects experienced olfactory disorders. Conclusion: Obesity and allergies are corelated with impaired smell in COVID-19 patients.

Downregulation of Exosomal hsa-miR-551b-3p in Obesity and Its Link to Type 2 Diabetes Mellitus.

Obesity is a significant risk factor for the development of type 2 diabetes mellitus (T2DM). Adipose tissue dysfunction can affect the pool of circulating exosomal miRNAs, driving concomitant disease in obesity. These exosomal miRNAs can reflect adipose tissue functionality, thus serving as prognostic biomarkers for disease monitoring in case of T2DM. In the present study, we conducted NanoString microRNA profiling of extracellular vesicles (EVs) secreted by adipose tissue of obese patients (body mass index (BMI) > 35) without T2DM and nonobese individuals (BMI < 30) as a control group. Functional and pathway enrichment analysis showed that miRNAs associated with obesity in this study were implicated in insulin signaling and insulin resistance biological pathways. Further, these microRNAs were screened in serum EVs in the following groups: (1) obese patients with T2DM, (2) obese patients without T2DM, and (3) nonobese individuals as a control group. has-miR-551b-3p was shown to be downregulated in adipose tissue EVs, as well as in serum EVs, of patients with obesity without T2DM. At the same time, the serum exosomal hsa-miR-551b-3p content was significantly higher in obese patients with T2DM when compared with obese patients without T2DM and may be a potential biomarker of T2DM development in obesity.

TGS1/PIMT knockdown reduces lipid accumulation in adipocytes, limits body weight gain and promotes insulin sensitivity in mice

PRIP Interacting protein with Methyl Transferase domain (PIMT/TGS1) is an integral upstream coactivator in the peroxisome proliferator-activated receptor gamma (PPARγ) transcriptional apparatus. PPARγ activation alleviates insulin resistance but promotes weight gain. Herein, we show how PIMT regulates body weight while promoting insulin sensitivity in diet induced obese mice. In vitro, we observed enhanced PIMT levels during adipogenesis. Knockdown of PIMT in 3T3-L1 results in reduced lipid accumulation and alters PPARγ regulated gene expression. Intraperitoneal injection of shPIMT lentivirus in high fat diet (HFD)-fed mice caused reduced adipose tissue size and decreased expression of lipid markers. This was accompanied by significantly lower levels of inflammation, hypertrophy and hyperplasia in the different adipose depots (eWAT and iWAT). Notably, PIMT depletion limits body weight gain in HFD-fed mice along with improved impaired oral glucose clearance. It also enhanced insulin sensitivity revealed by assessment of important insulin resistance markers and increased adiponectin levels. In addition, reduced PIMT levels did not alter the serum free fatty acid and TNFα levels. Finally, the relevance of our studies to human obesity is suggested by our finding that PIMT was upregulated in adipose tissue of obese patients along with crucial fat marker genes. We speculate that PIMT may be a potential target in maintaining energy metabolism, thus regulating obesity.

Obesity accelerates endothelial-to-mesenchymal transition in adipose tissues of mice and humans.

Vascular dysfunction and chronic inflammation are characteristics of obesity-induced adipose tissue dysfunction. Proinflammatory cytokines can drive an endothelial-to-mesenchymal transition (EndoMT), where endothelial cells undergo a phenotypic switch to mesenchymal-like cells that are pro-inflammatory and pro-fibrotic. In this study, we sought to determine whether obesity can promote EndoMT in adipose tissue. Mice in which endothelial cells are lineage-traced with eYFP were fed a high-fat/high-sucrose (HF/HS) or Control diet for 13, 26, and 52 weeks, and EndoMT was assessed in adipose tissue depots as percentage of CD45-CD31-Acta2+ mesenchymal-like cells that were eYFP +. EndoMT was also assessed in human adipose endothelial cells through cell culture assays and by the analysis of single cell RNA sequencing datasets obtained from the visceral adipose tissues of obese individuals. Quantification by flow cytometry showed that mice fed a HF/HS diet display a time-dependent increase in EndoMT over Control diet in subcutaneous adipose tissue (+3.0%, +2.6-fold at 13 weeks; +10.6%, +3.2-fold at 26 weeks; +11.8%, +2.9-fold at 52 weeks) and visceral adipose tissue (+5.5%, +2.3-fold at 13 weeks; +20.7%, +4.3-fold at 26 weeks; +25.7%, +4.8-fold at 52 weeks). Transcriptomic analysis revealed that EndoMT cells in visceral adipose tissue have enriched expression of genes associated with inflammatory and TGFβ signaling pathways. Human adipose-derived microvascular endothelial cells cultured with TGF-β1, IFN-γ, and TNF-α exhibited a similar upregulation of EndoMT markers and induction of inflammatory response pathways. Analysis of single cell RNA sequencing datasets from visceral adipose tissue of obese patients revealed a nascent EndoMT sub-cluster of endothelial cells with reduced PECAM1 and increased ACTA2 expression, which was also enriched for inflammatory signaling genes and other genes associated with EndoMT. These experimental and clinical findings show that chronic obesity can accelerate EndoMT in adipose tissue. We speculate that EndoMT is a feature of adipose tissue dysfunction that contributes to local inflammation and the systemic metabolic effects of obesity..

Analytical methods used for the characterisation of specific features of biological tissues related with obesity: A review

Obesity has become a global pandemic, leading to the development of many common disorders, such as type 2 diabetes, metabolic syndrome and cardiovascular diseases, and even increases the risk of several cancers. The adipose tissue of obese patients was characterised as a tissue microenvironment composed of adipose tissue macrophages, precursor and hypertrophic adipocytes, and other immune cells that predominantly produce pro-inflammatory cytokines for chronic, low-grade inflammation. In this study, several analytical techniques, such as gas and liquid chromatography, Fourier transform infrared (FTIR) and Raman spectroscopies, nuclear magnetic resonance (NMR) spectroscopy, scanning electron microscopy (SEM) and elemental analysis, were discussed as the main tools used for the characterisation of adipose tissue samples. The emphasis was focused on the relation between the obtained results which provide information about the chemical and structural composition of adipose tissue layers in the human body, as well as main microstructural features and obesity. It was demonstrated that these methods are indispensable tools in order to investigate some special features of human adipose tissue, identifying chemical composition and structural features. Moreover, the summarised results let us to conclude that such characterisation of adipose tissue is an essential step for the possible prediction of the appearance of symptoms of different diseases.

ANGPTL8 promotes adipogenic differentiation of mesenchymal stem cells: potential role in ectopic lipid deposition.

BackgroundEctopic lipid deposition plays a promoting role in many chronic metabolic diseases. Abnormal adipogenic differentiation of mesenchymal stem cells (MSCs) is an important cause of lipid deposition in organs. Studies have shown that serum angiopoietin-like protein 8 (ANGPTL8) levels are increased in patients with many chronic metabolic diseases (such as type 2 diabetes, obesity, and hepatic steatosis), while the role of ANGPTL8 in ectopic lipid accumulation has not been reported.MethodsWe used the Gene Expression Omnibus (GEO) database to analyze the expression of ANGPTL8 in subcutaneous adipose tissue of obese patients and qPCR to analyze the expression of ANGPTL8 in the liver of high-fat diet (HFD)-induced obese mice. To explore the potential roles of ANGPTL8 in the progression of ectopic lipid deposition, ANGPTL8 knockout (KO) mice were constructed, and obesity models were induced by diet and ovariectomy (OVX). We analyzed lipid deposition (TG) in the liver, kidney, and heart tissues of different groups of mice by Oil Red O, Sudan black B staining, and the single reagent GPO-PAP method. We isolated and characterized MSCs to analyze the regulatory effect of ANGPTL8 on Wnt/β-Catenin, a key pathway in adipogenic differentiation. Finally, we used the pathway activator LiCl and a GSK3β inhibitor (i.e., CHIR99021) to analyze the regulatory mechanism of this pathway by ANGPTL8.ResultsANGPTL8 is highly expressed in the subcutaneous adipose tissue of obese patients and the liver of HFD-induced obese mice. Both normal chow diet (NCD)- and HFD-treated ANGPTL8 KO male mice gained significantly less weight than wild-type (WT) male mice and reduced ectopic lipid deposition in organs. However, the female mice of ANGPTL8 KO, especially the HFD group, did not show differences in body weight or ectopic lipid deposition because HFD could induce estrogen overexpression and then downregulate ANGPTL8 expression, thereby counteracting the reduction in HFD-induced ectopic lipid deposition by ANGPTL8 deletion, and this result was also further proven by the OVX model. Mechanistic studies demonstrated that ANGPTL8 could promote the differentiation of MSCs into adipocytes by inhibiting the Wnt/β-Catenin pathway and upregulating PPARγ and c/EBPα mRNA expression.ConclusionsANGPTL8 promotes the differentiation of MSCs into adipocytes, suggesting that ANGPTL8 may be a new target for the prevention and treatment of ectopic lipid deposition in males.

Identification of key genes and their association with immune infiltration in adipose tissue of obese patients: a bioinformatic analysis

ABSTRACT Immune cell-mediated adipose tissue (AT) inflammation contributes to obesity-related metabolic disorders, but the precise underlying mechanisms remain largely elusive. In this study, we used the R software to screen key differentially expressed genes (DEGs) in AT from lean and obese individuals and conducted function enrichment analysis. We then analysed their PPI network by using the STRING database. Hub genes were screened by cytohubba plugin. Subsequently, CIBERSORTx was used to predict the proportion of immune cells in AT from lean and obese subjects. Finally, the correlation between hub genes and immune cell proportions was analysed. These studies identified 290 DEGs in the AT between lean and obese subjects. Among them, IL6, CCL19, CXCL8, CXCL12, CCL2, CCL3, CCL4, CXCL2, IL1B, and CXCL1 were proved to be hub genes in regulating the protein-protein interaction (PPI) network. We also found that CXCL8 is positively correlated with resting NK cells, monocytes, activated mast cells, and eosinophils, but negatively correlated with CD8+ T cells and activated NK cells in obese individuals. Taken together, our study identified key genes in AT that are correlated with immune cell infiltration, uncovering potential new targets for the prevention and treatment of obesity and its related complications via regulating the immune microenvironment.

P-112 Oleic acid promotes the malignant transformation of Kras-mutant colonic organoids via the expansion of tumorigenic stem cells and abnormal Paneth cells through upregulation of NFATc family

Although the five-year survival rate of colorectal cancer (CRC) is significantly high with localized stage (90%), only 38% of the patients are diagnosed at this stage. Therefore, finding high risk factors of CRC could prevent the disease at the early stage. Obesity and high-fat diet consumption are risk factors of CRC. In detail, oleic acids (OA) were found to accumulate in the adipose tissues of obese patients as well as being the most common long chain fatty acid in dietary lipid. The role of OA in colorectal cancer development is still controversary. On the other hand, organoids, which can be derived from adult tissue stem cells, are the miniatures of organs. Recent works suggest organoids are useful tools to dissect mechanisms involved in cancer development. The current work aims to utilize crypt stem cell-derived organoids to dissect how obesity can contribute to CRC development. Organoids were derived from Lgr5 + -EGFP mice (normal colon control), Lgr5 + -EGFP-creER; LSL-KrasG12D mice (colonic epithelium harbored KrasG12D mutation) and AOM/DSS-induced CRC mice (cancerous colon control). For in-vitro, the impact of OA on the malignant transformation of Kras-mutant colonic organoids was assessed by MTT proliferation assay, 2D transwell migration and invasion assay, irinotecan-resistant test and colony formation assay. The tumor formation in-vivo was induced by subcutaneous engrafting of OA-treated organoids on NOD/SCID mice. RNAseq was done to screen some differential expressed genes when treating OA. The existence of stem cell and abnormal Paneth cell population was demonstrated by immunostaining, flow cytometry and ELISA. OA enhanced the malignant of Kras-mutant colonic organoids through increasing proliferation, migration, invasion, drug resistance and colony formation. Besides, mice which were engrafted with OA-trained Lgr5-Kras organoids possessed larger tumors. The colonic stem cell population which were represented by positive Lgr5-GFP + cells were upregulated in OA-treated group. Interestingly, there is an existence of abnormal Lyz + /CD24 + Paneth cells in OA-treated Kras-mutant organoids. This suggested that OA may promote abnormal differentiation of colonic progenitor cells. Indeed, treatment of OA upregulated ATOH1 and GFI1, which contributed to select between goblet/Paneth and enteroendocrine cell fates. Besides, NFAT family, among which NFATc3 expressed the most, significantly increased in OA-treated organoids. The upregulation of NFATc was induced by inhibition of proteasomal degradation resulting from low expression of the complex RNF123, USP18 and TRIM30A. In addition, inhibition of the nuclear translocalization of NFATc family by VIVIT demonstrated the decline of stemness markers as well as Paneth cell markers. Finally, we showed the role of NFATc, especially NFATc3, in promoting the malignancy of OA-treated Kras-mutant organoids. Our findings suggested the impact of oleic acid on promoting the malignant transformation of Kras-mutant colonic organoids through NFATc-relating pathway. The expansion of tumorigenic stem cells via induction of abnormal Paneth cell, may contribute to the potential of cancer-toward metaplasia in Kras-mutant organoids when exposing to high level of oleic acid. Oleic acid is an unfavorable factor of colorectal cancer. The frequent usage of OA, which may benefit to cardiovascular diseases, may lead to the increased risk of CRC in latent sensitive Kras-mutant individuals.

Quantification of epicardial adipose tissue in obese patients using an open-bore MR scanner

BackgroundOur aim was to evaluate the reproducibility of epicardial adipose tissue (EAT) volume, measured on scans performed using an open-bore magnetic resonance scanner.MethodsConsecutive patients referred for bariatric surgery, aged between 18 and 65 years who agreed to undergo cardiac imaging (MRI), were prospectively enrolled. All those with cardiac pathology or contraindications to MRI were excluded. MRI was performed on a 1.0-T open-bore scanner, and EAT was segmented on all scans at both systolic and diastolic phase by two independent readers (R1 with four years of experience and R2 with one year). Data were reported as median and interquartile range; agreement and differences were appraised with Bland-Altman analyses and Wilcoxon tests, respectively.ResultsFourteen patients, 11 females (79%) aged 44 (41–50) years, underwent cardiac MRI. For the first and second readings, respectively, EAT volume was 86 (78–95) cm3 and 85 (79–91) cm3 at systole and 82 (74–95) cm3 and 81 (75–94) cm3 at diastole for R1, and 89 (79–99) cm3 and 93 (84–98) cm3 at systole and 92 (85–103) cm3 and 93 (82–94) cm3 at diastole for R2. R1 had the best reproducibility at diastole (bias 0.3 cm3, standard deviation of the differences (SD) 3.3 cm3). R2 had the worst reproducibility at diastole (bias 3.9 cm3, SD 12.1 cm3). The only significant difference between systole and diastole was at the first reading by R1 (p = 0.016). The greatest bias was that of inter-reader reproducibility at diastole (-9.4 cm3).ConclusionsReproducibility was within clinically acceptable limits in most instances.

Adipocyte Fatty Acid Binding Protein (A-FABP) as a Potential New Therapeutic Target for the Treatment of Obesity - Associated Cancers.

Fatty acid binding protein A (A-FABP) is one of FABPs isoforms found mainly in adipose tissue and macrophages. It works through many integrated pathways, regulating inflammation and lipid metabolism, promoting glucose production, impairing insulin function, and contributing to diseases such as atherosclerosis and diabetes. A-FABP is upregulated in the adipose tissue of obese patients and its increased release into the bloodstream is positively associated with body mass index. Consequently, A-FABP plays a key role in regulating metabolism in obese people. Recent studies in mouse models and humans demonstrated the role of A-FABP in increasing the risk of obesity-related cancers. Here we summarized the state of research on the link between obesity, cancer and A-FABP as a new potential therapeutic target for the treatment of obesity - associated cancers.

Healthy versus Unhealthy Adipose Tissue Expansion: the Role of Exercise.

Although the hallmark of obesity is the expansion of adipose tissue, not all adipose tissue expansion is the same. Expansion of healthy adipose tissue is accompanied by adequate capillary angiogenesis and mitochondria-centered metabolic integrity, whereas expansion of unhealthy adipose tissue is associated with capillary and mitochondrial derangement, resulting in deposition of immune cells (M1-stage macrophages) and excess production of pro-inflammatory cytokines. Accumulation of these dysfunctional adipose tissues has been linked to the development of obesity comorbidities, such as type 2 diabetes, hypertension, dyslipidemia, and cardiovascular disease, which are leading causes of human mortality and morbidity in modern society. Mechanistically, vascular rarefaction and mitochondrial incompetency (for example, low mitochondrial content, fragmented mitochondria, defective mitochondrial respiratory function, and excess production of mitochondrial reactive oxygen species) are frequently observed in adipose tissue of obese patients. Recent studies have demonstrated that exercise is a potent behavioral intervention for preventing and reducing obesity and other metabolic diseases. However, our understanding of potential cellular mechanisms of exercise, which promote healthy adipose tissue expansion, is at the beginning stage. In this review, we hypothesize that exercise can induce unique physiological stimuli that can alter angiogenesis and mitochondrial remodeling in adipose tissues and ultimately promote the development and progression of healthy adipogenesis. We summarize recent reports on how regular exercise can impose differential processes that lead to the formation of either healthy or unhealthy adipose tissue and discuss key knowledge gaps that warrant future research.

Antibiotic Azithromycin inhibits brown/beige fat functionality and promotes obesity in human and rodents.

Obesity, a metabolic disease caused by multiple factors, has become a global health problem. In addition to nutrient intake and sedentary lifestyle, environmental pollutants exposure has been shown to be involved in obesity epidemics. Antibiotics, a new type of environmental pollutant, have been widely used in animal husbandry, aquaculture and microorganism. However, the effects of antibiotics exposure on fat metabolism and metabolic diseases are largely unknown.Methods: We screened major types of antibiotics to examine their effects on the differentiation capacity and thermogenic functionality of brown and beige adipocytes, and found that azithromycin, one major kind of macrolide antibiotics suppressed brown and beige adipocyte functionality. We thus examined azithromycin accretion in adipose tissues of obese patients that correlates with BMI by high performance liquid chromatography-tandem mass spectrometry and systematically explore the influences of azithromycin on adiposity and metabolic performance in mice under high diet.Results: Azithromycin (macrolides) inhibits the mitochondrial and thermogenic gene programs of brown and beige adipocytes, thus disrupting their mitochondrial function and thermogenic response. Consistently, azithromycin treatment are more prone to diet-induced obesity in mice, and this was associated with impaired energy expenditure. Importantly, azithromycin is more accumulated in adipose tissue of obese patients and correlates with BMI and body weight. Mechanistically, we found that azithromycin inhibits mitochondria respiratory complex I protein levels and increases reactive oxidative species (ROS) levels, which causes damage of mitochondrial function in brown and beige adipocytes. The deleterious effects of azithromycin can be ameliorated by antioxidant N-acetyl-L-cysteine.Conclusions: Taken together, this work highlights the possible role of azithromycin in obesity epidemic and presents strategies for safe applications of antibiotics in the future.

PPAR-γ Gene Expression in Human Adipose Tissue Is Associated with Weight Loss After Sleeve Gastrectomy

BackgroundThe peroxisome proliferator-activated receptor (PPAR)-γ plays a key role in adipose tissue differentiation and fat metabolism. However, it is unclear which factors may regulate its expression and whether obese patients have changes in adipose tissue expression of PPAR-γor potential regulators such as miR-27. Thus, our aims were to analyze PPAR-γ and miR-27 expression in adipose tissue of obese patients, and to correlate their levels with clinical variables. Subjects and Methods.We included 43 morbidly obese subjects who underwent sleeve gastrectomy (31 of them completed 1-year follow-up) and 19 non-obese subjects. mRNA expression of PPAR-γ1 and PPAR-γ2, miR-27a, and miR-27b was measured by qPCR in visceral and subcutaneous adipose tissue. Clinical variables and serum adipokine and hormone levels were correlated with PPAR-γ and miR-27 expression. In addition, a systematic review of the literature regarding PPAR-γ expression in adipose tissue of obese patients was performed. ResultsWe found no differences in the expression of PPAR-γ and miR-27 in adipose tissue of obese patients vs. controls. The literature review revealed discrepant results regarding PPAR-γ expression in adipose tissue of obese patients. Of note, we described a significant negative correlation between pre-operative PPAR-γ1 expression in adipose tissue of obese patients and post-operative weight loss, potentially linked with insulin resistance markers. ConclusionPPAR-γ1 expression in adipose tissue is associated with weight loss after sleeve gastrectomy and may be used as a biomarker for response to surgery.

TRIB3 Is Highly Expressed in the Adipose Tissue of Obese Patients and Is Associated With Insulin Resistance.

The upregulation of TRIB3 (Tribbles homolog 3), a stress-inducible gene encoding a pseudokinase, has been implicated in the development of insulin resistance in the skeletal muscle and liver of patients with obesity and type 2 diabetes. However, there is little information regarding TRIB3 expression in human adipose tissue. To investigate whether TRIB3 expression is dysregulated in human adipose tissue in the context of obesity and type 2 diabetes and whether TRIB3 expression in adipose tissues is associated with insulin resistance. We measured metabolic parameters and TRIB3 expression in abdominal subcutaneous and visceral adipose tissue in obese (with or without type 2 diabetes) and normal-weight women. Regulation of TRIB3 expression was studied in human adipocytes. TRIB3 expression in both fat depots was higher in patients with obesity and/or type 2 diabetes; in addition, the expression level was significantly associated with insulin resistance. Incubating adipocytes under conditions mimicking the microenvironment of obese adipose tissue, including increased endoplasmic reticulum (ER) stress, induced TRIB3 expression. In human adipocytes, the overexpression of TRIB3 impaired insulin-stimulated protein kinase B (AKT) phosphorylation and caused dysregulation of the transcription of genes encoding bioactive molecules released from adipocytes, such as proinflammatory cytokines, adiponectin, and leptin. Pioglitazone, an insulin-sensitizing agent, reduced both these effects of TRIB3 and the ER stressor-induced expression of TRB3. Our data indicate that TRIB3 expression in adipose tissue is enhanced in patients with obesity and suggest that increased TRIB3 dysregulates adipocyte function, which may contribute to the development of insulin resistance.

The relationship between visceral fat depots and markers of renal dysfunction in patients with borderline arterial hypertension and obesity

Abstract Introduction Obesity is a potent risk factor for the development of kidney disease (CKD). The localization of adipose tissue and its hormonal activity plays an important role in the formation of the cardiorenal relationship. Purpose of work To assess the relationship between visceral fat stores with hormonal activity of adipose tissue, metabolic parameters and markers of renal dysfunction in patients with borderline arterial hypertension (AH) and obesity. Materials and methods The study included 100 people aged 44.8±6.4 years. Group 1 – patients with borderline hypertension – SBP 134.1±4.7 mm Hg; DBP – 84.3±5.9 mm Hg, BMI 36.1±3.2kg/m2. Group 2 was patients with BMI 35.5±3.9 kg/m2, SBP level 120.6±10.1 mm Hg and DBP 70.1±8.4 mm Hg. Albumin/creatinine ratio urine (ACRU), β2 microglobulin, tumor necrosis factor (TNF), interleukin 6 (IL6), monocytechemoattractant protein (MCP-1) was determined in a single portion of morning urine, the level of leptin, resistin and cystatin C was determined by ELISA. Glomerular filtration rate (GFR) was calculated using the CKD-EPI formula and cystatin C (Hoek's formula). The examination of visceral adipose tissue (VAT) was using an ultrasound method of investigation: the epi- and pericardial fat depots were assessed; VAT 1 – measurement at the level of the navel from the inner surface of the rectus abdominis to the posterior wall of the aorta and L4; VAT 2 – measurement at the level of the navel from the inner surface of the rectus abdominis to L4; the thickness of the posterior perirenal VAT on the right and left and the area of perirenal fat on both sides. Result The amount of fat depots in the groups is shown in Table 1. Indicators of hormonal activity of adipose tissue and renal markers are presented in Table 2. In the group with borderline hypertension the relationship between VAT 1 and 2 with ALT levels (r=0.40) and (r=0.42) was established, AST (r=0.52) and (r=0.47); HDL (r=−0.67) and (r=−0.70), TG (r=0.38) and (r=0, 39), HOMA index (r=0.45) and (r=0.39), MCP-1 (r=0.28) and (r=0.36). Perineal fat depot located to the right and left is correlated with LDL (r=0.40) and (r=0.37), glucose (r=0.49) and (r=0.50), ACRU (r=0.43) and (r=0.57), urinary excretion of cystatin C (r=0.28) and (r=0, 39). The connection with the optimal blood pressure level in control group was established between the perineal adipose tissue on the right and the left with the level of TG (r=0.35) and (r=0.29), GFR according to Hoek (r=0.29) and (r=0, 38), MCP-1 (r=0.36) and (r=0.29). Findings The increase of perinephral adipose tissue in obese patients is associated with an increase in cytokine excretion in the urine, an increase in VAT is accompanied by a deterioration in metabolic parameters. Funding Acknowledgement Type of funding sources: None.

Tumor Necrosis Receptor Superfamily Interact with Fusion and Fission of Mitochondria of Adipose Tissue in Obese Patients without Type 2 Diabetes.

Interactions between receptors and ligands of the tumor necrosis factor superfamily (TNFSF) provide costimulatory signals that control the survival, proliferation, differentiation, and effector function of immune cells. All components of the TNF superfamily are associated with NF-kB functions that are not limited to cell death and may promote survival in the face of adipose tissue inflammation in obesity. Inflammation dysfunction of mitochondria is a key factor associated with insulin resistance in obesity. The aim of the study was to analyze the relationship of soluble forms of receptors and ligands of the TNF superfamily in blood plasma with mitochondrial dynamics in adipose tissue (greater omentum (GO) and subcutaneous adipose tissue (Sat)) of obese patients with and without type 2 diabetes mellitus (T2DM). Increased plasma sTNF-R1, sTNF-R2, sTNFRSF8 receptors, and ligands TNFSF12, TNFSF13, TNFSF13B are characteristic of obese patients without T2DM. The TNF-a levels in blood plasma were associated with a decrease in MFN2 gene expression in GO and IL-10 in blood plasma. The TNFSF12 levels contributed to a decrease in glucose levels, a decrease in BMI, and an increase in IL-10 levels by influencing the MFN2 gene expression in GO, which supports mitochondrial fusion.