Adipose Tissue Of Obese Subjects Research Articles

Shift work promotes adipogenesis via cortisol-dependent downregulation of EGR3-HDAC6 pathway

The disruption of circadian rhythms caused by long-term shift work can cause metabolic diseases such as obesity. Early growth response 3 (EGR3) is a member of early growth response (EGR) family, which is involved in several cellular responses, had been reported as a circadian rhythm gene in suprachiasmatic nucleus. In this research, EGR3 was found to be widely expressed in the different tissue of human and mice, and downregulated in adipose tissue of obese subjects and high-fat diet mice. Moreover, EGR3 was found negatively regulated by cortisol. In addition, EGR3 is a key negative modulator of hADSCs and 3T3-L1 adipogenesis via regulating HDAC6, which is a downstream target gene of EGR3 and a negative regulator of adipogenesis and lipogenesis. These findings may explain how circadian rhythm disorder induced by shift works can cause obesity. Our study revealed a potential therapeutic target to alleviate metabolic disorders in shift workers and may provide better health guidance to shift workers.

FRI022 The Stress-Response Pathways Of NRF2 And Notch Are Upregulated In The Adipocytes But Not In The Immune Cells Of Obese Subjects Adipose Tissue

Abstract Disclosure: D. Chartoumpekis: None. I. Georgakopoulos-Soares: None. Introduction: Obesity is characterized by increased reactive oxygen species (ROS) in adipose tissue. Nrf2 is a transcription factor which regulates antioxidant and cytoprotective genes. ROS react with cysteines of Keap1, the cytoplasmic inhibitor of Nrf2, leading to conformational changes which render Keap1 unable to bind to Nrf2 molecules and lead them to degradation by the proteasome. Thus, Nrf2 accumulates, enters the nucleus and induces the expression of its target genes. Notch signaling is known for its roles in development, cell fate, cell differentiation, apoptosis and proliferation. Notch is a family of intermembrane receptors. The extracellular part of Notch interacts with a ligand of a neighboring cell and triggers two successive proteolytic cleavages by proteases. This permits the release of Notch Intracellular Domain (NICD) to enter the nucleus and induce the expression of target genes. ROS have been recently shown to activate the metalloproteases ADAM 10/17 and facilitate the cleavage of NICD and thus the activation of Notch pathway. A bidirectional transcriptional regulation of Nrf2-Notch has also been described. Hence, both Nrf2 and Notch can be considered as pathways that respond to oxidative stress. Hypothesis: We hypothesized that Nrf2 and Notch pathways are upregulated in the adipose tissue of obese subjects in response to increased ROS levels. Methods: We identified publicly available (series GSE176171) single-cell RNA sequencing data from adipose tissue from humans with BMI<25 kg/m2 (normal weight) or BMI>30 kg/m2 (obese) and from C57BL6 mice fed a high-fat diet (60% kcal fat) or a normal chow diet (6.4% kcal fat) for 13 weeks. R studio read RDS and fetchdata functions were employed to analyze the data in the different cell types of adipose tissue (vascular, immune, mesothelial cells and adipocytes). Results: An at least a 2-fold increase was seen in the RNA levels of several cytoprotective genes (such as NQO1, TXNRD1, GCLC, HMOX1, GSTA4), that are known to be regulated by Nrf2, in adipocytes from obese humans compared to the normal weight ones. Similar changes were found in the murine adipocytes of obese subjects. Interestingly, no significant differences were detected in these gene sets in immune cells from the mouse and human adipose tissue between lean and obese individuals. Notch 1-3 RNA was also found increased at least 2-fold in human adipocytes of obese patients while only Notch3 RNA was increased in adipocytes of obese mice. A common target gene of Notch signaling, Hes1, showed increased expression in both human (2-fold) and murine (4-fold) adipocytes of obese subjects. These changes were not seen in the immune cells of both species. Conclusions: This increased Nrf2 and Notch signaling in adipocytes in the obese state warrants further investigation as it may play roles in the homeostasis and the capacity of the adipose tissue and in the resulting metabolic phenotype. Presentation: Friday, June 16, 2023

THE ASSOCIATION OF HYPERTENSION AND OBESITY: WHAT IMPACT ON THE LONGITUDINAL SYSTOLIC FUNCTION OF THE LEFT VENTRICLE

Objective: Hypertension and obesity are well known each result in heart failure with preserved ejection fraction. Indeed, there is ample evidence that the accumulation of adipose tissue in obese subjects negatively affects the left atrial and ventricular structure, as well as diastolic and systolic function. Predisposing factors for heart failure with preserved LVEF are advanced age, hypertension, diabetes, dyslipidemia and obesity. The development of the 2D strain has made it possible to make an early diagnosis of ventricular dysfunction in patients with cardiovascular risk factors. Design and method: This work consists of performing in a series of 128 hypertensive patients divided into two subgroups: 58 obese patients and 70 patients with normal BMI. A complete cardiographic echo study was performed in both subgroups, including LVEF by Simpson biplane method, calculation of indexed left ventricular mass and parietal relative thickness, analysis of diastolic function and finally study of longitudinal LV deformation by speckle tracking technique. Results: We note in this work that dyslipidemia and diabetes were significantly more prevalent in the HTA+obesity arm. The average blood pressure figures were slightly higher in the HTA+obesity arm. LVH was clearly predominant in the HTA+obesity arm with a more consequent decrease in the longitudinal contraction index. In obese hypertensive patients, LVH was most often concentric (53.4%). An increase in filling pressures was found in 11 obese hypertensive patients compared to only 4 non-obese hypertensive patients (p = 0.0001), with a good correlation with the decrease in GLS. These results suggest that increased BMI is closely associated with atrioventricular interaction in patients with hypertension, with a perfect correlation with impairment of longitudinal systolic function and diastolic function compared to the control group. Conclusions: Although the pathophysiological mechanism behind obesity is disputed, several possible explanations have been proposed: obesity has been considered a state of chronic volume overload, increased blood volume, neurohormonal activation, thus increasing oxidative stress. Therefore, obesity is associated with mild ventricular dilation (eccentric remodeling). However, this finding is in contrast to other studies that associate obesity with a concentric rather than eccentric remodeling of the LV.

Hypertrophy and ER Stress Induced by Palmitate Are Counteracted by Mango Peel and Seed Extracts in 3T3-L1 Adipocytes.

A diet rich in saturated fatty acids (FAs) has been correlated with metabolic dysfunction and ROS increase in the adipose tissue of obese subjects. Thus, reducing hypertrophy and oxidative stress in adipose tissue can represent a strategy to counteract obesity and obesity-related diseases. In this context, the present study showed how the peel and seed extracts of mango (Mangifera indica L.) reduced lipotoxicity induced by high doses of sodium palmitate (PA) in differentiated 3T3-L1 adipocytes. Mango peel (MPE) and mango seed (MSE) extracts significantly lowered PA-induced fat accumulation by reducing lipid droplet (LDs) and triacylglycerol (TAGs) content in adipocytes. We showed that MPE and MSE activated hormone-sensitive lipase, the key enzyme of TAG degradation. In addition, mango extracts down-regulated the adipogenic transcription factor PPARγ as well as activated AMPK with the consequent inhibition of acetyl-CoA-carboxylase (ACC). Notably, PA increased endoplasmic reticulum (ER) stress markers GRP78, PERK and CHOP, as well as enhanced the reactive oxygen species (ROS) content in adipocytes. These effects were accompanied by a reduction in cell viability and the induction of apoptosis. Interestingly, MPE and MSE counteracted PA-induced lipotoxicity by reducing ER stress markers and ROS production. In addition, MPE and MSE increased the level of the anti-oxidant transcription factor Nrf2 and its targets MnSOD and HO-1. Collectively, these results suggest that the intake of mango extract-enriched foods in association with a correct lifestyle could exert beneficial effects to counteract obesity.

MicroRNA-27a, downregulated in human obesity, exerts an antiapoptotic function in adipocytes.

Adipocyte apoptosis is a key initial event that contributes to macrophage infiltration into adipose tissue (AT) and thus triggers AT inflammation in obesity. MicroRNA-27a (miR-27a) was shown to mediate the pathological processes of many metabolic disorders; however, whether miR-27a is involved in adipocyte apoptosis of obese AT remains unknown. The present study aimed to investigate the alteration of miR-27a in obese individuals and its antiapoptotic function in adipocytes. In vivo, serum samples and omental adipose tissue from humans as well as epididymal fat pads from mice were collected to detect miR-27a expression. In vitro, 3T3-L1 preadipocytes and mature adipocytes were treated with TNF-α to induce apoptosis and transfected with a mimic for overexpressing miR-27a-3p. The results showed that miR-27a was markedly decreased in the serum and AT of obese human patients and in the AT of high-fat diet-fed mice. Regression analyses revealed that the serum level of miR-27a was correlated with metabolic parameters in human obesity. Notably, TNF-α induced cell apoptosis in both preadipocytes and mature adipocytes, as evidenced by the upregulation of cleaved caspase 3 and cleaved caspase 8 and the ratio of Bax to Bcl-2, while these effects were partly diminished by miR-27a overexpression. In addition, TUNEL and Hoechst 33258 staining verified that miR-27a overexpression markedly inhibited the apoptosis of adipocytes under TNF-α stimulation. Thus, miR-27a was downregulated in the AT of obese subjects with proapoptotic status, and overexpression of miR-27a exerted an antiapoptotic effect on preadipocytes, providing a novel potential target for preventing AT dysfunction.

Differential gene expression in nasal airway epithelium from overweight or obese youth with asthma.

The mechanisms underlying the known link between overweight/obesity and childhood asthma are unclear. We aimed to identify differentially expressed genes and pathways associated with obesity-related asthma through a transcriptomic analysis of nasal airway epithelium. We compared the whole transcriptome in nasal airway epithelium of youth with overweight or obesity and asthma with that of youth of normal weight and asthma, using RNA sequencing data from a cohort of 235 Puerto Ricans aged 9-20years (EVA-PR) and an independent cohort of 66 children aged 6-16years in Pittsburgh (VDKA). Differential expression analysis adjusting for age, sex, sequencing plate number, and sample sorting protocol, and the first five principal components were performed independently in each cohort. Results from the two cohorts were combined in a transcriptome-wide meta-analysis. Gene enrichment and network analyses were performed on top genes. In the meta-analysis, 29genes were associated with obesity-related asthma at an FDR-adjusted p<.05, including pro-inflammatory genes known to be differentially expressed in adipose tissue of obese subjects (e.g., CXCL11, CXCL10, and CXCL9) and several novel genes. Functional enrichment analyses showed that pathways for interferon signaling, and innate and adaptive immune responses were down-regulated in overweight/obese youth with asthma, while pathways related to ciliary structure or function were up-regulated. Upstream regulatory analysis predicted significant inhibition of the IRF7 pathway. Network analyses identified "hub" genes like GBP5 and SOCS1. Our transcriptome-wide analysis of nasal airway epithelium identified biologically plausible genes and pathways for obesity-related asthma in youth.

Meta-analysis of gene expression data in adipose tissue reveals new obesity associated genes.

High-throughput transcriptomic and proteomic data like microarray data are deposited in public databases such as Gene Expression Omnibus (GEO). Omics data integration and processing from different and independent studies is achieved by using efficient and effective computational tools through meta-analysis. Meta-analysis is a statistical powerful tool combining data from numerous studies, minimizes bias and increases statistical power by increasing sample size compared to individual studies. Therefore, we performed a meta-analysis of gene expression data in adipose tissue to identify genes that are differentially expressed between obese and non-obese subjects as well as to detect gene expression signatures, pathways and networks associated with obesity. We identified 821 differentially expressed genes (DEGs) in adipose tissue of obese subjects compared to non-obese. A protein-protein interactions (PPIs) network was reconstructed consisting of 168 proteins. Functional enrichment analysis in the network revealed proteins involved in RNA and energy metabolism. The KEGG pathway analysis revealed 15 enriched pathway terms. Furthermore, multiple testing correction methods identified five statistically significant obesity associated genes (NDUFA12, SFI1, SSB, FAR2 and LACE1) that require further investigation.

Different Expression of Micro-RNA in the Subcutaneous and Visceral Adipose Tissue of Obese Subjects.

Obesity is a pathology characterized by an excessive accumulation of adipose tissue and it is a condition associated with complex alterations affecting different organs and systems. Obesity has great influences on cardiovascular and respiratory morbidity and mortality, and impairs the multiple aspects of metabolism. Since micro-RNAs (miRNAs) are thought to play a role in the regulation of various pathological processes, in this complex framework, the investigation of these classes of noncoding regulatory RNA seems to be promising. Selected group of obese subjects was recruited. We analyzed the expression of seven miRNAs from obese adipose tissue supposed to have a role in the pathogenesis of cardiovascular and respiratory disease related to obesity and we compared it with the expression of the same miRNAs in a group of nonobese controls. In this study what emerged is miR-27b and miR-483 significant downregulation in subcutaneous adipose tissue from obese group compared with nonobese ones. For visceral adipose tissue, a significant decrease in miR-27b and miR-223 expression was observed in obese group. Moreover, a different expression of miR-26a and miR-338 in the obese group was found. Those findings could help the individuation of previously unknown key players in the development of different diseases usually associated with obesity, such as cardiovascular and pulmonary diseases. Clinical Trials.gov ID: Ref 17/CE/2014.

Weight Loss and Short-Chain Fatty Acids Reduce Systemic Inflammation in Monocytes and Adipose Tissue Macrophages from Obese Subjects.

Background: Chronic low-grade systemic inflammation is a characteristic of obesity that leads to various non-communicable diseases. Weight loss and SCFAs are potential strategies for attenuating obese systemic inflammation. Methods: Blood samples were collected from 43 obese subjects (BMI ≥ 30 kg/m2) scheduled for laparoscopic bariatric sleeve surgery, 26 obese subjects at follow-up 12–18 months post-surgery and 8 healthy weight subjects (BMI 18.5–24.9 kg/m2). Monocytes were isolated from blood and adipose tissue macrophages from visceral adipose tissue of obese subjects only. Isolated cells stimulated with 1 ng/mL LPS and treated simultaneously with 300 mM of sodium acetate or 30 mM of sodium propionate or butyrate and supernatant were harvested after 15 h incubation. TNF-α and IL-6 cytokines were measured via ELISA and mRNA gene expression of FFAR2 and FFAR3, HDAC1, HDAC2 and HDAC9, RELA and NFKB1 and MAPK1 via RT-qPCR. Results: TNF-α and IL-6 production and NFKB1 and RELA mRNA expression were significantly decreased in follow-up subjects compared to baseline. SCFAs significantly reduced TNF-α and IL-6 and altered FFAR and HDAC mRNA expression in monocytes and macrophages from obese subjects. Conclusion: Weight loss and ex vivo SCFA treatments were successful in combatting systemic inflammation in obesity. Results highlighted molecular changes that occur with weight loss and as a result of SCFA treatment.

An Overview of Adipose Tissue ACE2 Modulation by Diet and Obesity. Potential Implications in COVID-19 Infection and Severity.

The present review is aimed at analysing the current evidence concerning the potential modulation of obesity and/or diet in adipose tissue ACE2. Additionally, the potential implications of these effects on COVID-19 are also addressed. The results published show that diet and obesity are two factors that effectively influence the expression of Ace2 gene in adipose tissue. However, the shifts in this gene do not always occur in the same direction, nor with the same intensity. Additionally, there is no consensus regarding the implications of increased adipose tissue ACE2 expression in health. Thus, while in some studies a protective role is attributed to ACE2 overexpression, other studies suggest otherwise. Similarly, there is much debate regarding the role played by ACE2 in COVID-19 in terms of degree of infection and disease outcomes. The greater risk of infection that may hypothetically derive from enhanced ACE2 expression is not clear since the functionality of the enzyme seems to be as important as the abundance. Thus, the greater abundance of ACE2 in adipose tissue of obese subjects may be counterbalanced by its lower activation. In addition, a protective role of ACE2 overexpression has also been suggested, associated with the increase in anti-inflammatory factors that it may produce.

Review: Obesity and COVID-19: A Detrimental Intersection.

Obesity has been recognized as an independent risk factor for critical illness and major severity in subjects with coronavirus disease 2019 (COVID-19). The role of fat distribution, particularly visceral fat (often linked to metabolic abnormalities), is still unclear. The adipose tissue represents a direct source of cytokines responsible for the pathological modifications occurring within adipose tissue in obese subjects. Adipokines are a crucial connection between metabolism and immune system: their dysregulation in obesity contributes to chronic low-grade systemic inflammation and metabolic comorbidities. Therefore the increased amount of visceral fat can lead to a proinflammatory phenotypic shift. This review analyzes the interrelation between obesity and COVID-19 severity, as well as the cellular key players and molecular mechanisms implicated in adipose inflammation, investigating if adipose tissue can constitute a reservoir for viral spread, and contribute to immune activation and cytokines storm. Targeting the underlying molecular mechanisms might have therapeutic potential in the management of obesity-related complications in COVID-19 patients.

Adipogenesia, osasunaren etsai edo lagun?

Gantz-ehun zuria (GEZ) gorputzeko energia-biltegia da eta adipozito izena duten zelulez osaturik dago. Giza gorputzean duen kokalekuaren arabera, larruazalpeko GEZ (LGEZ) eta erraietako GEZ (EGEZ) bereizten dira. Adipozitoei dagokienez, EGEZko adipozitoak LGEZkoak baino aktiboagoak dira metabolikoki; azken horiek, berriz, tamaina handiagoa eta lipidoak hartzeko gaitasun handiagoa dute. Obesitateak GEZren hazkunde edo hedapena eragiten du, bi modutan: adipozitoen kopurua edo tamaina handituz (hiperplasia eta hipertrofia, hurrenez hurren). GEZn gertatzen diren aldaketa horiek, ehun honen funtzionamendu egokian eragin dezakete. Horrela, hipertrofia bidez gertatzen den GEZren hedapena obesitatearekin eta hari lotutako gaixotasun metabolikoekin erlazio- natzen da. Adipozitoen hipertrofiak eta hiperplasiak obesitatearekin lotutako komorbilitateetan duten garrantziaz jabetzeko, «metabolikoki osasuntsuak diren obesoak» eta «argal faltsuak» terminoak aipatu behar dira. Lehenengoen kasuan, obesitateaz gain ez da gainerako asaldura metabolikorik izango. Bigarrengoen kasuan, berriz, pisu egokia izan arren zitokina hantura-eragileen maila handiagoak izaten dituzte odolean. Etorkizunari begira, argi geratzen da pertsona obesoen gantz-gordailuen hedapena ezaugarritu eta «metabolikoki osasuntsuak diren obesoak» zein «argal faltsuak» identifikatzea ahalbidetuko duten ikerketa gehiagoren beharra.

Changes in VGF and C3aR1 gene expression in human adipose tissue in obesity.

The VGF gene, which has been shown to be metabolically associated with energy balance, glucose homeostasis, insulin secretion process, and biological processes related to overeating, is prominent in relation to obesity. TLQP-21 neuropeptide, derived from the VGF, is considered to promote lipolysis by the beta-adrenergic pathway through targeting the C3aR1 receptor located in the adipocyte membrane. In this study, we aimed to measure the expression levels of the VGF and C3aR1 genes in the adipose tissue of obese subjects and individuals with normal weight determined based on body mass index (BMI), and to reveal the correlation of these levels with obesity. VGF and C3aR1 gene expression levels were measured using Real Time Polymerase Chain Reaction (RT PCR) in the visceral adipose tissue (VAT) samples of 52 obese patients (BMI ≥ 35kg/m2) and 21 non-obese controls (BMI = 18.5-24.9kg/m2). The results were statistically analyzed. The VGF expression was lower and the C3aR1 gene expression was higher in obese patients compared to the non-obese control group (p < 0.05). In obese patients, there was a statistically significant positive correlation of 85.6% between VGF and C3aR1, in which when one level increased, the other also increased (p < 0.05, r = 0.856). The findings show that the VGF may be significantly associated with obesity and is very important since it is the first to measure the level of VGF gene expression in human adipose tissue. This research provides new evidence of a link between obesity and VGF/C3aR1 and in the future may help design strategies to combat obesity.

The role of uncoupling protein 2 in macrophages and its impact on obesity-induced adipose tissue inflammation and insulin resistance

The development of a chronic, low-grade inflammation originating from adipose tissue in obese subjects is widely recognized to induce insulin resistance, leading to the development of type 2 diabetes. The adipose tissue microenvironment drives specific metabolic reprogramming of adipose tissue macrophages, contributing to the induction of tissue inflammation. Uncoupling protein 2 (UCP2), a mitochondrial anion carrier, is thought to separately modulate inflammatory and metabolic processes in macrophages and is up-regulated in macrophages in the context of obesity and diabetes. Here, we investigate the role of UCP2 in macrophage activation in the context of obesity-induced adipose tissue inflammation and insulin resistance. Using a myeloid-specific knockout of UCP2 (Ucp2ΔLysM), we found that UCP2 deficiency significantly increases glycolysis and oxidative respiration, both unstimulated and after inflammatory conditions. Strikingly, fatty acid loading abolished the metabolic differences between Ucp2ΔLysM macrophages and their floxed controls. Furthermore, Ucp2ΔLysM macrophages show attenuated pro-inflammatory responses toward Toll-like receptor-2 and -4 stimulation. To test the relevance of macrophage-specific Ucp2 deletion in vivo, Ucp2ΔLysM and Ucp2fl/fl mice were rendered obese and insulin resistant through high-fat feeding. Although no differences in adipose tissue inflammation or insulin resistance was found between the two genotypes, adipose tissue macrophages isolated from diet-induced obese Ucp2ΔLysM mice showed decreased TNFα secretion after ex vivo lipopolysaccharide stimulation compared with their Ucp2fl/fl littermates. Together, these results demonstrate that although UCP2 regulates both metabolism and the inflammatory response of macrophages, its activity is not crucial in shaping macrophage activation in the adipose tissue during obesity-induced insulin resistance.

Loss of Histone Deacetylase 4 in Hepatocytes Increases De Novo Lipogenesis in Diet-Induced Obesity Mice

Abstract Objectives Evidence suggests that histone deacetylase 4 (HDAC4) is downregulated in adipose tissue of obese subjects. We determined the role of HDAC4 in the regulation of energy metabolism of metabolically active tissues, such as the liver and adipose tissue. Methods Hepatocyte-specific (Hdac4HKO) and adipocyte-specific (Hdac4AKO) Hdac4 knockout mice were generated by crossing homozygous Hdac4 floxed (Hdac4fl/fl) mice with mice expressing Cre recombinase under the control of the enhancer/promoter of Albumin or Adipoq gene, respectively. Hdac4fl/fl and Hdac4HKO mice were fed a high fat/high sucrose (HF/HS; 57%/28% energy from fat/sucrose) with 2% cholesterol (w/w) diet for 16 weeks. Hdac4fl/fl and Hdac4AKO mice were fed an obesogenic HF/HS diet for 16 weeks. The final serum was collected by cardiopuncture for blood analysis. Tissues were snap frozen for mRNA and protein analysis. Results Both Hdac4HKO and Hdac4AKO mice did not show differences in body weight compared to Hdac4fl/fl mice following the 16-week of experimental diet. However, loss of hepatic HDAC4 increased serum alanine transaminase levels, a marker for liver injury. Also, Hdac4HKO mice had exacerbated hepatic steatosis with higher liver weights and triglyceride levels than Hdac4fl/fl mice. Consistently, hepatic expression of genes for de novo lipogenesis, including Srebf1c and its target genes, fatty acid synthase and acetyl CoA carboxylase 1, was significantly higher in Hdac4HKO mice compared with control mice. Interestingly, the loss of hepatocyte HDAC4 aggravated inflammation and fibrosis in white adipose tissue. Serum cytokine array indicated increases in fibroblast growth factor 1, pentraxin 3, tissue inhibitor of metalloproteinases 1, and decrease in endocan, which may contribute to the crosstalk between the liver and adipose tissue in Hdac4HKO. On the other hand, the loss of adipocyte HDAC4 elicited minimal changes in mRNA levels of lipogenic, inflammatory, and fibrogenic genes in adipose tissue and the liver. Conclusions The lack of functional hepatocyte HDAC4 increased lipid accumulation in the liver of obesity mice via increasing hepatic de novo lipogenesis, and also aggravated adipose tissue inflammation and fibrosis. Further investigation is warranted to elucidate the crosstalk between the liver and adipose tissue in Hdac4HKO. Funding Sources This study was supported by NIH.

Influence of obese phenotype on metabolic profile, inflammatory mediators and stemness of hADSC in adipose tissue.

Unhealthy dietary practices, sedentary life style and lack of physical exercise in developing countries like India are major contributors of metabolic syndrome like obesity and diabetes. Obesity in Indians is defined at Body Mass Index (BMI, kg/m2) >25 and characterized as metabolically obese. A preliminary study performed to explore ramification of obesity on metabolic profile of adipose tissue and adipose derived stem cells (ADSC) from control and obese Indians. Adipose tissue/lipoaspirates from both control (BMI≤23) subjects, and non-diabetic obese Indians subjects (BMI≥25), were scrutinized for expressions of lipogenic genes, inflammatory mediators, stored adipokine levels, and insulin signaling proteins. Further, hADSC were isolated and immune-phenotyped from both the subject groups. Comparative assessments between chADSC and ohADSC were carried out for growth kinetics, expressions of pluripotent genes, adipogenic transcriptional factors, RUNX2, inflammatory mediators (IM), insulin signaling proteins, adipogenic and osteogenic differentiation. Adipose tissue of obese subjects depicted high leptin and resistin levels with reduced adiponectin levels. Expressions of IM and insulin signaling proteins were elevated compared to those of control subjects. hADSC of obese subjects demonstrated diminished proliferation, altered pluripotent genes, aggravated inflammation, adipogenesis with reduced osteogenesis. hADSC of obese had established insulin resistance compared to those of control subjects. This is the first study that describes hADSC of metabolically obese Indians have insulin resistance at lower BMI compared to Caucasians exemplifying plausible role in diminishing stemness of hADSC. Study alarms Indians to restore healthy dietary habits and assess quality of hADSC in regenerative therapy.

Chronic Adipose Tissue Inflammation Linking Obesity to Insulin Resistance and Type 2 Diabetes.

Obesity is one of the major health burdens of the 21st century as it contributes to the growing prevalence of its related comorbidities, including insulin resistance and type 2 diabetes. Growing evidence suggests a critical role for overnutrition in the development of low-grade inflammation. Specifically, chronic inflammation in adipose tissue is considered a crucial risk factor for the development of insulin resistance and type 2 diabetes in obese individuals. The triggers for adipose tissue inflammation are still poorly defined. However, obesity-induced adipose tissue expansion provides a plethora of intrinsic signals (e.g., adipocyte death, hypoxia, and mechanical stress) capable of initiating the inflammatory response. Immune dysregulation in adipose tissue of obese subjects results in a chronic low-grade inflammation characterized by increased infiltration and activation of innate and adaptive immune cells. Macrophages are the most abundant innate immune cells infiltrating and accumulating into adipose tissue of obese individuals; they constitute up to 40% of all adipose tissue cells in obesity. In obesity, adipose tissue macrophages are polarized into pro-inflammatory M1 macrophages and secrete many pro-inflammatory cytokines capable of impairing insulin signaling, therefore promoting the progression of insulin resistance. Besides macrophages, many other immune cells (e.g., dendritic cells, mast cells, neutrophils, B cells, and T cells) reside in adipose tissue during obesity, playing a key role in the development of adipose tissue inflammation and insulin resistance. The association of obesity, adipose tissue inflammation, and metabolic diseases makes inflammatory pathways an appealing target for the treatment of obesity-related metabolic complications. In this review, we summarize the molecular mechanisms responsible for the obesity-induced adipose tissue inflammation and progression toward obesity-associated comorbidities and highlight the current therapeutic strategies.

Adipose tissue fatty acid and lipid mediator composition in obesity and response to chronic marine omega-3 fatty acid supplementation

AbstractIntroduction:Obesity is an excess of adipose tissue (AT) and is linked with increased inflammation that enhances risk of type-2 diabetes and cardiovascular disease. The BIOCLAIMS study assessed the fatty acid (FA) and lipid mediator composition in normal weight and obese individuals, and their response to chronic omega-3 FA supplementation.Materials and methods:AT biopsies were collected pre- and post-12 week supplementation with 1.1 g EPA + 0.8 g DHA/day or corn oil. The composition of FA in the total lipid extract (TLE) of AT from 37 normal weight and 44 obese subjects was assessed by gas chromatography (GC) and the concentration of lipid mediators in AT TLE of 36 normal weight and 45 obese subjects by coupled GC-mass spectrometry.Results:AT of obese subjects had higher concentrations of arachidonic acid (AA), EPA, DPA, PGF2α, arachidonoylethanolamine (AEA), and eicosapentaenoylethanolamine (EPEA) than that of normal weight subjects (P &lt; 0.05). Obese subjects also had and lower concentrations of mediators derived from linoleic and α-linolenic acids, DHA-derived mediators including RvD2 and hydroxydocosahexaenoic acids (HDHAs), AA-derived mediators including lipoxin-B4, hepoxilin-A3, 11,12-dihydroxyeicosatetrienoic acid (DHET), and 6-keto-PGF1α, and the FA ethanolamine of myristic acid and glycerol ester of palmitic acid (P &lt; 0.05 all) than normal weight subjects.Chronic supplementation with EPA + DHA increased the concentration of EPA (P = 0.006) and EPA-derived lipid mediators including dihydroxyeicosatetrienoic acids, EPEA, and EPA-glycerol ester (P &lt; 0.05), and increased the concentration of DHA (P &lt; 0.001), docosahexaenoylethanolamine, and 8-, 11-, 14-, and 16-HDHA (P &lt; 0.05). Chronic supplementation with EPA + DHA also decreased the concentration 4-, 17-, and 20-HDHA, and AA-derived lipid mediators including DHETs, AEA, and LTs in normal weight subjects (P &lt; 0.05), and decreased 2-AG in obese subjects (P &lt; 0.05).Discussion:These data indicate altered lipid signalling in AT in obesity (at baseline) suggesting dysregulation of adipose tissue expansion and inflammatory signalling, including lack of self-resolution, as well as dysregulation in the utilization of supplementary EPA + DHA for synthesis of anti-inflammatory lipid mediators. EPA + DHA are able to modulate synthesis of EPA-, DHA- and AA-derived lipid mediators but obesity may involve resistance to these effects particularly in endocannabinoid synthesis.

Melatonin Supplementation Decreases Hypertrophic Obesity and Inflammation Induced by High-Fat Diet in Mice.

Obesity results from critical periods of positive energy balance characterized by caloric intake greater than energy expenditure. This disbalance promotes adipose tissue dysfunction which is related to other comorbidities. Melatonin is a low-cost therapeutic agent and studies indicate that its use may improve obesity-related disorders. To evaluate if the melatonin is efficient in delaying or even blocking the damages caused by excessive ingestion of a high-fat diet (HFD) in mice, as well as improving the inflammatory profile triggered by obesity herein, male C57BL/6 mice of 8 weeks were induced to obesity by a HFD and treated for 10 weeks with melatonin. The results demonstrate that melatonin supplementation attenuated serum triglyceride levels and total and LDL cholesterol and prevented body mass gain through a decreased lipogenesis rate and increased lipolytic capacity in white adipocytes, with a concomitant increment in oxygen consumption and Pgc1a and Prdm16 expression. Altogether, these effects prevented adipocyte hypertrophy caused by HFD and reflected in decreased adiposity. Finally, melatonin supplementation reduced the crown-like-structure (CLS) formation, characteristic of the inflammatory process by macrophage infiltration into white adipose tissue of obese subjects, as well as decreased the gene expression of inflammation-related factors, such as leptin and MCP1. Thus, the melatonin can be considered a potential therapeutic agent to attenuate the metabolic and inflammatory disorders triggered by obesity.

Vitamin D Receptor Gene Expression in Adipose Tissue of Obese Individuals is Regulated by miRNA and Correlates with the Pro-Inflammatory Cytokine Level.

Background: Given the role that vitamin D (VD) plays in the regulation of the inflammatory activity of adipocytes, we aimed to assess whether obesity changes the expression of VD-related genes in adipose tissue and, if so, to investigate whether this phenomenon depends on microRNA interference and how it may influence the local inflammatory milieu. Methods: The expression of genes encoding VD 1α-hydroxylase (CYP27B1), 24-hydroxylase (CYP24A1) and receptor (VDR), selected interleukins and microRNAs was evaluated by real-time PCR in visceral (VAT) and in subcutaneous (SAT) adipose tissues of 55 obese (BMI > 40 kg/m2) and 31 normal-weight (BMI 20–24.9 kg/m2) individuals. Results: VDR mRNA levels were higher, while CYP27B1 levels were lower in adipose tissues of obese patients than in those of normal-weight controls (VAT: P = 0.04, SAT: P < 0.0001 and VAT: P = 0.004, SAT: P = 0.016, respectively). The expression of VDR in VAT of obese subjects correlated negatively with levels of miR-125a-5p (P = 0.0006, rs = −0.525), miR-125b-5p (P = 0.001, rs = −0.495), and miR-214-3p (P = 0.009, rs = −0.379). Additionally, VDR mRNA concentrations in visceral adipose tissues of obese subjects correlated positively with mRNA levels of interleukins: 1β, 6 and 8. Conclusions: We observed obesity-associated up-regulation of VDR and down-regulation of CYP27B mRNA levels in adipose tissue. VDR expression correlates with the expression of pro-inflammatory cytokines and may be regulated by miRNAs.