scholarly journals A TRAIL-TL1A paracrine network involving adipocytes, macrophages and lymphocytes induces adipose tissue dysfunction downstream of E2F1 in human obesity

2020 ◽  
Author(s):  
Ada Admin ◽  
Nitzan Maixner ◽  
Tal Pecht ◽  
Yulia Haim ◽  
Vered Chalifa-Caspi ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Stromal Vascular Fraction ◽  
Metabolic Dysfunction ◽  
Trail Expression ◽  
Adipose Tissue Dysfunction ◽  
M1 Polarization ◽  
Tnf Superfamily ◽  
Diabetes Status ◽  
Elevated Expression ◽  
Visceral Adipose

Elevated expression of E2F1 in adipocyte-fraction of human visceral adipose-tissue(hVAT) associates with a poor cardio-metabolic profile. We hypothesized that beyond directly activating autophagy and MAP3K5(ASK)-MAP-kinase signaling, E2F1 governs a distinct transcriptome that contributes to adipose-tissue and metabolic dysfunction in obesity. We performed RNA-sequencing of hVAT samples from age-, sex- and BMI–matched patients, all obese, whose visceral-E2F1 protein expression was either high(E2F1<sup>high</sup>) or low(E2F1<sup>low</sup>). TNF-superfamily members, including <i>TRAIL</i>(<i>TNFSF10</i>), <i>TL1A</i>(<i>TNFSF15</i>) and their receptors were enriched in E2F1<sup>high</sup>. While <i>TRAIL</i> was equally expressed in adipocytes and stromal-vascular fraction(SVF), <i>TL1A </i>was mainly expressed in SVF, and TRAIL-induced <i>TL1A</i> was attributed to CD4+ and CD8<sup>+</sup>-subclasses of hVAT T-lymphocytes. In human adipocytes TL1A enhanced basal and impaired insulin-inhibitable lipolysis, and altered adipokine secretion, and in human macrophages induced foam-cells biogenesis and M1-polarization. Two independent human cohorts confirmed associations between TL1A and TRAIL expression in hVAT and higher leptin and IL6 serum concentrations, diabetes status, and hVAT-macrophage lipid content. Jointly, we propose an intra-adipose tissue E2F1-associated TNF-superfamily paracrine loop engaging lymphocytes, macrophages and adipocytes, ultimately contributing to adipose-tissue dysfunction in obesity.

scholarly journals A TRAIL-TL1A paracrine network involving adipocytes, macrophages and lymphocytes induces adipose tissue dysfunction downstream of E2F1 in human obesity

2020 ◽  
Author(s):  
Ada Admin ◽  
Nitzan Maixner ◽  
Tal Pecht ◽  
Yulia Haim ◽  
Vered Chalifa-Caspi ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Stromal Vascular Fraction ◽  
Metabolic Dysfunction ◽  
Trail Expression ◽  
Adipose Tissue Dysfunction ◽  
M1 Polarization ◽  
Tnf Superfamily ◽  
Diabetes Status ◽  
Elevated Expression ◽  
Visceral Adipose

Elevated expression of E2F1 in adipocyte-fraction of human visceral adipose-tissue(hVAT) associates with a poor cardio-metabolic profile. We hypothesized that beyond directly activating autophagy and MAP3K5(ASK)-MAP-kinase signaling, E2F1 governs a distinct transcriptome that contributes to adipose-tissue and metabolic dysfunction in obesity. We performed RNA-sequencing of hVAT samples from age-, sex- and BMI–matched patients, all obese, whose visceral-E2F1 protein expression was either high(E2F1<sup>high</sup>) or low(E2F1<sup>low</sup>). TNF-superfamily members, including <i>TRAIL</i>(<i>TNFSF10</i>), <i>TL1A</i>(<i>TNFSF15</i>) and their receptors were enriched in E2F1<sup>high</sup>. While <i>TRAIL</i> was equally expressed in adipocytes and stromal-vascular fraction(SVF), <i>TL1A </i>was mainly expressed in SVF, and TRAIL-induced <i>TL1A</i> was attributed to CD4+ and CD8<sup>+</sup>-subclasses of hVAT T-lymphocytes. In human adipocytes TL1A enhanced basal and impaired insulin-inhibitable lipolysis, and altered adipokine secretion, and in human macrophages induced foam-cells biogenesis and M1-polarization. Two independent human cohorts confirmed associations between TL1A and TRAIL expression in hVAT and higher leptin and IL6 serum concentrations, diabetes status, and hVAT-macrophage lipid content. Jointly, we propose an intra-adipose tissue E2F1-associated TNF-superfamily paracrine loop engaging lymphocytes, macrophages and adipocytes, ultimately contributing to adipose-tissue dysfunction in obesity.

scholarly journals Role of Arginase 2 in Systemic Metabolic Activity and Adipose Tissue Fatty Acid Metabolism in Diet-Induced Obese Mice

2019 ◽  
Vol 20 (6) ◽  
pp. 1462 ◽  
Author(s):  
Reem Atawia ◽  
Haroldo Toque ◽  
Mohamed Meghil ◽  
Tyler Benson ◽  
Nicole Yiew ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Fatty Acid ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Normal Diet ◽  
Metabolic Dysfunction ◽  
Ppar Γ ◽  
Obesity And Diabetes ◽  
Visceral Adipose ◽  
Upregulated Genes

Visceral adipose tissue (VAT) inflammation and metabolic dysregulation are key components of obesity-induced metabolic disease. Upregulated arginase, a ureahydrolase enzyme with two isoforms (A1-cytosolic and A2-mitochondrial), is implicated in pathologies associated with obesity and diabetes. This study examined A2 involvement in obesity-associated metabolic and vascular disorders. WT and globally deleted A2(−/−) or A1(+/−) mice were fed either a high fat/high sucrose (HFHS) diet or normal diet (ND) for 16 weeks. Increases in body and VAT weight of HFHS-fed WT mice were abrogated in A2−/−, but not A1+/−, mice. Additionally, A2−/− HFHS-fed mice exhibited higher energy expenditure, lower blood glucose, and insulin levels compared to WT HFHS mice. VAT and adipocytes from WT HFHS fed mice showed greater A2 expression and adipocyte size and reduced expression of PGC-1α, PPAR-γ, and adiponectin. A2 deletion blunted these effects, increased levels of active AMPK-α, and upregulated genes involved in fatty acid metabolism. A2 deletion prevented HFHS-induced VAT collagen deposition and inflammation, which are involved in adipocyte metabolic dysfunction. Endothelium-dependent vasorelaxation, impaired by HFHS diet, was significantly preserved in A2−/− mice, but more prominently maintained in A1+/− mice. In summary, A2 is critically involved in HFHS-induced VAT inflammation and metabolic dysfunction.

scholarly journals Visceral adiposopathy: a vascular perspective

2015 ◽  
Vol 21 (2) ◽  
Author(s):  
Melissa G. Farb ◽  
Noyan Gokce
Keyword(s):  
Cardiovascular Disease ◽  
Adipose Tissue ◽  
Multiple Organ ◽  
Vascular Endothelial ◽  
Metabolic Dysfunction ◽  
Central Adiposity ◽  
Organ Systems ◽  
Tissue Characteristics ◽  
Care Problems ◽  
Visceral Adipose

AbstractObesity has emerged as one of the most critical health care problems globally that is associated with the development of insulin resistance, type 2 diabetes mellitus, metabolic dysfunction and cardiovascular disease. Central adiposity with intra-abdominal deposition of visceral fat, in particular, has been closely linked to cardiometabolic consequences of obesity. Increasing epidemiological, clinical and experimental data suggest that both adipose tissue quantity and perturbations in its quality termed “adiposopathy” contribute to mechanisms of cardiometabolic disease. The current review discusses regional differences in adipose tissue characteristics and highlights profound abnormalities in vascular endothelial function and angiogenesis that are manifest within the visceral adipose tissue milieu of obese individuals. Clinical data demonstrate up-regulation of pro-inflammatory and pro-atherosclerotic mediators in dysfunctional adipose tissue that may support pathological vascular changes not only locally in fat but also in multiple organ systems, including coronary and peripheral circulations, potentially contributing to mechanisms of obesity-related cardiovascular disease.

scholarly journals Unique Genetic and Histological Signatures of Mouse Pericardial Adipose Tissue

Nutrients ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1855
Author(s):  
A. Al-Dibouni ◽  
R. Gaspar ◽  
S. Ige ◽  
S. Boateng ◽  
F. R. Cagampang ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Visceral Fat ◽  
Uncoupling Protein ◽  
Subcutaneous Fat ◽  
Metabolic Dysfunction ◽  
High Fat ◽  
Adipose Depot ◽  
Pericardial Adipose Tissue ◽  
Visceral Adipose ◽  
Adipose Tissue Depot

Obesity is a major risk factor for a plethora of metabolic disturbances including diabetes and cardiovascular disease. Accumulating evidence is showing that there is an adipose tissue depot-dependent relationship with obesity-induced metabolic dysfunction. While some adipose depots, such as subcutaneous fat, are generally metabolically innocuous, others such as visceral fat, are directly deleterious. A lesser known visceral adipose depot is the pericardial adipose tissue depot. We therefore set out to examine its transcriptional and morphological signature under chow and high-fat fed conditions, in comparison with other adipose depots, using a mouse model. Our results revealed that under chow conditions pericardial adipose tissue has uncoupling-protein 1 gene expression levels which are significantly higher than classical subcutaneous and visceral adipose depots. We also observed that under high-fat diet conditions, the pericardial adipose depot exhibits greatly upregulated transcript levels of inflammatory cytokines. Our results collectively indicate, for the first time, that the pericardial adipose tissue possesses a unique transcriptional and histological signature which has features of both a beige (brown fat-like) but also pro-inflammatory depot, such as visceral fat. This unique profile may be involved in metabolic dysfunction associated with obesity.

scholarly journals Dipeptidyl peptidase IV inhibitor sitagliptin reduces local inflammation in adipose tissue and in pancreatic islets of obese mice

2011 ◽  
Vol 300 (2) ◽  
pp. E410-E421 ◽  
Author(s):  
A. D. Dobrian ◽  
Q. Ma ◽  
J. W. Lindsay ◽  
K. A. Leone ◽  
K. Ma ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Mrna Expression ◽  
Pancreatic Islets ◽  
Pancreatic Islet ◽  
Cell Function ◽  
Fasting Blood Glucose ◽  
Stromal Vascular Fraction ◽  
Metabolic Dysfunction ◽  
Reduced Body ◽  
Β Cell Function

Adipose tissue inflammation and reduced pancreatic β-cell function are key issues in the development of cardiovascular disease and progressive metabolic dysfunction in type 2 diabetes mellitus. The aim of this study was to determine the effect of the DPP IV inhibitor sitagliptin on adipose tissue and pancreatic islet inflammation in a diet-induced obesity model. C57Bl/6J mice were placed on a high-fat (60% kcal fat) diet for 12 wk, with or without sitagliptin (4 g/kg) as a food admix. Sitagliptin significantly reduced fasting blood glucose by 21% as well as insulin by ∼25%. Sitagliptin treatment reduced body weight without changes in overall body mass index or in the epididymal and retroperitoneal fat mass. However, sitagliptin treatment led to triple the number of small adipocytes despite reducing the number of the very large adipocytes. Sitagliptin significantly reduced inflammation in the adipose tissue and pancreatic islet. Macrophage infiltration in adipose tissue evaluated by immunostaining for Mac2 was reduced by sitagliptin ( P < 0.01), as was the percentage of CD11b+/F4/80+ cells in the stromal vascular fraction ( P < 0.02). Sitagliptin also reduced adipocyte mRNA expression of inflammatory genes, including IL-6, TNFα, IL-12(p35), and IL-12(p40), 2.5- to fivefold as well as 12-lipoxygenase protein expression. Pancreatic islets were isolated from animals after treatments. Sitagliptin significantly reduced mRNA expression of the following inflammatory cytokines: MCP-1 (3.3-fold), IL-6 (2-fold), IL-12(p40) (2.2-fold), IL-12(p35) (5-fold, P < 0.01), and IP-10 (2-fold). Collectively, the results indicate that sitagliptin has anti-inflammatory effects in adipose tissue and in pancreatic islets that accompany the insulinotropic effect.

scholarly journals DecreasedSTAMP2Expression in Association with Visceral Adipose Tissue Dysfunction

2011 ◽  
Vol 96 (11) ◽  
pp. E1816-E1825 ◽  
Author(s):  
José María Moreno-Navarrete ◽  
Francisco Ortega ◽  
Marta Serrano ◽  
Rafael Pérez-Pérez ◽  
Mònica Sabater ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Visceral Adipose Tissue ◽  
Adipose Tissue Dysfunction ◽  
Visceral Adipose

scholarly journals ICOS signaling limits regulatory T cell accumulation and function in visceral adipose tissue

2021 ◽  
Vol 218 (6) ◽  
Author(s):  
Kristen L. Mittelsteadt ◽  
Erika T. Hayes ◽  
Daniel J. Campbell
Keyword(s):  
Adipose Tissue ◽  
T Cell ◽  
Insulin Sensitivity ◽  
Visceral Adipose Tissue ◽  
Cell Accumulation ◽  
Elevated Expression ◽  
Phosphoinositide 3 Kinase ◽  
And Function ◽  
Adipose Inflammation ◽  
Visceral Adipose

A unique population of Foxp3+ regulatory T cells (TRs) resides in visceral adipose tissue (VAT) that regulates adipose inflammation and helps preserve insulin sensitivity. Inducible T cell co-stimulator (ICOS) is highly expressed on effector (e)TRs that migrate to nonlymphoid tissues, and contributes to their maintenance and function in models of autoimmunity. In this study, we report an unexpected cell-intrinsic role for ICOS expression and downstream phosphoinositide 3-kinase (PI3K) signaling in limiting the abundance, VAT-associated phenotype, and function of TRs specifically in VAT. Icos−/− mice and mice expressing a knock-in form of ICOS that cannot activate PI3K had increased VAT-TR abundance and elevated expression of canonical VAT-TR markers. Loss of ICOS signaling facilitated enhanced accumulation of TRs to VAT associated with elevated CCR3 expression, and resulted in reduced adipose inflammation and heightened insulin sensitivity in the context of a high-fat diet. Thus, we have uncovered a new and surprising molecular pathway that regulates VAT-TR accumulation and function.

scholarly journals ICOS signaling limits regulatory T cell accumulation and function in visceral adipose tissue

2020 ◽  
Author(s):  
Kristen L. Mittelsteadt ◽  
Daniel J. Campbell
Keyword(s):  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Visceral Adipose Tissue ◽  
High Fat Diet ◽  
Costimulatory Molecule ◽  
Cell Accumulation ◽  
Elevated Expression ◽  
And Function ◽  
Adipose Inflammation ◽  
Visceral Adipose

AbstractA unique population of Foxp3+ regulatory T cells (TR) resides in visceral adipose tissue (VAT) that regulates adipose inflammation and helps preserve insulin sensitivity. The costimulatory molecule ICOS is highly expressed on effector (e)TR that migrate to nonlymphoid tissues, and contributes to their maintenance and function in models of autoimmunity. In this study, we report an unexpected cell-intrinsic role for ICOS expression and downstream PI3K signaling in limiting the abundance, VAT-associated phenotype, and function of TR specifically in VAT. Icos−/− mice and mice expressing a knock-in form of ICOS that cannot activate PI3K had increased VAT-TR abundance and elevated expression of canonical VAT-TR markers. Loss of ICOS signaling facilitated enhanced accumulation of TR to VAT associated with elevated CCR3 expression, and resulted in reduced adipose inflammation and heightened insulin sensitivity in the context of high-fat diet. Thus, we have uncovered a new and surprising molecular pathway that regulates VAT-TR accumulation and function.

scholarly journals Cancer cachexia differentially regulates visceral adipose tissue turnover

2017 ◽  
Vol 232 (3) ◽  
pp. 493-500 ◽  
Author(s):  
Felipe de Oliveira Franco ◽  
Magno Alves Lopes ◽  
Felipe dos Santos Henriques ◽  
Rodrigo Xavier das Neves ◽  
Cesário Bianchi Filho ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Cancer Cachexia ◽  
Stromal Vascular Fraction ◽  
Body Weight Loss ◽  
Early Event ◽  
Mrna Levels ◽  
Adipose Tissue Depots ◽  
Cellular Turnover ◽  
Visceral Adipose ◽  
And Control

Cancer cachexia (CC) is a progressive metabolic syndrome that is marked by severe body weight loss. Metabolic disarrangement of fat tissues is a very early event in CC, followed by adipose tissue (AT) atrophy and remodelling. However, there is little information regarding the possible involvement of cellular turnover in this process. Thus, in this study, we evaluated the effect of CC on AT turnover and fibrosis of mesenteric (MEAT) and retroperitoneal (RPAT) adipose tissue depots as possible factors that contribute to AT atrophy. CC was induced by a subcutaneous injection of Walker tumour cells (2 × 107) in Wistar rats, and control animals received only saline. The experimental rats were randomly divided into four experimental groups: 0 days, 4 days, 7 days and 14 days after injection. AT turnover was analysed according to the Pref1/Adiponectin ratio of gene expression from the stromal vascular fraction and pro-apoptotic CASPASE3 and CASPASE9 from MEAT and RPAT. Fibrosis was verified according to the total collagen levels and expression of extracellular matrix genes. AT turnover was verified by measurements of lipolytic protein expression. We found that the Pref1/Adiponectin ratio was decreased in RPAT (81.85%, P < 0.05) with no changes in MEAT compared with the respective controls. CASPASE3 and CASPASE9 were activated on day 14 only in RPAT. Collagen was increased on day 7 in RPAT (127%) and MEAT (4.3-fold). The Collagen1A1, Collagen3A1, Mmp2 and Mmp9 mRNA levels were upregulated only in MEAT in CC. Lipid turnover was verified in RPAT and was not modified in CC. We concluded that the results suggest that CC affects RPAT cellular turnover, which may be determinant for RPAT atrophy.

scholarly journals Higher Ratio of Abdominal Subcutaneous to Visceral Adipose Tissue Related with Preservation of Islet β-Cell Function in Healthy Individuals

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Juan Liu ◽  
Jianbin Liu ◽  
Hai Li ◽  
Liehua Liu ◽  
Jing Zheng ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Visceral Adipose Tissue ◽  
Protective Factor ◽  
Cell Function ◽  
Late Phase ◽  
Metabolic Dysfunction ◽  
Healthy Group ◽  
Matsuda Index ◽  
Β Cell Function ◽  
Visceral Adipose

Objective. To investigate the relationship between abdominal adipose tissue distribution, β-cell function, and insulin sensitivity (IS) in a Chinese population. Methods. One hundred and eighty-eight healthy subjects (healthy group), 239 with normal glucose, and 1~4 abnormal metabolic traits (metabolic dysfunction group, MD group) and 125 with hyperglycemia (hyperglycemia group) were studied. HOMA-IR, HOMA-B, Matsuda index, early- (I0–30/G0–30) and late-phase (I30–120/G30–120) insulin responses and the corresponding disposition indexes (DI) were calculated. The area of abdominal subcutaneous adipose tissue (ASAT) and visceral adipose tissue (VAT) was measured and the ratio of ASAT to VAT (SVR) was calculated. Results. SVR was correlated positively with Matsuda index in healthy, MD, and hyperglycemia groups, and inversely with HOMA-IR. SVR positively related with both early- and late-phase DI in the healthy group only. In the healthy group, the hyperbolas of I0–30/G0–30 and I30–120/G30–120 versus Matsuda index in the highest quarter of SVR were significantly right shifted compared to those in the lowest (both P<0.05). Conclusions. In healthy adults, higher SVR was a protective factor for β-cell function and IS, while in those with glucometabolic abnormality, higher SVR contributed to a relative better IS, indicating SVR is possible to be an early predicator of type 2 diabetes development.

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