scholarly journals Hypoxia in adipose tissue: a basis for the dysregulation of tissue function in obesity?

2008 ◽  
Vol 100 (2) ◽  
pp. 227-235 ◽  
Author(s):  
Paul Trayhurn ◽  
Bohan Wang ◽  
I. Stuart Wood
Keyword(s):  
Adipose Tissue ◽  
Inflammatory Response ◽  
Marker Gene ◽  
Hypoxia Inducible Factor ◽  
Subsequent Development ◽  
Obese Mouse ◽  
Human Adipocytes ◽  
Tissue Mass ◽  
Monocyte Chemoattractant Protein 1 ◽  
The Metabolic Syndrome

White adipose tissue is a key endocrine and secretory organ, releasing multiple adipokines, many of which are linked to inflammation and immunity. During the expansion of adipose tissue mass in obesity there is a major inflammatory response in the tissue with increased expression and release of inflammation-related adipokines, including IL-6, leptin, monocyte chemoattractant protein-1 and TNF-α, together with decreased adiponectin production. We proposed in 2004 (Trayhurn & Wood, Br J Nutr92, 347–355) that inflammation in adipose tissue in obesity is a response to hypoxia in enlarged adipocytes distant from the vasculature. Hypoxia has now been directly demonstrated in adipose tissue of several obese mouse models (ob/ob, KKAy, diet-induced) and molecular studies indicate that the level of the hypoxia-inducible transcription factor, hypoxia-inducible factor-1α, is increased, as is expression of the hypoxia-sensitive marker gene, GLUT1. Cell- culture studies on murine and human adipocytes show that hypoxia (induced by low O2 or chemically) leads to stimulation of the expression and secretion of a number of inflammation-related adipokines, including angiopoietin-like protein 4, IL-6, leptin, macrophage migration inhibitory factor and vascular endothelial growth factor. Hypoxia also stimulates the inflammatory response of macrophages and inhibits adipocyte differentiation from preadipocytes. GLUT1 gene expression, protein level and glucose transport by human adipocytes are markedly increased by hypoxia, indicating that low O2 tension stimulates glucose utilisation. It is suggested that hypoxia has a pervasive effect on adipocyte metabolism and on overall adipose tissue function, underpinning the inflammatory response in the tissue in obesity and the subsequent development of obesity-associated diseases, particularly type 2 diabetes and the metabolic syndrome.

scholarly journals Cellular hypoxia and adipose tissue dysfunction in obesity

2009 ◽  
Vol 68 (4) ◽  
pp. 370-377 ◽  
Author(s):  
I. Stuart Wood ◽  
Fátima Pérez de Heredia ◽  
Bohan Wang ◽  
Paul Trayhurn
Keyword(s):  
Adipose Tissue ◽  
Inflammatory Responses ◽  
Strong Support ◽  
Low Grade ◽  
Tissue Mass ◽  
Diverse Range ◽  
Monocyte Chemoattractant Protein 1 ◽  
The Metabolic Syndrome ◽  
Adipose Tissue Dysfunction ◽  
Cellular Hypoxia

Expansion of adipose tissue mass, the distinctive feature of obesity, is associated with low-grade inflammation. White adipose tissue secretes a diverse range of adipokines, a number of which are inflammatory mediators (such as TNFα, IL-1β, IL-6, monocyte chemoattractant protein 1). The production of inflammatory adipokines is increased with obesity and these adipokines have been implicated in the development of insulin resistance and the metabolic syndrome. However, the basis for the link between increased adiposity and inflammation is unclear. It has been proposed previously that hypoxia may occur in areas within adipose tissue in obesity as a result of adipocyte hypertrophy compromising effective O2 supply from the vasculature, thereby instigating an inflammatory response through recruitment of the transcription factor, hypoxic inducible factor-1. Studies in animal models (mutant mice, diet-induced obesity) and cell-culture systems (mouse and human adipocytes) have provided strong support for a role for hypoxia in modulating the production of several inflammation-related adipokines, including increased IL-6, leptin and macrophage migratory inhibition factor production together with reduced adiponectin synthesis. Increased glucose transport into adipocytes is also observed with low O2 tension, largely as a result of the up-regulation of GLUT-1 expression, indicating changes in cellular glucose metabolism. Hypoxia also induces inflammatory responses in macrophages and inhibits the differentiation of preadipocytes (while inducing the expression of leptin). Collectively, there is strong evidence to suggest that cellular hypoxia may be a key factor in adipocyte physiology and the underlying cause of adipose tissue dysfunction contributing to the adverse metabolic milieu associated with obesity.

scholarly journals Characterisation of 11β-hydroxysteroid dehydrogenase 1 in human orbital adipose tissue: a comparison with subcutaneous and omental fat

2007 ◽  
Vol 192 (2) ◽  
pp. 279-288 ◽  
Author(s):  
Iwona J Bujalska ◽  
Omar M Durrani ◽  
Joseph Abbott ◽  
Claire U Onyimba ◽  
Pamela Khosla ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Inflammatory Disease ◽  
Reductase Activity ◽  
Primary Cultures ◽  
Hydroxysteroid Dehydrogenase ◽  
Maximum Diameter ◽  
Tissue Remodelling ◽  
Tissue Mass ◽  
Disease States ◽  
The Metabolic Syndrome

Glucocorticoids (GCs) have a profound effect on adipose biology increasing tissue mass causing central obesity. The pre-receptor regulation of GCs by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) that activates cortisol from cortisone has been postulated as a fundamental mechanism underlying the metabolic syndrome mediating adipocyte hyperplasia and hypertrophy in the omental (OM) depot. Orbital adipose tissue (OF) is the site of intense inflammation and tissue remodelling in several orbital inflammatory disease states. In this study, we describe features of the GC metabolic pathways in normal human OF depot and compare it with subcutaneous (SC) and OM depots. Using an automated histological characterisation technique, OF adipocytes were found to be significantly smaller (parameters: area, maximum diameter and perimeter) than OM and SC adipocytes (P<0.001). Although immunohistochemical analyses demonstrated resident CD68+ cells in all three whole tissue adipose depots, OF CD68 mRNA and protein expression exceeded that of OM and SC (mRNA, P<0.05; protein, P<0.001). In addition, there was higher expression of glucocorticoid receptor (GR)α mRNA in the OF whole tissue depot (P<0.05). Conversely, 11β-HSD1 mRNA together with the markers of late adipocyte differentiation (FABP4 and G3PDH) were significantly lower in OF. Primary cultures of OF preadipocytes demonstrated predominant 11β-HSD1 oxo-reductase activity with minimal dehydrogenase activity. Orbital adipocytes are smaller, less differentiated, and express low levels of 11β-HSD1 but abundant GRα compared with SC and OM. OF harbours a large CD68+ population. These characteristics define an orbital microenvironment that has the potential to respond to sight-threatening orbital inflammatory disease.

scholarly journals Accurate quantification of brown adipose tissue mass by xenon-enhanced computed tomography

2017 ◽  
Vol 115 (1) ◽  
pp. 174-179 ◽  
Author(s):  
Rosa T. Branca ◽  
Andrew McCallister ◽  
Hong Yuan ◽  
Amir Aghajanian ◽  
James E. Faber ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Imaging Techniques ◽  
Tomographic Imaging ◽  
Obese Mouse ◽  
Vascular Perfusion ◽  
Tissue Mass ◽  
Brown Adipose ◽  
Enhanced Computed Tomography

Detection and quantification of brown adipose tissue (BAT) mass remains a major challenge, as current tomographic imaging techniques are either nonspecific or lack the necessary resolution to quantify BAT mass, especially in obese phenotypes, in which this tissue may be present but inactive. Here, we report quantification of BAT mass by xenon-enhanced computed tomography. We show that, during stimulation of BAT thermogenesis, the lipophilic gas xenon preferentially accumulates in BAT, leading to a radiodensity enhancement comparable to that seen in the lungs. This enhancement is mediated by a selective reduction in BAT vascular resistance, which greatly increases vascular perfusion of BAT. This enhancement enables precise identification and quantification of BAT mass not only in lean, but also in obese, mouse phenotypes, in which this tissue is invisible to conventional tomographic imaging techniques. The method is developed and validated in rodents and then applied in macaques to assess its feasibility in larger species.

scholarly journals A Metalloproteinase Induces an Inflammatory Response in Preadipocytes with the Activation of COX Signalling Pathways and Participation of Endogenous Phospholipases A2

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 921
Author(s):  
Priscila Motta Janovits ◽  
Elbio Leiguez ◽  
Viviane Portas ◽  
Catarina Teixeira
Keyword(s):  
Adipose Tissue ◽  
Inflammatory Response ◽  
Phospholipase A2 ◽  
Proteolytic Enzymes ◽  
Inflammatory Diseases ◽  
Prostaglandin E ◽  
Monocyte Chemoattractant Protein 1 ◽  
Phospholipases A2 ◽  
Proinflammatory Mediators ◽  
Adipose Tissue Cells

Matrix metalloproteinases (MMPs) are proteolytic enzymes that have been associated with the pathogenesis of inflammatory diseases and obesity. Adipose tissue in turn is an active endocrine organ capable of secreting a range of proinflammatory mediators with autocrine and paracrine properties, which contribute to the inflammation of adipose tissue and adjacent tissues. However, the potential inflammatory effects of MMPs in adipose tissue cells are still unknown. This study investigates the effects of BmooMPα-I, a single-domain snake venom metalloproteinase (SVMP), in activating an inflammatory response by 3T3-L1 preadipocytes in culture, focusing on prostaglandins (PGs), cytokines, and adipocytokines biosynthesis and mechanisms involved in prostaglandin E2 (PGE2) release. The results show that BmooMPα-I induced the release of PGE2, prostaglandin I2 (PGI2), monocyte chemoattractant protein-1 (MCP-1), and adiponectin by preadipocytes. BmooMPα-I-induced PGE2 biosynthesis was dependent on group-IIA-secreted phospholipase A2 (sPLA2-IIA), cytosolic phospholipase A2-α (cPLA2-α), and cyclooxygenase (COX)-1 and -2 pathways. Moreover, BmooMPα-I upregulated COX-2 protein expression but not microsomal prostaglandin E synthase-1 (mPGES-1) expression. In addition, we demonstrate that the enzymatic activity of BmooMPα-I is essential for the activation of prostanoid synthesis pathways in preadipocytes. These data highlight preadipocytes as important targets for metalloproteinases and provide new insights into the contribution of these enzymes to the inflammation of adipose tissue and tissues adjacent to it.

scholarly journals Evaluation of adipose tissue mass with anthropometric and visualization methods; its relation to the components of the metabolic syndrome

2013 ◽  
Vol 10 (2) ◽  
pp. 23-27
Author(s):  
T N Markova ◽  
V A Kichigin ◽  
V N Diomidova ◽  
D S Markov ◽  
O V Petrova
Keyword(s):  
Metabolic Syndrome ◽  
Adipose Tissue ◽  
Visceral Fat ◽  
Subcutaneous Fat ◽  
Tissue Mass ◽  
The Metabolic Syndrome ◽  
Adipose Tissue Mass ◽  
Different Types ◽  
Magnetic Resonance Imaging Mri ◽  
Mri Measurements

We performed an estimation of body fat using ultrasound, magnetic resonance imaging (MRI) and anthropometry in 60 patients with different types of body weight (BW). Correlation of waist circumference (WC), thickness of subcutaneous fat and visceral fat with components of the metabolic syndrome was studied comparatively between ultrasound and MRI measurements. We noted a preferential increase in the thickness of visceral fat compared with subcutaneous with increasing degree of BW. Significant increase in adipose tissue and the development of metabolic disorders occurs in overweight, making it the state close to obesity. During a routine ultrasound of the abdomen it is advisable to determine the thickness of subcutaneous and visceral fat separately.

scholarly journals Appearance and disappearance of the mRNA signature characteristic of Tregcells in visceral adipose tissue: Age, diet, and PPARγ effects

2014 ◽  
Vol 112 (2) ◽  
pp. 482-487 ◽  
Author(s):  
Daniela Cipolletta ◽  
Paul Cohen ◽  
Bruce M. Spiegelman ◽  
Christophe Benoist ◽  
Diane Mathis
Keyword(s):  
Adipose Tissue ◽  
T Cell ◽  
Visceral Adipose Tissue ◽  
Obese Mouse ◽  
The Metabolic Syndrome ◽  
Fat Depot ◽  
Visceral Adipose ◽  
High Representation ◽  
Very High

A unique population of Foxp3+CD4+regulatory T (Treg) cells resides in visceral adipose tissue (VAT) of lean mice, especially in the epididymal fat depot. VAT Tregsare unusual in their very high representation within the CD4+T-cell compartment, their transcriptome, and their repertoire of antigen-specific T-cell receptors. They are important regulators of local and systemic inflammation and metabolism. The overall goal of this study was to learn how the VAT Tregtranscriptome adapts to different stimuli; in particular, its response to aging in lean mice, to metabolic perturbations associated with obesity, and to certain signaling events routed through PPARγ, the “master-regulator” of adipocyte differentiation. We show that the VAT Tregsignature is imposed early in life, well before age-dependent expansion of the adipose-tissue Tregpopulation. VAT Tregsin obese mice lose the signature typical of lean individuals but gain an additional set of over- and underrepresented transcripts. This obese mouse VAT Tregsignature depends on phosphorylation of the serine residue at position 273 of PPARγ, in striking parallel to a pathway recently elucidated in adipocytes. These findings are important to consider in designing drugs to target type 2 diabetes and other features of the “metabolic syndrome.”

scholarly journals Toll-Like Receptor Ligands Cause Proinflammatory and Prodiabetic Activation of Adipocytes via Phosphorylation of Extracellular Signal-Regulated Kinase and c-Jun N-Terminal Kinase But Not Interferon Regulatory Factor-3

Endocrinology ◽  
2010 ◽  
Vol 151 (3) ◽  
pp. 1097-1108 ◽  
Author(s):  
Andrea Kopp ◽  
Christa Buechler ◽  
Margarita Bala ◽  
Markus Neumeier ◽  
Juergen Schölmerich ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Interferon Regulatory Factor ◽  
Mitogen Activated Protein Kinase ◽  
Human Adipocytes ◽  
Toll Like Receptor ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 3 ◽  
Monocyte Chemoattractant Protein 1 ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal

Here, we aim to investigate the mechanisms of Toll-like receptor (TLR)-induced prodiabetic and proinflammatory activation of adipocytes and to detect differences in the responsiveness of TLRs to their respective ligands between adipocytes isolated from inflamed vs. noninflamed adipose tissue. Experiments using specific ligands for all known TLRs were performed in murine 3T3-L1 adipocytes and in human adipocytes isolated from noninflamed and inflamed adipose tissue. IL-6 and monocyte chemoattractant protein-1 (MCP-1) release were measured by ELISA. The expression of the signal transduction proteins phospho-extracellular signal-regulated kinase (P-Erk), P-c-Jun N-terminal kinase (JNK), and P-interferon regulatory factor-3 was investigated by Western blot analysis. Additionally, functional inhibitors of MAPK kinase-1/-2 and JNK-1/-2 were used in the stimulation experiments. Activation of TRL4 by lipopolysaccharide (LPS) and TLR1/2 by Pam3Cys up-regulates IL-6 and MCP-1 release in adipocytes via specific activation of Erk. Stimulation of adipocytes by macrophage activating lipopeptide-2 (MALP-2) induces MCP-1 but has no effect on IL-6 release. This stimulatory effect on MCP-1 release is antagonized by inhibition of both mitogen-activated protein kinase-1/-2 and JNK-1/-2. Phosphorylation of Erk and JNK is up-regulated after stimulation by MALP-2. In human adipocytes isolated from noninflamed adipose tissue, LPS and Pam3Cys, but not MALP-2, are potent inducers of IL-6 and MCP-1. MALP-2 is able to induce IL-6 and MCP-1 release in adipocytes isolated from inflamed adipose tissue, whereas these adipocytes lost their ability to respond to LPS. The present results point to a role of the adipose tissue in innate immunity. TLR-ligand-induced proinflammatory and prodiabetic activation of adipocytes might couple visceral adipose tissue dysfunction with insulin resistance and type 2 diabetes mellitus.

Abstract 597: Diet-induced Obesity Requires Signalling Through Tumor Necrosis Factor Receptor-associated Factor 1 (TRAF-1) in Adipocytes

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Dennis Wolf ◽  
Nathaly Anto Michel ◽  
Ingo Hilgendorf ◽  
Christoph Bode ◽  
Andreas Zirlik
Keyword(s):  
Metabolic Syndrome ◽  
Adipose Tissue ◽  
Hormone Sensitive Lipase ◽  
Obese Mouse ◽  
Adipose Tissue Inflammation ◽  
Tissue Inflammation ◽  
Diet Induced Obesity ◽  
The Metabolic Syndrome ◽  
Adipose Tissue Macrophages ◽  
Genetic Deficiency

Background: Accumulation of inflammatory leukocytes is a prerequisite of adipose tissue inflammation during cardio-metabolic disease. We recently reported that a genetic deficiency of the intracellular signalling adaptor TRAF-1 attenuates inflammatory cell recruitment and vascular inflammation in atherosclerosis. Here, we tested the contribution of TRAF-1 to diet-induced obesity (DIO) in mice. Methods and Results: To test the association of TRAFs and obesity we screened for expression of different TRAFs in adipose tissue. We found an up-regulation of TRAF-1 mRNA in obese mouse and human adipose tissue, resulting from higher gene expression in adipocytes, but not in adipose tissue macrophages. To test a functional relevance of TRAF-1 signalling in obesity, WT or TRAF-1 -/- mice consumed a high fat diet HFD for 20 weeks. Surprisingly, genetic deficiency of TRAF-1 abolished diet-induced weight gain by supressing peripheral fat depositions. Consequently, TRAF-1 -/- mice demonstrated ameliorated glucose levels after glucose and insulin tolerance tests and dampened insulin signalling. Consistently, we also found reduced accumulation of adipose tissue macrophages. Mechanistically, TRAF-1 -/- mice demonstrated no differences in basic energy metabolism, such as in energy expenditure. However, TRAF-1 -/- adipocytes had higher expression of Adipose Triglyceride Lipase (ATGL) and Hormone-sensitive Lipase (HSL), suggesting increased lipid breakdown in adipocytes. In accord, plasma levels of free fatty acids were higher, while leptin levels were reduced in TRAF-1 -/- mice. Finally, in a collective of patients with a high prevalence of the metabolic syndrome, TRAF-1 expression correlated with the metabolic syndrome, suggesting clinical relevance of our findings. Conclusion: We present the novel finding that the signalling adapter TRAF-1 correlates with obesity in mice and humans. Genetic deficiency of TRAF-1 attenuates diet-induced obesity by increasing lipolysis in adipocytes. These findings identify TRAF-1 as a novel therapeutic target in obesity and adipose-tissue inflammation.

scholarly journals Inflammatory adipokines contribute to insulin resistance in active acromegaly and respond differently to different treatment modalities

2014 ◽  
Vol 170 (1) ◽  
pp. 39-48 ◽  
Author(s):  
Nicoleta C Olarescu ◽  
Thor Ueland ◽  
Kristin Godang ◽  
Rune Lindberg-Larsen ◽  
Jens Otto L Jørgensen ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Glucose Metabolism ◽  
Somatostatin Analogs ◽  
Treatment Modalities ◽  
Human Adipocytes ◽  
Analysis Model ◽  
Tissue Mass ◽  
Active Acromegaly

BackgroundActive acromegaly is associated with insulin resistance, but it is uncertain whether inflammation in adipose tissue is a contributing factor.AimTo test if GH/IGF1 promotes inflammation in adipocytes, and if this is relevant for systemic insulin resistance in acromegaly. Furthermore, to investigate the effect of treatment modalities (transsphenoidal surgery (TS), somatostatin analogs (SAs), and pegvisomant (PGV)) on glucose metabolism and inflammatory biomarkers in acromegaly.MethodsThe in vitro effects of GH/IGF1 on gene expression of adipokines in human adipocytes were investigated. Body composition, glucose metabolism, and circulating adipokines (adiponectin (AD), high-molecular weight AD (HMWAD), leptin, vascular endothelial growth factor-A (VEGF-A), monocyte chemotactic protein 1 (MCP1), and thioredoxin (TRX)) were measured in 37 patients with active acromegaly before and after treatment.ResultsIn vitro GH, but not IGF1, increased VEGF and MCP1 in human adipocytes. In all treatment groups, body fat increased and IGF1 decreased to the same extent. Fasting glucose decreased in the TS (P=0.016) and PGV (P=0.042) groups, but tended to increase in the SA group (P=0.078). Insulin and HOMA-IR decreased in both TS and SA groups, while the PGV group showed no changes. Serum VEGF and MCP1 decreased significantly in the TS group only (P=0.010, P=0.002), while HMWAD increased with PGV treatment only (P=0.018). A multivariate analysis model identified the changes in GH and VEGF as predictors of improvement in HOMA-IR after treatment (R2=0.39, P=0.002).Conclusionsi) GH directly promotes inflammation of human adipocytes by increasing VEGF and MCP1 levels; ii) glucose metabolism and inflammation (VEGF and MCP1) improve to some extent after treatment, despite an increase in adipose tissue mass; and iii) the decrease in insulin resistance after therapy in acromegaly depends, to some extent, on treatment modalities.

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