scholarly journals My D88-Dependent Interplay Between Myeloid and Endothelial Cells in the Initiation and Progression of Obesity-Associated Inflammatory Diseases

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. SCI-44-SCI-44
Author(s):  
Xiaoxia Li
Keyword(s):  
Insulin Resistance ◽  
Endothelial Cells ◽  
Adipose Tissue ◽  
Systemic Inflammation ◽  
Conflicts Of Interest ◽  
Ex Vivo ◽  
Inflammatory Diseases ◽  
Critical Role ◽  
Low Grade

Abstract Low-grade systemic inflammation is often associated with metabolic syndrome, which plays a critical role in the development of the obesity-associated inflammatory diseases, including insulin resistance and atherosclerosis. Here, we investigate how Toll-like receptor-MyD88 signaling in myeloid and endothelial cells coordinately participates in the initiation and progression of high fat diet-induced systemic inflammation and metabolic inflammatory diseases. MyD88 deficiency in myeloid cells inhibits macrophage recruitment to adipose tissue and their switch to an M1-like phenotype. This is accompanied by substantially reduced diet-induced systemic inflammation, insulin resistance, and atherosclerosis. MyD88 deficiency in endothelial cells results in a moderate reduction in diet-induced adipose macrophage infiltration and M1 polarization, selective insulin sensitivity in adipose tissue, and amelioration of spontaneous atherosclerosis. Both in vivo and ex vivo studies suggest that MyD88-dependent GM-CSF production from the endothelial cells might play a critical role in the initiation of obesity-associated inflammation and development of atherosclerosis by priming the monocytes in the adipose and arterial tissues to differentiate into M1-like inflammatory macrophages. Collectively, these results implicate a critical MyD88-dependent interplay between myeloid and endothelial cells in the initiation and progression of obesity-associated inflammatory diseases. Disclosures No relevant conflicts of interest to declare.

scholarly journals MyD88-dependent interplay between myeloid and endothelial cells in the initiation and progression of obesity-associated inflammatory diseases

2014 ◽  
Vol 211 (5) ◽  
pp. 887-907 ◽  
Author(s):  
Minjia Yu ◽  
Hao Zhou ◽  
Junjie Zhao ◽  
Nengming Xiao ◽  
Sanjoy Roychowdhury ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Endothelial Cells ◽  
Adipose Tissue ◽  
Systemic Inflammation ◽  
Ex Vivo ◽  
Inflammatory Diseases ◽  
Critical Role ◽  
Low Grade ◽  
Gm Csf

Low-grade systemic inflammation is often associated with metabolic syndrome, which plays a critical role in the development of the obesity-associated inflammatory diseases, including insulin resistance and atherosclerosis. Here, we investigate how Toll-like receptor–MyD88 signaling in myeloid and endothelial cells coordinately participates in the initiation and progression of high fat diet–induced systemic inflammation and metabolic inflammatory diseases. MyD88 deficiency in myeloid cells inhibits macrophage recruitment to adipose tissue and their switch to an M1-like phenotype. This is accompanied by substantially reduced diet-induced systemic inflammation, insulin resistance, and atherosclerosis. MyD88 deficiency in endothelial cells results in a moderate reduction in diet-induced adipose macrophage infiltration and M1 polarization, selective insulin sensitivity in adipose tissue, and amelioration of spontaneous atherosclerosis. Both in vivo and ex vivo studies suggest that MyD88-dependent GM-CSF production from the endothelial cells might play a critical role in the initiation of obesity-associated inflammation and development of atherosclerosis by priming the monocytes in the adipose and arterial tissues to differentiate into M1-like inflammatory macrophages. Collectively, these results implicate a critical MyD88-dependent interplay between myeloid and endothelial cells in the initiation and progression of obesity-associated inflammatory diseases.

scholarly journals Multinucleated giant cells in adipose tissue are specialized in adipocyte degradation

2020 ◽  
Author(s):  
Ada Admin ◽  
Julia Braune ◽  
Andreas Lindhorst ◽  
Janine Fröba ◽  
Constance Hobusch ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
High Fat Diet ◽  
Ex Vivo ◽  
Giant Cells ◽  
Low Grade ◽  
Adipose Tissue Macrophages ◽  
Visceral Adipose ◽  
Low Grade Inflammation

Obesity is associated with a chronic low-grade inflammation in visceral adipose tissue (AT) characterized by an increasing number of adipose tissue macrophages (ATMs) and linked to type 2 diabetes. AT inflammation is histologically indicated by the formation of so-called crown-like structures (CLS), as accumulation of ATMs around dying adipocytes, and the occurrence of multi-nucleated giant cells (MGCs). However to date, the function of MGCs in obesity is unknown. Hence, the aim of this study was to characterize MGCs in AT and unravel the function of these cells. <p>We demonstrate that MGCs occur in obese patients and after 24 weeks of high fat diet (HFD) in mice, accompanying signs of AT inflammation and then represent ~3% of ATMs in mice. Mechanistically, we found evidence that adipocyte death triggers MGC formation. Most importantly, MGCs in obese AT have a higher capacity to phagocytose oversized particles, such as adipocytes, as shown by live-imaging of AT, 45 µm bead uptake <i>ex vivo</i> and a higher lipid content <i>in vivo</i>. Finally, we show that IL-4 treatment is sufficient to increase the number of MGCs in AT, whereas other factors maybe more important for endogenous MGC formation <i>in vivo</i>.</p>

Disruption of endothelial Pfkfb3 ameliorates diet-induced murine insulin resistance

2021 ◽  
Author(s):  
Qiuhua Yang ◽  
Jiean Xu ◽  
Qian Ma ◽  
Zhiping Liu ◽  
Yaqi Zhou ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Endothelial Cells ◽  
High Fat Diet ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Endothelial Inflammation ◽  
Glucose Clearance ◽  
Deficient Mice

Overnutrition-induced endothelial inflammation plays a crucial role in high fat diet (HFD)-induced insulin resistance in animals. Endothelial glycolysis plays a critical role in endothelial inflammation and proliferation, but its role in diet-induced endothelial inflammation and subsequent insulin resistance has not been elucidated. PFKFB3 is a critical glycolytic regulator, and its increased expression has been observed in adipose vascular endothelium of C57BL/6J mice fed with HFD in vivo, and in palmitate (PA)-treated primary human adipose microvascular endothelial cells (HAMECs) in vitro. We generated mice with Pfkfb3 deficiency selective for endothelial cells to examine the effect of endothelial Pfkfb3 in endothelial inflammation in metabolic organs and in the development of HFD-induced insulin resistance. EC Pfkfb3-deficient mice exhibited mitigated HFD-induced insulin resistance, including decreased body weight and fat mass, improved glucose clearance and insulin sensitivity, and alleviated adiposity and hepatic steatosis. Mechanistically, cultured PFKFB3 knockdown HAMECs showed decreased NF-κB activation induced by PA, and consequent suppressed adhesion molecule expression and monocyte adhesion. Taken together, these results demonstrate that increased endothelial PFKFB3 expression promotes diet-induced inflammatory responses and subsequent insulin resistance, suggesting that endothelial metabolic alteration plays an important role in the development of insulin resistance.

scholarly journals Novel Vascular Molecule Involved in Monocyte Adhesion to Aortic Endothelium in Models of Atherogenesis

1997 ◽  
Vol 185 (12) ◽  
pp. 2069-2077 ◽  
Author(s):  
Leslie M. McEvoy ◽  
Hailing Sun ◽  
Philip S. Tsao ◽  
John P. Cooke ◽  
Judith A. Berliner ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Ex Vivo ◽  
Critical Role ◽  
Constitutive Expression ◽  
Monocyte Adhesion ◽  
Aortic Endothelial Cells ◽  
Aortic Endothelium ◽  
Aortic Endothelial

Adhesion of monocytes to the endothelium in lesion-prone areas is one of the earliest events in fatty streak formation leading to atherogenesis. The molecular basis of increased monocyte adhesion is not fully characterized. We have identified a novel vascular monocyte adhesion-associated protein, VMAP-1, that plays a role in adhesion of monocytes to activated endothelium. Originally selected for its ability to block binding of a mouse monocyte-like cell line (WEHI78/24) to cytokine- or LPS-stimulated cultured mouse endothelial cells in vitro, antiVMAP-1 mAb LM151 cross-reacts with rabbit endothelium and blocks binding of human monocytes to cultured rabbit aortic endothelial cells stimulated with minimally modified low density lipoprotein, thought to be a physiologically relevant atherogenic stimulus. Most importantly, LM151 prevents adhesion of normal monocytes and monocytoid cells to intact aortic endothelium from cholesterol-fed rabbits in an ex vivo assay. VMAP-1 is a 50-kD protein. Immunohistology of vessels reveals focal constitutive expression in aorta and other large vessels. VMAP-1 is thus a novel vascular adhesion-associated protein that appears to play a critical role in monocyte adhesion to aortic endothelial cells in atherogenesis in vivo.

scholarly journals CD40 deficiency in mice exacerbates obesity-induced adipose tissue inflammation, hepatic steatosis, and insulin resistance

2013 ◽  
Vol 304 (9) ◽  
pp. E951-E963 ◽  
Author(s):  
Chang-An Guo ◽  
Sophia Kogan ◽  
Shinya U. Amano ◽  
Mengxi Wang ◽  
Sezin Dagdeviren ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Hepatic Steatosis ◽  
Immune Cell ◽  
Ex Vivo ◽  
Liver Steatosis ◽  
Epididymal Adipose Tissue ◽  
Low Grade ◽  
Wild Type ◽  
Cytokine Levels

The pathophysiology of obesity and type 2 diabetes in rodents and humans is characterized by low-grade inflammation in adipose tissue and liver. The CD40 receptor and its ligand CD40L initiate immune cell signaling promoting inflammation, but conflicting data on CD40L-null mice confound its role in obesity-associated insulin resistance. Here, we demonstrate that CD40 receptor-deficient mice on a high-fat diet display the expected decrease in hepatic cytokine levels but paradoxically exhibit liver steatosis, insulin resistance, and glucose intolerance compared with their age-matched wild-type controls. Hyperinsulinemic-euglycemic clamp studies also demonstrated insulin resistance in glucose utilization by the CD40-null mice compared with wild-type mice. In contrast to liver, adipose tissue in CD40-deficient animals harbors elevated cytokine levels and infiltration of inflammatory cells, particularly macrophages and CD8+effector T cells. In addition, ex vivo explants of epididymal adipose tissue from CD40−/−mice display elevated basal and isoproterenol-stimulated lipolysis, suggesting a potential increase of lipid efflux from visceral fat to the liver. These findings reveal that 1) CD40-null mice represent an unusual model of hepatic steatosis with reduced hepatic inflammation, and 2) CD40 unexpectedly functions in adipose tissue to attenuate its inflammation in obesity, thereby protecting against hepatic steatosis.

scholarly journals Mitochondrial Dysfunction, Insulin Resistance, and Potential Genetic Implications

Endocrinology ◽  
2020 ◽  
Vol 161 (4) ◽  
Author(s):  
Panjamaporn Sangwung ◽  
Kitt Falk Petersen ◽  
Gerald I Shulman ◽  
Joshua W Knowles
Keyword(s):  
Insulin Resistance ◽  
Mitochondrial Function ◽  
Ex Vivo ◽  
Critical Role ◽  
Whole Body ◽  
Genetic Studies ◽  
Cellular Energy

Abstract Insulin resistance (IR) is fundamental to the development of type 2 diabetes (T2D) and is present in most prediabetic (preDM) individuals. Insulin resistance has both heritable and environmental determinants centered on energy storage and metabolism. Recent insights from human genetic studies, coupled with comprehensive in vivo and ex vivo metabolic studies in humans and rodents, have highlighted the critical role of reduced mitochondrial function as a predisposing condition for ectopic lipid deposition and IR. These studies support the hypothesis that reduced mitochondrial function, particularly in insulin-responsive tissues such as skeletal muscle, white adipose tissue, and the liver, is inextricably linked to tissue and whole body IR through the effects on cellular energy balance. Here we discuss these findings as well as address potential mechanisms that serve as the nexus between mitochondrial malfunction and IR.

scholarly journals Bone marrow adipocytes drive the development of tissue invasive Ly6Chigh monocytes during obesity

2020 ◽  
Author(s):  
Parastoo Boroumand ◽  
David Prescott ◽  
Michael Wong ◽  
Jeff Shen ◽  
Ivan Tattoli ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Adipose Tissue ◽  
Ex Vivo ◽  
Mitochondrial Fission ◽  
Metabolic Reprogramming ◽  
Low Grade ◽  
Oxidative Potential ◽  
Tissue Macrophage ◽  
White Adipocytes

SummaryDuring obesity and high fat-diet (HFD) feeding in mice, sustained low-grade inflammation includes not only increased pro-inflammatory macrophages in the expanding adipose tissue, but also bone marrow (BM) production of invasive Ly6Chigh monocytes. As BM adiposity also accrues with HFD, we explored the relationship between the gains in BM white adipocytes and invasive Ly6Chigh monocytes in vivo and through ex vivo paradigms. We find a temporal and causal link between BM adipocyte whitening and the Ly6Chigh monocyte surge, preceding the adipose tissue macrophage rise during HFD. Phenocopying this, ex vivo treatment of BM cells with conditioned media from BM adipocytes or from bona fide white adipocytes favoured Ly6Chigh monocyte preponderance. Notably, Ly6Chigh skewing was preceded by monocyte metabolic reprogramming towards glycolysis, reduced oxidative potential and increased mitochondrial fission. In sum, short-term HFD changes BM cellularity, resulting in local adipocyte whitening driving a gradual increase and activation of invasive Ly6Chigh monocytes.

scholarly journals Local and Systemic Impact of Transcriptional Up-Regulation of 11β-Hydroxysteroid Dehydrogenase Type 1 in Adipose Tissue in Human Obesity

2003 ◽  
Vol 88 (8) ◽  
pp. 3983-3988 ◽  
Author(s):  
Deborah J. Wake ◽  
Eva Rask ◽  
Dawn E. W. Livingstone ◽  
Stefan Söderberg ◽  
Tommy Olsson ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Ex Vivo ◽  
Hydroxysteroid Dehydrogenase ◽  
Mrna Levels ◽  
Urinary Cortisol ◽  
Cortisol Metabolism ◽  
The Impact

In idiopathic obesity circulating cortisol levels are not elevated, but high intraadipose cortisol concentrations have been implicated. 11β-Hydroxysteroid dehydrogenase type 1 (11HSD1) catalyzes the conversion of inactive cortisone to active cortisol, thus amplifying glucocorticoid receptor (GR) activation. In cohorts of men and women, we have shown increased ex vivo 11HSD1 activity in sc adipose tissue associated with in vivo obesity and insulin resistance. Using these biopsies, we have now validated this observation by measuring 11HSD1 and GR mRNA and examined the impact on intraadipose cortisol concentrations, putative glucocorticoid regulated adipose target gene expression (angiotensinogen and leptin), and systemic measurements of cortisol metabolism. From aliquots of sc adipose biopsies from 16 men and 16 women we extracted RNA for real-time PCR and steroids for immunoassays. Adipose 11HSD1 mRNA was closely related to 11HSD1 activity [standardized β coefficient (SBC) = 0.58; P &lt; 0.01], and both were positively correlated with parameters of obesity (e.g. for BMI, SBC = 0.48; P &lt; 0.05 for activity, and SBC = 0.63; P &lt; 0.01 for mRNA) and insulin sensitivity (log fasting plasma insulin; SBC = 0.44; P &lt; 0.05 for activity, and SBC = 0.33; P = 0.09 for mRNA), but neither correlated with urinary cortisol/cortisone metabolite ratios. Adipose GR-α and angiotensinogen mRNA levels were not associated with obesity or insulin resistance, but leptin mRNA was positively related to 11HSD1 activity (SBC = 0.59; P &lt; 0.05) and tended to be associated with parameters of obesity (BMI: SBC = 0.40; P = 0.09), fasting insulin (SBC = 0.65; P &lt; 0.05), and 11HSD1 mRNA (SBC = 0.40; P = 0.15). Intraadipose cortisol (142 ± 30 nmol/kg) was not related to 11HSD1 activity or expression, but was positively correlated with plasma cortisol. These data confirm that idiopathic obesity is associated with transcriptional up-regulation of 11HSD1 in adipose, which is not detected by conventional in vivo measurements of urinary cortisol metabolites and is not accompanied by dysregulation of GR. Although this may drive a compensatory increase in leptin synthesis, whether it has an adverse effect on intraadipose cortisol concentrations and GR-dependent gene regulation remains to be established.

scholarly journals Adipokines as Drug Targets in Diabetes and Underlying Disturbances

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Vinícius Andrade-Oliveira ◽  
Niels O.S. Câmara ◽  
Pedro M. Moraes-Vieira
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Drug Targets ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Low Grade ◽  
Adipose Tissue Inflammation ◽  
Tissue Inflammation ◽  
Therapeutic Implications ◽  
Insulin Resistant

Diabetes and obesity are worldwide health problems. White fat dynamically participates in hormonal and inflammatory regulation. White adipose tissue is recognized as a multifactorial organ that secretes several adipose-derived factors that have been collectively termed “adipokines.” Adipokines are pleiotropic molecules that gather factors such as leptin, adiponectin, visfatin, apelin, vaspin, hepcidin, RBP4, and inflammatory cytokines, including TNF and IL-1β, among others. Multiple roles in metabolic and inflammatory responses have been assigned to these molecules. Several adipokines contribute to the self-styled “low-grade inflammatory state” of obese and insulin-resistant subjects, inducing the accumulation of metabolic anomalies within these individuals, including autoimmune and inflammatory diseases. Thus, adipokines are an interesting drug target to treat autoimmune diseases, obesity, insulin resistance, and adipose tissue inflammation. The aim of this review is to present an overview of the roles of adipokines in different immune and nonimmune cells, which will contribute to diabetes as well as to adipose tissue inflammation and insulin resistance development. We describe how adipokines regulate inflammation in these diseases and their therapeutic implications. We also survey current attempts to exploit adipokines for clinical applications, which hold potential as novel approaches to drug development in several immune-mediated diseases.

scholarly journals Androgen Effects on Adipose Tissue Architecture and Function in Nonhuman Primates

Endocrinology ◽  
2012 ◽  
Vol 153 (7) ◽  
pp. 3100-3110 ◽  
Author(s):  
Oleg Varlamov ◽  
Ashley E. White ◽  
Julie M. Carroll ◽  
Cynthia L. Bethea ◽  
Arubala Reddy ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Nonhuman Primates ◽  
Ex Vivo ◽  
Hormone Replacement ◽  
Fatty Acid Uptake ◽  
Acid Uptake ◽  
Specific Effects ◽  
Androgen Effects

The differential association of hypoandrogenism in men and hyperandrogenism in women with insulin resistance and obesity suggests that androgens may exert sex-specific effects on adipose and other tissues, although the underlying mechanisms remain poorly understood. Moreover, recent studies also suggest that rodents and humans may respond differently to androgen imbalance. To achieve better insight into clinically relevant sex-specific mechanisms of androgen action, we used nonhuman primates to investigate the direct effects of gonadectomy and hormone replacement on white adipose tissue. We also employed a novel ex vivo approach that provides a convenient framework for understanding of adipose tissue physiology under a controlled tissue culture environment. In vivo androgen deprivation of males did not result in overt obesity or insulin resistance but did induce the appearance of very small, multilocular white adipocytes. Testosterone replacement restored normal cell size and a unilocular phenotype and stimulated adipogenic gene transcription and improved insulin sensitivity of male adipose tissue. Ex vivo studies demonstrated sex-specific effects of androgens on adipocyte function. Female adipose tissue treated with androgens displayed elevated basal but reduced insulin-dependent fatty acid uptake. Androgen-stimulated basal uptake was greater in adipose tissue of ovariectomized females than in adipose tissue of intact females and ovariectomized females replaced with estrogen and progesterone in vivo. Collectively, these data demonstrate that androgens are essential for normal adipogenesis in males and can impair essential adipocyte functions in females, thus strengthening the experimental basis for sex-specific effects of androgens in adipose tissue.

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