scholarly journals Tumor Necrosis Factor-α-Mediated Suppression of Adipocyte Apolipoprotein E Gene Transcription: Primary Role for the Nuclear Factor (NF)-κB Pathway and NFκB p50

Endocrinology ◽  
2008 ◽  
Vol 149 (8) ◽  
pp. 4051-4058 ◽  
Author(s):  
Lili Yue ◽  
John W. Christman ◽  
Theodore Mazzone
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Apolipoprotein E ◽  
Apoe Gene ◽  
Site Directed Mutagenesis ◽  
Primary Role ◽  
Nuclear Factor ◽  
Adipose Tissue Inflammation ◽  
Tissue Inflammation ◽  
Apoe Gene Expression

The adipose tissue inflammation accompanying obesity has important consequences for adipocyte lipid metabolism, and increased adipose tissue TNFα plays an important role for mediating the effect of inflammation on adipocyte function. Recent studies have shown that apolipoprotein E (apoE) is highly expressed in adipose tissue where it plays an important role in modulating adipocyte triglyceride metabolism, triglyceride mass, and adipocyte size. We have previously reported that TNFα reduces adipocyte apoE, and the current studies were undertaken to evaluate the molecular mechanism for this regulation. TNFα repression of adipocyte apoE gene expression required an intact nuclear factor (NF)-κB binding site at −43 in the apoE promoter. Site-directed mutagenesis at this site completely eliminated TNFα regulation of an apoE gene reporter. TNFα treatment activated binding of NFκB p50, isolated from adipocyte nuclei, to the apoE promoter. Two structurally distinct inhibitors of NFκB complex activation or translocation abrogated the TNFα effect on the apoE gene. Using chromatin immunoprecipitation assays, we demonstrated that treatment of adipocytes with TNFα led to increased binding of NFκB p50, and decreased binding of p65 and Sp1, to this region of the apoE promoter in living cells. The key role played by increased p50 binding was confirmed by p50 knockdown experiments. Reduction of p50 expression using small interference RNA completely eliminated TNFα-mediated reduction of endogenous adipocyte apoE gene expression. These results establish the molecular link between adipose tissue inflammation and apoE gene expression in adipocytes. The suppression of adipocyte apoE by the proinflammatory adipose tissue milieu associated with obesity will have important downstream effects on adipocyte triglyceride turnover and content.

scholarly journals Tart Cherry Reduces Inflammation in Adipose Tissue of Zucker Fatty Rats and Cultured 3T3-L1 Adipocytes

Nutrients ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 1576 ◽  
Author(s):  
Shasika Jayarathne ◽  
April Stull ◽  
Alexandra Miranda ◽  
Shane Scoggin ◽  
Kate Claycombe-Larson ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Fatty Acid Synthase ◽  
Related Factor ◽  
Mrna Levels ◽  
Nuclear Factor ◽  
Adipose Tissue Inflammation ◽  
Tart Cherry ◽  
Tissue Inflammation ◽  
Anti Inflammatory

Obesity increases adipose tissue inflammation and secretion of pro-inflammatory adipokines, which have systemic effects on the organism’s health status. Our objective was to dissect mechanisms of anti-inflammatory effects of tart cherry (TC) in adipose tissue of Zucker fatty rats, and cultured 3T3-L1 adipocytes. Rats were fed either a control diet, or 4% TC powder diets for eight weeks. Body and epididymal fat pad weights were not significantly different between control and TC groups. However, rats fed the TC diet had significantly reduced adipose tissue inflammation (p < 0.05), as determined by reduced mRNA levels of pro-inflammatory markers including interleukin-6 (IL-6), tumor necrosis factor alpha (TNFα), interleukin-1beta (IL-1β), monocyte chemoattractant protein 1 (MCP-1), inducible nitric oxide synthase (iNOS), and CD-11b, and increased mRNA levels of type-1 arginase (Arg-1) anti-inflammatory marker. Consistent with these in vivo results, TC significantly decreased expression of IL-6 mRNA and protein levels in lipopolysaccharide (LPS) stimulated adipocytes compared to those stimulated with LPS, but no TC. Moreover, both in vivo (rat adipose tissue) and in vitro (3T3-L1 adipocytes), phosphorylation of p65-NF-κB subunit was significantly reduced by TC. Additionally, TC decreased mRNA expression of fatty acid synthase (FASN), and increased expression of peroxisome proliferator-activated receptor alpha (PPARα), master regulator of lipid oxidation, and anti-oxidant markers nuclear factor erythroid-derived 2-related factor (NRFs) in both models. In conclusion, our findings indicate that TC downregulates inflammation in part via the nuclear factor kappa B (NF-κB) pathway in adipose tissue. Thus, TC may serve as a potential intervention to reduce obesity-associated inflammation.

Nutrient-Adjusted High-Fat Diet is Associated with Absence of Periepididymal Adipose Tissue Inflammation: Is there a Link with Adequate Micronutrient Levels?

2013 ◽  
Vol 83 (5) ◽  
pp. 299-310 ◽  
Author(s):  
Monica Yamada ◽  
Marina Maintinguer Norde ◽  
Maria C. Borges ◽  
Tatiane Mieko de Meneses Fujii ◽  
Patrícia Silva Jacob ◽  
...  
Keyword(s):  
Gene Expression ◽  
Body Weight ◽  
Adipose Tissue ◽  
High Fat Diet ◽  
Adipose Tissue Inflammation ◽  
C Reactive Protein ◽  
High Fat ◽  
Tissue Inflammation ◽  
Reactive Protein ◽  
Tnf Α

The aim of this study was to investigate the real impact of dietary lipids on metabolic and inflammatory response in rat white adipose tissue. Male healthy Wistar rats were fed ad libitum with a control diet (CON, n=12) or with an adjusted high-fat diet (HFD, n=12) for 12 weeks. Oral glucose and insulin tolerance tests were performed during the last week of the protocol. Plasma fatty acid, lipid profile, body adiposity, and carcass chemical composition were analyzed. Plasma concentration of leptin, adiponectin, C-reactive protein (CRP), TNF-α, IL-6, and monocyte chemotactic protein (MCP-1) was measured. Periepididymal adipose tissue was employed to evaluate TNF-α, MCP-1, and adiponectin gene expression as well as NF-κB pathway and AKT proteins. Isocaloric intake of the adjusted HFD did not induce hyperphagia, but promoted an increase in periepididymal (HFD = 2.94 ± 0.77 vs. CON = 1.99 ± 0.26 g/100 g body weight, p = 0.01) and retroperitoneal adiposity (HFD = 3.11 ± 0.81 vs. CON = 2.08 ± 0.39 g/100 g body weight, p = 0.01) and total body lipid content (HFD = 105.3 ± 20.8 vs. CON = 80.5 ± 7.6 g carcass, p = 0.03). Compared with control rats, HFD rats developed glucose intolerance (p=0.01), dyslipidemia (p = 0.02) and exhibited higher C-reactive protein levels in response to the HFD (HFD = 1002 ± 168 vs. CON = 611 ± 260 ng/mL, p = 0.01). The adjusted HFD did not affect adipokine gene expression or proteins involved in inflammatory signaling, but decreased AKT phosphorylation after insulin stimulation in periepididymal adipose tissue (p = 0.01). In this study, nutrient-adjusted HFD did not induce periepididymal adipose tissue inflammation in rats, suggesting that the composition of HFD differently modulates inflammation in rats, and adequate micronutrient levels may also influence inflammatory pathways.

Inflammation, but not recruitment, of adipose tissue macrophages requires signalling through Mac-1 (CD11b/CD18) in diet-induced obesity (DIO)

2017 ◽  
Vol 117 (02) ◽  
pp. 325-338 ◽  
Author(s):  
Dennis Wolf ◽  
Nora Bukosza ◽  
David Engel ◽  
Marjorie Poggi ◽  
Felix Jehle ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Adipose Tissue Inflammation ◽  
Inflammatory Gene Expression ◽  
Tissue Inflammation ◽  
Inflammatory Gene ◽  
Diet Induced Obesity ◽  
Adipose Tissue Macrophages ◽  
Cell Accumulation

SummaryCell accumulation is a prerequisite for adipose tissue inflammation. The leukocyte integrin Mac-1 (CD11b/CD18, αMβ2) is a classic adhesion receptor critically regulating inflammatory cell recruitment. Here, we tested the hypothesis that a genetic deficiency and a therapeutic modulation of Mac-1 regulate adipose tissue inflammation in a mouse model of diet-induced obesity (DIO). C57Bl6/J mice genetically deficient (Mac-1-/-) or competent for Mac-1 (WT) consumed a high fat diet for 20 weeks. Surprisingly, Mac-1-/- mice presented with increased diet-induced weight gain, decreased insulin sensitivity in skeletal muscle and in the liver in insulin-clamps, insulin secretion deficiency and elevated glucose levels in fasting animals, and dyslipidaemia. Unexpectedly, accumulation of adipose tissue macrophages (ATMs) was unaffected, while gene expression indicated less inflamed adipose tissue and macrophages in Mac-1-/- mice. In contrast, inflammatory gene expression at distant locations, such as in skeletal muscle, was not changed. Treatment of ATMs with an agonistic anti-Mac-1 antibody, M1/70, induced pro-inflammatory genes in cell culture. In vivo, treatment with M1/70 induced a hyper-inflammatory phenotype with increased expression of IL-6 and MCP-1, whereas accumulation of ATMs did not change. Finally, inhibition of Mac-1’s adhesive interaction to CD40L by the peptide inhibitor cM7 did not affect myeloid cell accumulation in adipose tissue. We present the surprising finding that adhesive properties of the leukocyte integrin Mac-1 are not required for macrophage accumulation in adipose tissue. Instead, Mac-1 modulates inflammatory gene expression in macrophages. These findings question the net effect of integrin blockade in cardio-metabolic disease.D. W., N. B., and D. E. equally contributed to this work.K. P., E. L., and A. Z. share senior authorship.Note: The review process for this manuscript was fully handled by Gregory Y. H. Lip, Editor in Chief.Supplementary Material to this article is available online at www.thrombosis-online.com.

scholarly journals Visceral Adipose Tissue Inflammation Accelerates Atherosclerosis in Apolipoprotein E–Deficient Mice

Circulation ◽  
2008 ◽  
Vol 117 (6) ◽  
pp. 798-805 ◽  
Author(s):  
Miina K. Öhman ◽  
Yuechun Shen ◽  
Chinyere I. Obimba ◽  
Andrew P. Wright ◽  
Mark Warnock ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Apolipoprotein E ◽  
Visceral Adipose Tissue ◽  
Adipose Tissue Inflammation ◽  
Tissue Inflammation ◽  
Visceral Adipose ◽  
Deficient Mice

Increased GIP signaling induces adipose inflammation via a HIF-1α-dependent pathway and impairs insulin sensitivity in mice

2015 ◽  
Vol 308 (5) ◽  
pp. E414-E425 ◽  
Author(s):  
Shu Chen ◽  
Fumiaki Okahara ◽  
Noriko Osaki ◽  
Akira Shimotoyodome
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Adipose Tissue Inflammation ◽  
Obese Mice ◽  
Plasminogen Activator Inhibitor 1 ◽  
Tissue Inflammation ◽  
Obesity And Diabetes ◽  
Gut Hormone

Glucose-dependent insulinotropic polypeptide (GIP) is a gut hormone secreted in response to dietary fat and glucose. The blood GIP level is elevated in obesity and diabetes. GIP stimulates proinflammatory gene expression and impairs insulin sensitivity in cultured adipocytes. In obesity, hypoxia within adipose tissue can induce inflammation. The aims of this study were 1) to examine the proinflammatory effect of increased GIP signaling in adipose tissues in vivo and 2) to clarify the association between GIP and hypoxic signaling in adipose tissue inflammation. We administered GIP intraperitoneally to misty (lean) and db/db (obese) mice and examined adipose tissue inflammation and insulin sensitivity. We also examined the effects of GIP and hypoxia on expression of the GIP receptor (GIPR) gene and proinflammatory genes in 3T3-L1 adipocytes. GIP administration increased monocyte chemoattractant protein-1 (MCP-1) expression and macrophage infiltration into adipose tissue and increased blood glucose in db/db mice. GIPR and hypoxia-inducible factor-1α (HIF-1α) expressions were positively correlated in the adipose tissue in mice. GIPR expression increased dramatically in differentiated adipocytes. GIP treatment of adipocytes increased MCP-1 and interleukin-6 (IL-6) production. Adipocytes cultured either with RAW 264 macrophages or under hypoxia expressed more GIPR and HIF-1α, and GIP treatment increased gene expression of plasminogen activator inhibitor 1 and IL-6. HIF-1α gene silencing diminished both macrophage- and hypoxia-induced GIPR expression and GIP-induced IL-6 expression in adipocytes. Thus, increased GIP signaling plays a significant role in adipose tissue inflammation and thereby insulin resistance in obese mice, and HIF-1α may contribute to this process.

scholarly journals Inhibition of CXCR2 by Glucocorticoids in Adipose Tissue

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A51-A51
Author(s):  
Shripa Amatya ◽  
Hemangini Dhaibar ◽  
Maria Grazia Petrillo ◽  
John A Cidlowski ◽  
Diana Cruz Topete
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Inflammatory Response ◽  
Immune Cell ◽  
Significant Risk ◽  
Significant Risk Factor ◽  
The United States ◽  
Adipose Tissue Inflammation ◽  
Tissue Inflammation

Abstract Obesity-induced chronic adipose tissue inflammation is a significant risk factor for metabolic and cardiovascular disease (CVD), which affects 30.3 million adults in the United States. Interaction of adipocytes with hormonal, metabolic and immune systems play an integral role in the underlying pathophysiological mechanisms that leads to development of obesity-related complications. Despite this association, the mechanisms that coordinate the inflammatory mediators in causing adipose tissue inflammation are not well understood. Glucocorticoids (GC) are well known for their potent anti-inflammatory actions; however, the mechanism by which GC coordinate the inflammatory response of adipocytes are unknown. From our genome-wide microarray data derived from adipocyte-specific glucocorticoid receptor (GR) knockout (AdipoGRKO) mice, we found that GR inactivation leads to a significant increase in pro-inflammatory gene in white adipose tissue (WAT). Additionally, WAT isolated from AdipoGRKO mice showed significant increase in immune cell infiltration, which correlates with our gene expression data. Among the top up-regulated genes, we found the C-X-C Motif Chemokine Receptor 2 (Cxcr2), which is a powerful mediator of chemotaxis to the sites of inflammation. Although studies have shown the presence of Cxcr2 in adipocytes and suggested the contribution of Cxcr2 signaling in adipocyte development, its role in integrating adipose tissue inflammatory response is unknown. This led us to hypothesize that GR is critical to repress Cxcr2 gene expression and its pro inflammatory effects in adipocytes. Our in vitro studies using 3T3-L1 cells derived adipocytes showed that treatment with the synthetic glucocorticoid, Dexamethasone (Dex) led to a significant repression of Cxcr2 mRNA and protein levels. Furthermore, these effects are mediated by GR acting directly to repress Cxcr2 gene expression. Systemic administration of corticosterone significantly altered Cxcr2 expression in adipose tissue compared to untreated mice further supporting our results. Together our findings suggest that administration of glucocorticoids could inhibit adipose tissue inflammation and alleviate the comorbidities that arise from inflamed adipose tissue.

scholarly journals Autophagy Activity Is Up-Regulated in Adipose Tissue of Obese Individuals and Modulates Proinflammatory Cytokine Expression

Endocrinology ◽  
2012 ◽  
Vol 153 (12) ◽  
pp. 5866-5874 ◽  
Author(s):  
H. J. Jansen ◽  
P. van Essen ◽  
T. Koenen ◽  
L. A. B. Joosten ◽  
M. G. Netea ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Proinflammatory Cytokine ◽  
Adipose Tissue Inflammation ◽  
Inflammatory Gene Expression ◽  
Tissue Inflammation ◽  
Inflammatory Gene ◽  
Tissue Explants ◽  
Autophagy Activity ◽  
Human And Mouse

Abstract Autophagy, an evolutionary conserved process aimed at recycling damaged organelles and protein aggregates in the cell, also modulates proinflammatory cytokine production in peripheral blood mononuclear cells. Because adipose tissue inflammation accompanied by elevated levels of proinflammatory cytokines is characteristic for the development of obesity, we hypothesized that modulation of autophagy alters adipose tissue inflammatory gene expression and secretion. We tested our hypothesis using ex vivo and in vivo studies of human and mouse adipose tissue. Levels of the autophagy marker LC3 were elevated in sc adipose tissue of obese vs. lean human subjects and positively correlated to both systemic insulin resistance and morphological characteristics of adipose tissue inflammation. Similarly, autophagic activity levels were increased in adipose tissue of obese and insulin resistant animals as compared with lean mice. Inhibition of autophagy by 3-methylalanine in human and mouse adipose tissue explants led to a significant increase in IL-1β, IL-6, and IL-8 mRNA expression and protein secretion. Noticeably, the enhancement in IL-1β, IL-6, and keratinocyte-derived chemoattractant (KC) by inhibition of autophagy was more robust in the presence of obesity. Similar results were obtained by blocking autophagy using small interfering RNA targeted to ATG7 in human Simpson-Golabi-Behmel syndrome adipocytes. Our results demonstrate that autophagy activity is up-regulated in the adipose tissue of obese individuals and inhibition of autophagy enhances proinflammatory gene expression both in adipocytes and adipose tissue explants. Autophagy may function to dampen inflammatory gene expression and thereby limit excessive inflammation in adipose tissue during obesity.

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