Pioglitazone reduces inflammatory responses of human adipocytes to factors secreted by monocytes/macrophages

2009 ◽  
Vol 296 (5) ◽  
pp. E1076-E1084 ◽  
Author(s):  
Paska A. Permana ◽  
Weiyang Zhang ◽  
Martin Wabitsch ◽  
Pamela Fischer-Posovszky ◽  
William C. Duckworth ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Inflammatory Responses ◽  
Cell Types ◽  
Beneficial Effects ◽  
Proinflammatory Responses ◽  
Glucose Tolerant ◽  
Visceral Adipose ◽  
Adipose Tissue Cells ◽  
In Vitro Data

Infiltration of monocyte-derived macrophages into adipose tissue may contribute to tissue and systemic inflammation and insulin resistance. We hypothesized that pioglitazone (Pio) could specifically reduce the inflammatory response of adipocytes to factors released by monocytes/macrophages. We show that macrophage factors (Mφ-factors) greatly increase expression levels of proinflammatory adipokines, chemokines, and adhesion molecules in human subcutaneous and visceral adipose tissue (SAT and VAT) as well as in adipocytes (up to several hundredfold of control). Compared with SAT, VAT showed enhanced basal and Mφ-factor-induced inflammatory responses. Mφ-factors also induced greater lipolysis in adipocytes, as assessed by concentrations of glycerol released from the cells (196 ± 13 vs. 56 ± 7 μM in control, P < 0.05). Pretreatment of adipose tissue or adipocytes with Pio reduced these responses to Mφ-factors (by 13–86%, P < 0.05) and prevented Mφ-factor suppression of adiponectin expression. Furthermore, Pio pretreatment of adipocytes and macrophages tended to further reduce inflammatory responses of adipocytes to Mφ-factors and monocyte adhesion to Mφ-factor-activated adipocytes. In support of these in vitro data, media conditioned by monocytes isolated from impaired glucose-tolerant subjects treated with Pio (compared with placebo) induced release of lower concentrations of proinflammatory adipokines and glycerol (100 ± 7 vs. 150 ± 15 μM, P < 0.05) from adipocytes. In summary, Pio decreases inflammatory responses in adipose tissue/cells induced by monocytes/macrophages by acting on either or both cell types. These beneficial effects of Pio may attenuate proinflammatory responses resulting from monocyte/macrophage infiltration into adipose tissue and suppress tissue inflammation resulting from the interaction between both cell types.

scholarly journals Histone Carbonylation Is a Redox-Regulated Epigenomic Mark That Accumulates with Obesity and Aging

Antioxidants ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 1210
Author(s):  
Amy K. Hauck ◽  
Tong Zhou ◽  
Ambuj Upadhyay ◽  
Yuxiang Sun ◽  
Michael B. O’Connor ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Metabolic Disease ◽  
Adipose Tissue ◽  
Fat Depots ◽  
Michael Adducts ◽  
Lipid Aldehydes ◽  
Visceral Adipose ◽  
Fat Feeding

Oxidative stress is a hallmark of metabolic disease, though the mechanisms that define this link are not fully understood. Irreversible modification of proteins by reactive lipid aldehydes (protein carbonylation) is a major consequence of oxidative stress in adipose tissue and the substrates and specificity of this modification are largely unexplored. Here we show that histones are avidly modified by 4-hydroxynonenal (4-HNE) in vitro and in vivo. Carbonylation of histones by 4-HNE increased with age in male flies and visceral fat depots of mice and was potentiated in genetic (ob/ob) and high-fat feeding models of obesity. Proteomic evaluation of in vitro 4-HNE- modified histones led to the identification of both Michael and Schiff base adducts. In contrast, mapping of sites in vivo from obese mice exclusively revealed Michael adducts. In total, we identified 11 sites of 4-hydroxy hexenal (4-HHE) and 10 sites of 4-HNE histone modification in visceral adipose tissue. In summary, these results characterize adipose histone carbonylation as a redox-linked epigenomic mark associated with metabolic disease and aging.

scholarly journals Divergent functions of endotrophin on different cell populations in adipose tissue

2016 ◽  
Vol 311 (6) ◽  
pp. E952-E963 ◽  
Author(s):  
Yueshui Zhao ◽  
Xue Gu ◽  
Ningyan Zhang ◽  
Mikhail G. Kolonin ◽  
Zhiqiang An ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Lipid Accumulation ◽  
Lysyl Oxidase ◽  
Stromal Vascular Fraction ◽  
Cell Types ◽  
Marker Genes ◽  
New Perspective ◽  
Collagen Genes ◽  
Different Cell Types

Endotrophin is a cleavage product of collagen 6 (Col6) in adipose tissue (AT). Previously, we demonstrated that endotrophin serves as a costimulator to trigger fibrosis and inflammation within the unhealthy AT milieu. However, how endotrophin affects lipid storage and breakdown in AT and how different cell types in AT respond to endotrophin stimulation remain unknown. In the current study, by using a doxycycline-inducible mouse model, we observed significant upregulation of adipogenic genes in the white AT (WAT) of endotrophin transgenic mice. We further showed that the mice exhibited inhibited lipolysis and accelerated hypertrophy and hyperplasia in WAT. To investigate the effects of endotrophin in vitro, we incubated different cell types from AT with conditioned medium from endotrophin-overexpressing 293T cells. We found that endotrophin activated multiple pathological pathways in different cell types. Particularly in 3T3-L1 adipocytes, endotrophin triggered a fibrotic program by upregulating collagen genes and promoted abnormal lipid accumulation by downregulating hormone-sensitive lipolysis gene and decreasing HSL phosphorylation levels. In macrophages isolated from WAT, endotrophin stimulated higher expression of the collagen-linking enzyme lysyl oxidase and M1 proinflammatory marker genes. In the stromal vascular fraction isolated from WAT, endotrophin induced upregulation of both profibrotic and proinflammatory genes. In conclusion, our study provides a new perspective on the effect of endotrophin in abnormal lipid accumulation and a mechanistic insight into the roles played by adipocytes and a variety of other cell types in AT in shaping the unhealthy microenvironment upon endotrophin treatment.

scholarly journals Current Status of Human Adipose–Derived Stem Cells: Differentiation into Hepatocyte-Like Cells

2011 ◽  
Vol 11 ◽  
pp. 1568-1581 ◽  
Author(s):  
Feras Al Battah ◽  
Joery De Kock ◽  
Tamara Vanhaecke ◽  
Vera Rogiers
Keyword(s):  
Stem Cells ◽  
Adipose Tissue ◽  
Therapeutic Potential ◽  
Tissue Injury ◽  
Study Drug ◽  
Current Status ◽  
Human Organ ◽  
Beneficial Effects ◽  
Stems Cells

The shortage of human organ donors and the low cell quality of available liver tissues represent major obstacles for the clinical application of orthotropic liver transplantation and hepatocyte transplantation, respectively. Therefore, worldwide research groups are investigating alternative extrahepatic cell sources. Recentin vitrostudies have demonstrated that mesenchymal stem cells (MSCs) from various sources, including human bone marrow, adipose tissue, and umbilical cord, can be differentiated into hepatocyte-like cells when appropriate conditions are used. In particular, interest exists for human adipose–derived stems cells (hASCs) as an attractive cell source for generating hepatocyte-like cells. The hASCs are multipotent MSCs that reside in adipose tissue, with the ability to self-renew and differentiate into multiple cell lineages. Moreover, these cells can secrete multiple growth factors and cytokines that exert beneficial effects on organ or tissue injury. In this review, we will not only present recent data regarding hASC biology, their isolation, and differentiation capability towards hepatocytes, but also the potential application of hASC-derived hepatocytes to study drug toxicity. Additionally, this review will discuss the therapeutic potential of hASCs as undifferentiated cells in liver regeneration.

scholarly journals Cardioprotective Effects of Puerarin-V on Isoproterenol-Induced Myocardial Infarction Mice Is Associated with Regulation of PPAR-Υ/NF-κB Pathway

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3322 ◽  
Author(s):  
Xuguang Li ◽  
Tianyi Yuan ◽  
Di Chen ◽  
Yucai Chen ◽  
Shuchan Sun ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Inflammatory Responses ◽  
Therapeutic Option ◽  
Crystal Form ◽  
Human Coronary Artery ◽  
Beneficial Effects ◽  
Ppar Γ ◽  
Cardioprotective Effects

Puerarin is a well-known traditional Chinese medicine which has been used for the treatment of cardiovascular diseases. Recently, a new advantageous crystal form of puerarin, puerarin-V, has been developed. However, the cardioprotective effects of puerarin-V on myocardial infarction (MI) heart failure are still unclear. In this research, we aim to evaluate the cardioprotective effects of puerarin-V on the isoproterenol (ISO)-induced MI mice and elucidate the underlying mechanisms. To induce MI in C57BL/6 mice, ISO was administered at 40 mg/kg subcutaneously every 12 h for three times in total. The mice were randomly divided into nine groups: (1) control; (2) ISO; (3) ISO + puerarin injection; (4–9) ISO + puerarin-V at different doses and timings. After treatment, cardiac function was evaluated by electrocardiogram (ECG), biochemical and histochemical analysis. In vitro inflammatory responses and apoptosis were evaluated in human coronary artery endothelial cells (HCAECs) challenged by lipopolysaccharide (LPS). LPS-induced PPAR-Υ/NF-κB and subsequently activation of cytokines were assessed by the western blot and real-time polymerase chain reaction (PCR). Administration of puerarin-V significantly inhibits the typical ST segment depression compared with that in MI mice. Further, puerarin-V treatment significantly improves ventricular wall infarction, decreases the incidence of mortality, and inhibits the levels of myocardial injury markers. Moreover, puerarin-V treatment reduces the inflammatory milieu in the heart of MI mice, thereby blocking the upregulation of proinflammatory cytokines (TNF-α, IL-1β and IL-6). The beneficial effects of puerarin-V might be associated with the normalization in gene expression of PPAR-Υ and PPAR-Υ/NF-κB /ΙκB-α/ΙΚΚα/β phosphorylation. In the in vitro experiment, treatment with puerarin-V (0.3, 1 and 3 μM) significantly reduces cell death and suppresses the inflammation cytokines expression. Likewise, puerarin-V exhibits similar mechanisms. The cardioprotective effects of puerarin-V treatment on MI mice in the pre + post-ISO group seem to be more prominent compared to those in the post-ISO group. Puerarin-V exerts cardioprotective effects against ISO-induced MI in mice, which may be related to the activation of PPAR-γ and the inhibition of NF-κB signaling in vivo and in vitro. Taken together, our research provides a new therapeutic option for the treatment of MI in clinic.

scholarly journals Protocatechuic acids protects against high glucose- induced insulin resistance in human visceral adipose tissue

2016 ◽  
Vol 62 (5) ◽  
pp. 45-46
Author(s):  
Paulina Ormazabal ◽  
Beatrice Scazzocchio ◽  
Rosaria Varì ◽  
Annunziata Iacovelli ◽  
Roberta Masella
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Visceral Adipose Tissue ◽  
High Glucose ◽  
Protective Role ◽  
Insulin Sensitizer ◽  
20 Nm ◽  
Visceral Adipose

Adipocytes exposed to high glucose concentrations exhibit impaired insulin signaling. Binding of insulin to its membrane receptor activates insulin metabolic pathway leading to IRS-1 and AKT phosphorylations. The accumulation of visceral adipose tissue (VAT) correlates with insulin resistance and metabolic syndrome. Anthocyanins (ACN) are bioactive food compounds of great nutritional interest. We have shown that protocatechuic acid (PCA), a major metabolite of ACN, might exert insulin-sensitizer activities in human visceral adipose tissue. The aim of this work was to define the protective role of PCA against insulin-resistance induced by high glucose in VAT.Methodology: VAT obtained from control subject (BMI≤25) were separated in four experimental groups: i) PCA: samples treated for 24 h with 100 μM PCA, ii) GLU: VAT treated with 30 mM glucose for 24 h, iii) PCA+GLU: 1 hour incubation with 100 μM PCA before adding glucose (30 mM, 24 h), iv) CTR: vehicle. After treatment, VAT groups were (or not) acutely stimulated with insulin (20 nM, 20 min). Tyr-IRS-1 and Ser-Akt phosphorylations were assessed by Western blotting (WB) in basal or insulin stimulated tissues in all experimental groups. Samples were assessed for IRS-1, IR, Akt and GLUT4 protein content by WB. Results: No differences in protein contents between experimental groups were found. GLU tissues showed a lower increment in insulin-stimulated phosphorylation of IRS-1 and Akt compared to CTR and PCA samples. This impaired activation was completely reversed by the pretreatment with PCA.Conclusion: An in-vitro insulin-resistance condition induced by high glucose was established in biopsies of VAT. PCA restores the ability of GLU-tissues to fully respond to insulin by increasing IRS-1 and Akt phosphorylations. These results confirm the insulin-sensitizer effect of PCA on VAT previously reported by our group. An anthocyanin rich diet might help to protect against insulin-resistance in VAT.

Abstract WP139: Intranasal Administration of Mesenchymal Stem Cell (MSC)-Derived Exosomes Confers Acute Neuroprotection After Neonatal Stroke

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Praneeti Pathipati ◽  
Joel Faustino ◽  
Matthieu Lecuyer ◽  
Jacqueline Strivelli ◽  
Donald Phinney ◽  
...  
Keyword(s):  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Intranasal Administration ◽  
Therapeutic Option ◽  
Cell Types ◽  
Artery Occlusion ◽  
Neonatal Stroke ◽  
Beneficial Effects ◽  
The Status

Background: Brain injury caused by stroke is a surprisingly common occurrence in neonates and is associated with significant long-term disabilities. We and others have shown delayed mesenchymal stem cell (MSC)-based therapy to be beneficial after neonatal stroke. Mounting evidence suggests MSC-derived soluble factors as key mediators of their neuroprotective/regenerative effects. We wanted to test whether Exosomes (Exo) derived from MSC carry beneficial effects after neonatal stroke. Objectives: Characterize effects of intranasal administration of MSC-derived Exo after neonatal stroke. Methods: MSCs enriched from the bone marrow of C57Bl6 mice (immuno-depletion) were cultured for 3 days in Exo-free FBS and confirmed by flow cytometry to be CD44 + /CD29 + and CD11b - /CD45 - . Exo were isolated (ExoQuick, SBI), their size distribution determined (NanoSight™), and Exo labeled with CellVue® before intranasal administration. Postnatal day 9 (P9) mice were subjected to a 3h middle cerebral artery occlusion (tMCAO), Exo (5ug, 1uL in PBS) administered into the nostril ipsilateral to injury, and injury volume and cell types that uptake Exo determined. Results: By 24h after administration, labelled Exo were visible ipsilateral along the lateral ventricle, in the SVZ, corpus callosum and in the penumbra, localized largely to Glut1 + -vessels and Iba1 + -microglia (MG). By 72h, labeled Exo were predominantly localized in Iba1 + -MG peri-infarct. Very few Exo were seen contralateral. Compared to vehicle/untreated mice, intranasal Exo significantly reduced injury volume at 72h (p<0.01, n=5). Preliminary in vitro experiments using MG isolated from acutely injured neonatal brain (CD11b-conjugated beads) confirmed significantly higher Exo uptake by MG from the ipsilateral Vs. contralateral cortex (p<0.05, n=2). Summary: We demonstrate that MSC-Exo exert short-term protection against neonatal stroke and that the magnitude of Exo uptake depends on the status of MG activation after injury. We are characterizing longer-term effects of MSC-Exo on stroke outcome to further explore potential for intranasal MSC-Exo as a clinically suitable therapeutic option for neonatal stroke. Funding: CPA PG0816 (ZV); AHA Innovation Award 17IRG33430004 (ZV); R01HL139685 (ZV)

Hepatobiliary Differentiation: Principles from Embryonic Liver Development

2020 ◽  
Vol 40 (04) ◽  
pp. 365-372
Author(s):  
Scott H. Freeburg ◽  
Wolfram Goessling
Keyword(s):  
Molecular Mechanisms ◽  
Alagille Syndrome ◽  
Cell Types ◽  
Extrinsic Cues ◽  
Hepatic Portal Vein ◽  
Hepatic Portal ◽  
Transcription Factor Expression ◽  
In Vitro Data

AbstractHepatocytes and biliary epithelial cells (BECs), the two endodermal cell types of the liver, originate from progenitor cells called hepatoblasts. Based principally on in vitro data, hepatoblasts are thought to be bipotent stem cells with the potential to produce both hepatocytes and BECs. However, robust in vivo evidence for this model has only recently emerged. We examine the molecular mechanisms that stimulate hepatoblast differentiation into hepatocytes or BECs. In the absence of extrinsic cues, the default fate of hepatoblasts is hepatocyte differentiation. Inductive cues from the hepatic portal vein, however, initiate transcription factor expression in hepatoblasts, driving biliary specification. Defining the mechanisms of hepatobiliary differentiation provides important insights into congenital disorders, such as Alagille syndrome, and may help to better characterize the poorly understood hepatic lineage relationships observed during regeneration from liver injury.

scholarly journals Loss of Oncostatin M Signaling in Adipocytes Induces Insulin Resistance and Adipose Tissue Inflammation in Vivo

2016 ◽  
Vol 291 (33) ◽  
pp. 17066-17076 ◽  
Author(s):  
Carrie M. Elks ◽  
Peng Zhao ◽  
Ryan W. Grant ◽  
Hardy Hang ◽  
Jennifer L. Bailey ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Cell Types ◽  
Oncostatin M ◽  
Adipose Tissue Inflammation ◽  
High Fat ◽  
Tissue Inflammation ◽  
Fat Feeding

Oncostatin M (OSM) is a multifunctional gp130 cytokine. Although OSM is produced in adipose tissue, it is not produced by adipocytes. OSM expression is significantly induced in adipose tissue from obese mice and humans. The OSM-specific receptor, OSM receptor β (OSMR), is expressed in adipocytes, but its function remains largely unknown. To better understand the effects of OSM in adipose tissue, we knocked down Osmr expression in adipocytes in vitro using siRNA. In vivo, we generated a mouse line lacking Osmr in adiponectin-expressing cells (OSMRFKO mice). The effects of OSM on gene expression were also assessed in vitro and in vivo. OSM exerts proinflammatory effects on cultured adipocytes that are partially rescued by Osmr knockdown. Osm expression is significantly increased in adipose tissue T cells of high fat-fed mice. In addition, adipocyte Osmr expression is increased following high fat feeding. OSMRFKO mice exhibit increased insulin resistance and adipose tissue inflammation and have increased lean mass, femoral length, and bone volume. Also, OSMRFKO mice exhibit increased expression of Osm, the T cell markers Cd4 and Cd8, and the macrophage markers F4/80 and Cd11c. Interestingly, the same proinflammatory genes induced by OSM in adipocytes are induced in the adipose tissue of the OSMRFKO mouse, suggesting that increased expression of proinflammatory genes in adipose tissue arises both from adipocytes and other cell types. These findings suggest that adipocyte OSMR signaling is involved in the regulation of adipose tissue homeostasis and that, in obesity, OSMR ablation may exacerbate insulin resistance by promoting adipose tissue inflammation.

scholarly journals Mannan rich fraction from yeast modulates inflammatory responses in intestinal cells (HT-29) exposed toEscherichia coli

2019 ◽  
Vol 7 ◽  
Author(s):  
Niall Browne ◽  
Aimee Traynor ◽  
Karina A. Horgan
Keyword(s):  
Inflammatory Responses ◽  
Economic Cost ◽  
Intestinal Cell ◽  
Cell Protein ◽  
Intestinal Cells ◽  
E Coli ◽  
Intestinal Cell Line ◽  
Proinflammatory Responses ◽  
Ht 29

AbstractMannan from yeast has been demonstrated to limit infection in animals susceptible to gastrointestinal infection, including pigs, poultry and cows, by blocking the mechanism by which gram-negative bacteria adhere to and invade the intestines. EnterotoxigenicEscherichia coli(ETEC) cause post weaning diarrhoea (PWD) which results in poor weight gain and potential death at great economic cost to the farmer. A mannan rich fraction (MRF) was assessedin vitrofor its impact on ETEC infection of HT-29 intestinal cell line. Gene expression markers for inflammation (TNFαandIL-1β) and TLR4 (TICAM-1andLY96) associated recognition of bacteria were significantly elevated following exposure toE. colialone, but not in combination with MRF compared to the control. HT-29 cells exposed to MRF alone demonstrated significantly reduced expression of immune signalling genesIRAK1,IRF7andJUNwhen compared to the control. HT-29 cell protein abundance for TNFα and TLR4 associated proteins were significantly increased in response toE. coliexposure alone while no significant change was observed for MRF treatment withE. coliinfection.E. coliadhesion to HT-29 cells was significantly decreased with addition of MRF compared toE. coliinfection alone. The action of MRF demonstrated its potential capacity to limit infection on anin vitrolevel through blocking bacterial interaction with the intestines that leads to infection as marked by a reduction in proinflammatory responses. MRF on its own demonstrated potential anti-inflammatory effects on intestinal cells with the reduction of proinflammatory responses observed.

scholarly journals A Representative GIIA Phospholipase A2 Activates Preadipocytes to Produce Inflammatory Mediators Implicated in Obesity Development

Biomolecules ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1593
Author(s):  
Elbio Leiguez ◽  
Priscila Motta ◽  
Rodrigo Maia Marques ◽  
Bruno Lomonte ◽  
Suely Vilela Sampaio ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Phospholipase A2 ◽  
Proinflammatory Mediators ◽  
Ep4 Receptor ◽  
Prostaglandin Synthase ◽  
Proinflammatory Responses ◽  
Cox 2 ◽  
Ep3 Receptor ◽  
Cytosolic Pla2 ◽  
Adipose Tissue Cells

Adipose tissue secretes proinflammatory mediators which promote systemic and adipose tissue inflammation seen in obesity. Group IIA (GIIA)-secreted phospholipase A2 (sPLA2) enzymes are found to be elevated in plasma and adipose tissue from obese patients and are active during inflammation, generating proinflammatory mediators, including prostaglandin E2 (PGE2). PGE2 exerts anti-lipolytic actions and increases triacylglycerol levels in adipose tissue. However, the inflammatory actions of GIIA sPLA2s in adipose tissue cells and mechanisms leading to increased PGE2 levels in these cells are unclear. This study investigates the ability of a representative GIIA sPLA2, MT-III, to activate proinflammatory responses in preadipocytes, focusing on the biosynthesis of prostaglandins, adipocytokines and mechanisms involved in these effects. Our results showed that MT-III induced biosynthesis of PGE2, PGI2, MCP-1, IL-6 and gene expression of leptin and adiponectin in preadipocytes. The MT-III-induced PGE2 biosynthesis was dependent on cytosolic PLA2 (cPLA2)-α, cyclooxygenases (COX)-1 and COX-2 pathways and regulated by a positive loop via the EP4 receptor. Moreover, MT-III upregulated COX-2 and microsomal prostaglandin synthase (mPGES)-1 protein expression. MCP-1 biosynthesis induced by MT-III was dependent on the EP4 receptor, while IL-6 biosynthesis was dependent on EP3 receptor engagement by PGE2. These data highlight preadipocytes as targets for GIIA sPLA2s and provide insight into the roles played by this group of sPLA2s in obesity.

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