54 results on '"Markus Neumeier"'
Search Results
2. Adiponectin Isoforms Differentially Affect Gene Expression and the Lipidome of Primary Human Hepatocytes
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Josef Wanninger, Gerhard Liebisch, Kristina Eisinger, Markus Neumeier, Charalampos Aslanidis, Lisa Voggenreiter, Rebekka Pohl, Thomas S. Weiss, Sabrina Krautbauer, and Christa Buechler
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ceramide ,phospholipids ,gene expression ,trimer ,lipidomic ,Microbiology ,QR1-502 - Abstract
Adiponectin (APN) exerts multiple beneficial effects in obesity and protects from liver injury. Different APN isoforms circulate in serum, and here, the effect of low molecular weight (LMW) and higher molecular weight (HMW) APN on primary human hepatocytes (PHH) has been analyzed. APN is not detected in hepatocyte lysates; levels are strongly increased by HMW-APN, but not by LMW-APN, suggesting the distinct uptake/degradation of APN isoforms by PHH. Several genes with a role in fibrosis, glucose and lipid metabolism known to be regulated by HMW-APN are not affected by the LMW-isoform. Follistatin is reduced by HMW-APN and induced by LMW-APN in supernatants of PHH. Fibroblast growth factor 21 is repressed by both isoforms. Cellular triglycerides and cholesterol levels are not reduced by APN. Total phospholipids, including plasmalogens and sphingomyelins, are not changed upon APN incubation, while distinct species are either induced or repressed. Unexpectedly, total ceramide is increased by LMW-APN. Current data show that APN isoforms differentially affect hepatocyte gene expression, but do not grossly alter the hepatocyte lipidome.
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- 2014
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3. Free fatty acids, lipopolysaccharide and IL-1α induce adipocyte manganese superoxide dismutase which is increased in visceral adipose tissues of obese rodents.
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Sabrina Krautbauer, Kristina Eisinger, Markus Neumeier, Yvonne Hader, Roland Buettner, Peter M Schmid, Charalampos Aslanidis, and Christa Buechler
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Medicine ,Science - Abstract
Excess fat storage in adipocytes is associated with increased generation of reactive oxygen species (ROS) and impaired activity of antioxidant mechanisms. Manganese superoxide dismutase (MnSOD) is a mitochondrial enzyme involved in detoxification of ROS, and objective of the current study is to analyze expression and regulation of MnSOD in obesity. MnSOD is increased in visceral but not subcutaneous fat depots of rodents kept on high fat diets (HFD) and ob/ob mice. MnSOD is elevated in visceral adipocytes of fat fed mice and exposure of differentiating 3T3-L1 cells to lipopolysaccharide, IL-1α, saturated, monounsaturated and polyunsaturated free fatty acids (FFA) upregulates its level. FFA do not alter cytochrome oxidase 4 arguing against overall induction of mitochondrial enzymes. Upregulation of MnSOD in fat loaded cells is not mediated by IL-6, TNF or sterol regulatory element binding protein 2 which are induced in these cells. MnSOD is similarly abundant in perirenal fat of Zucker diabetic rats and non-diabetic animals with similar body weight and glucose has no effect on MnSOD in 3T3-L1 cells. To evaluate whether MnSOD affects adipocyte fat storage, MnSOD was knocked-down in adipocytes for the last three days of differentiation and in mature adipocytes. Knock-down of MnSOD does neither alter lipid storage nor viability of these cells. Heme oxygenase-1 which is induced upon oxidative stress is not altered while antioxidative capacity of the cells is modestly reduced. Current data show that inflammation and excess triglyceride storage raise adipocyte MnSOD which is induced in epididymal adipocytes in obesity.
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- 2014
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4. Alpha-syntrophin deficient mice are protected from adipocyte hypertrophy and ectopic triglyceride deposition in obesity
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Andrea Kopp, Lisa Rein-Fischboeck, Sandra Schmidhofer, Kristina Eisinger, Rebekka Pohl, Markus Neumeier, Elisabeth M. Haberl, Andreas Schmid, Sabrina Krautbauer, Christa Buechler, and Gerhard Liebisch
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Male ,0301 basic medicine ,medicine.medical_specialty ,Clinical Biochemistry ,Mice, Obese ,Muscle Proteins ,Adipose tissue ,White adipose tissue ,Intra-Abdominal Fat ,Diet, High-Fat ,Pathology and Forensic Medicine ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Insulin resistance ,Internal medicine ,Lipid droplet ,Adipocytes ,medicine ,Animals ,Obesity ,Molecular Biology ,Cells, Cultured ,Triglycerides ,Mice, Knockout ,Triglyceride ,Chemistry ,Calcium-Binding Proteins ,Fatty liver ,Membrane Proteins ,Hypertrophy ,medicine.disease ,030104 developmental biology ,Endocrinology ,Insulin Resistance ,Adipocyte hypertrophy ,Diet-induced obese - Abstract
Alpha-syntrophin (SNTA) is a molecular adapter protein which is expressed in adipocytes. Knock-down of SNTA in 3T3-L1 preadipocytes increases cell proliferation, and differentiated adipocytes display small lipid droplets. These effects are both characteristics of healthy adipose tissue growth which is associated with metabolic improvements in obesity. To evaluate a role of SNTA in adipose tissue morphology and obesity associated metabolic dysfunction, SNTA deficient mice were fed a standard chow or a high fat diet. Mice deficient of SNTA had less fat mass and smaller adipocytes in obesity when compared to control animals. Accordingly, these animals did not develop liver steatosis and did not store excess triglycerides in skeletal muscle upon high fat diet feeding. SNTA-/- animals were protected from hyperinsulinemia and hepatic insulin resistance. Of note, body-weight, food uptake, and serum lipids were normal in the SNTA null mice. SNTA was induced in adipose tissues but not in the liver of diet induced obese and ob/ob mice. In human subcutaneous and visceral fat of seven patients SNTA was similarly expressed and was not associated with body mass index. Current data demonstrate beneficial effects of SNTA deficiency in obesity which is partly attributed to smaller adipocytes and reduced white adipose tissue mass. Higher SNTA protein in fat depots of obese mice may contribute to adipose tissue hypertrophy and ectopic lipid deposition which has to be confirmed in humans.
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- 2018
5. Manganese superoxide dismutase knock-down in 3T3-L1 preadipocytes impairs subsequent adipogenesis
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Christa Buechler, Sabrina Krautbauer, Markus Neumeier, Yvonne Hader, and Kristina Eisinger
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medicine.medical_specialty ,Clinical Biochemistry ,Biology ,Mice ,chemistry.chemical_compound ,Downregulation and upregulation ,3T3-L1 Cells ,Internal medicine ,Adipocyte ,Adipocytes ,medicine ,Animals ,RNA, Small Interfering ,Buthionine Sulfoximine ,Molecular Biology ,Triglycerides ,Adipogenesis ,Superoxide Dismutase ,Superoxide ,Gene Expression Regulation, Developmental ,Cell Differentiation ,3T3-L1 ,Cell Biology ,General Medicine ,Glutathione ,Heme oxygenase ,Fatty acid synthase ,Endocrinology ,chemistry ,Gene Knockdown Techniques ,biology.protein ,Signal Transduction - Abstract
Adipogenesis is associated with the upregulation of the antioxidative enzyme manganese superoxide dismutase (MnSOD) suggesting a vital function of this enzyme in adipocyte maturation. In the current work, MnSOD was knocked-down with small-interference RNA in preadipocytes to study its role in adipocyte differentiation. In mature adipocytes differentiated from these cells, proteins characteristic for mature adipocytes, which are strongly induced in late adipogenesis like adiponectin and fatty acid-binding protein 4, are markedly reduced. Triglycerides begin to accumulate after about 6 days of the induction of adipogenesis, and are strongly diminished in cells with low MnSOD. Proteins upregulated early during differentiation, like fatty acid synthase and cytochrome C oxidase-4, are not altered. Cell viability, insulin-mediated phosphorylation of Akt, antioxidative capacity (AOC), superoxide levels, and heme oxygenase 1 with the latter being induced upon oxidative stress are not affected. L-Buthionine-(S,R)-sulfoximine (BSO) depletes glutathione and modestly lowers AOC of mature adipocytes. Addition of BSO to 3T3-L1 cells 3 days after the initiation of differentiation impairs triglyceride accumulation and expression of proteins induced in late adipogenesis. Of note, proteins that increased early during adipogenesis are also diminished, suggesting that BSO causes de-differentiation of these cells. Preadipocyte proliferation is not considerably affected by low MnSOD and BSO. These data suggest that glutathione and MnSOD are essential for adipogenesis.
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- 2014
6. LDL but not HDL increases adiponectin release of primary human adipocytes
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Markus Neumeier, Kristina Eisinger, Charalampos Aslanidis, Ashraf Dada, Gerd Schmitz, Yvonne Hader, Sabrina Krautbauer, and Christa Buechler
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Adult ,Male ,medicine.medical_specialty ,Lipoproteins ,Clinical Biochemistry ,Enzyme-Linked Immunosorbent Assay ,Pathology and Forensic Medicine ,Hypobetalipoproteinemias ,Mice ,chemistry.chemical_compound ,3T3-L1 Cells ,Internal medicine ,Adipocytes ,Animals ,Humans ,Medicine ,Lovastatin ,Molecular Biology ,Adiponectin ,Cholesterol ,business.industry ,Anticholesteremic Agents ,Cholesterol, HDL ,Familial Hypobetalipoproteinemia ,nutritional and metabolic diseases ,Cholesterol, LDL ,Middle Aged ,medicine.disease ,Obesity ,In vitro ,Endocrinology ,chemistry ,LDL apheresis ,Female ,lipids (amino acids, peptides, and proteins) ,business ,hormones, hormone substitutes, and hormone antagonists ,Lipoprotein ,medicine.drug - Abstract
Adipocytes in obesity have inappropriately low cholesterol while adiponectin release is reduced. Cholesterol shortage may contribute to low adiponectin and 3T3-L1 cells treated with lovastatin have diminished adiponectin in cell supernatants. LDL and HDL deliver cholesterol to adipocytes. LDL but not HDL increases adiponectin in cell supernatants of primary human adipocytes. The effect of LDL is not blocked by receptor associated protein suggesting that members of the LDL-receptor family are not involved. To evaluate whether these in vitro observations translate into changes in systemic adiponectin, adiponectin was measured in serum of three patients before, immediately after and 3d after LDL-apheresis. Whereas circulating lipoproteins are reduced immediately after apheresis adiponectin is not changed. Therefore, acute lowering of lipoproteins does not affect systemic adiponectin also excluding that plenty of adiponectin is bound to lipoprotein particles. Accordingly, levels of adiponectin in purified lipoproteins are quite low. Familial hypobetalipoproteinemia (FHBL) is a rare disorder associated with low plasma LDL. Serum adiponectin is, however, similar compared to healthy controls. Thus, neither LDL nor HDL directly contributes to circulating adiponectin concentrations.
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- 2013
7. Adiponectin receptor 1 C-terminus interacts with PDZ-domain proteins such as syntrophins
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E. Eggenhofer, Sandra Schmidhofer, Christa Buechler, Yvonne Hader, Markus Neumeier, Marvin E. Adams, Sabrina Krautbauer, Stanley C. Froehner, Wolfgang Mages, and Kristina Eisinger
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Male ,Two-hybrid screening ,Immunoblotting ,Clinical Biochemistry ,PDZ domain ,Fluorescent Antibody Technique ,PDZ Domains ,Peptide ,Biology ,Transfection ,p38 Mitogen-Activated Protein Kinases ,Article ,Cell Line ,Pathology and Forensic Medicine ,Mice ,AMP-Activated Protein Kinase Kinases ,Two-Hybrid System Techniques ,Animals ,Humans ,Receptor ,Molecular Biology ,Syntrophin ,Mice, Knockout ,chemistry.chemical_classification ,Adiponectin receptor 1 ,C-terminus ,Enzyme Activation ,Mice, Inbred C57BL ,chemistry ,Biochemistry ,Dystrophin-Associated Proteins ,Hepatocytes ,Phosphorylation ,Receptors, Adiponectin ,Protein Kinases - Abstract
Adiponectin receptor 1 (AdipoR1) is one of the two signaling receptors of adiponectin with multiple beneficial effects in metabolic diseases. AdipoR1 C-terminal peptide is concordant with the consensus sequence of class I PSD-95, disc large, ZO-1 (PDZ) proteins, and screening of a liver yeast two hybrid library identified binding to β2-syntrophin (SNTB2). Hybridization of a PDZ-domain array with AdipoR1 C-terminal peptide shows association with PDZ-domains of further proteins including β1- and α-syntrophin (SNTA). Interaction of PDZ proteins and C-terminal peptides requires a free carboxy terminus next to the PDZ-binding region and is blocked by carboxy terminal added tags. N-terminal tagged AdipoR1 is more highly expressed than C-terminal tagged receptor suggesting that the free carboxy terminus may form a complex with PDZ proteins to regulate cellular AdipoR1 levels. The C- and N-terminal tagged AdipoR1 proteins are mainly localized in the cytoplasma. N-terminal but not C-terminal tagged AdipoR1 colocalizes with syntrophins in adiponectin incubated Huh7 cells. Adiponectin induced hepatic phosphorylation of AMPK and p38 MAPK which are targets of AdipoR1 is, however, not blocked in SNTA and SNTB2 deficient mice. Further, AdipoR1 protein is similarly abundant in the liver of knock-out and wild type mice when kept on a standard chow or a high fat diet. In summary these data suggest that AdipoR1 protein levels are regulated by so far uncharacterized class I PDZ proteins which are distinct from SNTA and SNTB2.
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- 2013
8. Annexin A6 regulates adipocyte lipid storage and adiponectin release
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Carlos Enrich, Kristina Eisinger, Rebekka Pohl, Lisa Rein-Fischboeck, Thomas Grewal, Carles Rentero, Anna Alvarez-Guaita, Elisabeth M. Haberl, Markus Neumeier, Christa Buechler, and Sabrina Krautbauer
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0301 basic medicine ,Lipopolysaccharides ,Male ,Adipose tissue ,Biochemistry ,Arsenicals ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Endocrinology ,Arsenic Trioxide ,Adipocyte ,Lipid droplet ,Adipocytes ,Insulin ,Adiponectin secretion ,Annexin A6 ,Mice, Knockout ,Adipogenesis ,biology ,Fatty Acids ,Oxides ,030220 oncology & carcinogenesis ,Gene Knockdown Techniques ,Intercellular Signaling Peptides and Proteins ,Adiponectin ,Chemokines ,Signal Transduction ,medicine.medical_specialty ,Lipolysis ,Adipokine ,Intra-Abdominal Fat ,03 medical and health sciences ,Internal medicine ,3T3-L1 Cells ,medicine ,Chemerin ,Animals ,Humans ,Hypoglycemic Agents ,Obesity ,Molecular Biology ,Triglycerides ,Lipid Droplets ,Lipid Metabolism ,Mice, Inbred C57BL ,030104 developmental biology ,chemistry ,biology.protein ,Hydroxymethylglutaryl-CoA Reductase Inhibitors - Abstract
Lipid storage and adipokine secretion are critical features of adipocytes. Annexin A6 (AnxA6) is a lipid-binding protein regulating secretory pathways and its role in adiponectin release was examined. The siRNA-mediated AnxA6 knock-down in 3T3-L1 preadipocytes impaired proliferation, and differentiation of AnxA6-depleted cells to mature adipocytes was associated with higher soluble adiponectin and increased triglyceride storage. The latter was partly attributed to reduced lipolysis. Accordingly, AnxA6 overexpression in 3T3-L1 adipocytes lowered cellular triglycerides and adiponectin secretion. Indeed, serum adiponectin was increased in AnxA6 deficient mice. Expression analysis identified AnxA6 protein to be more abundant in intra-abdominal compared to subcutaneous adipose tissues of mice and men. AnxA6 protein levels increased in white adipose tissues of obese mice and here, levels were highest in subcutaneous fat. AnxA6 protein in adipocytes was upregulated by oxidative stress which might trigger AnxA6 induction in adipose tissues and contribute to impaired fat storage and adiponectin release.
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- 2016
9. Adiponectin stimulates release of CCL2, -3, -4 and -5 while the surface abundance of CCR2 and -5 is simultaneously reduced in primary human monocytes
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Hilke Brühl, Sabrina Bauer, Andrea Kopp, Christa Buechler, Sabine Abke, Kristina Eisinger, Andreas Schäffler, Markus Neumeier, and Roland Walter
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Adult ,Male ,medicine.medical_specialty ,Chemokine ,Receptors, CCR5 ,Receptors, CCR2 ,Immunology ,Adipokine ,CCL4 ,Biology ,CCL2 ,Biochemistry ,Monocytes ,Downregulation and upregulation ,Internal medicine ,parasitic diseases ,medicine ,Humans ,Immunology and Allergy ,RNA, Messenger ,Chemokine CCL4 ,Chemokine CCL5 ,Molecular Biology ,Cells, Cultured ,Chemokine CCL2 ,Aged ,Chemokine CCL3 ,Adiponectin ,Monocyte ,Body Weight ,Cell Membrane ,nutritional and metabolic diseases ,hemic and immune systems ,Hematology ,Middle Aged ,Overweight ,Up-Regulation ,Endocrinology ,medicine.anatomical_structure ,Diabetes Mellitus, Type 2 ,Chemokines, CC ,biology.protein ,CC chemokine receptors ,Subcellular Fractions - Abstract
The adipokine adiponectin is well known to affect the function of immune cells and upregulation of CCL2 by adiponectin in monocytes/macrophages has already been reported. In the current study the effect of adiponectin on CCL2, -3, -4, and -5 and their corresponding receptors CCR1, CCR2, and CCR5 has been analyzed. Adiponectin elevates mRNA and protein of the CC chemokines in primary human monocytes. Simultaneously the surface abundance of CCR2 and CCR5 is reduced while CCR1 is not affected. Downregulation of CCR2 by adiponectin is blocked by a CCR2 antagonist although expression of the CCL2 regulated genes CCR2 and TGF-beta 1 is not altered in the adiponectin-incubated monocytes. CCL2, -3, and -5 concentrations measured in supernatants of monocytes of normal-weight (NW), overweight (OW), and type 2 diabetic (T2D) patients positively correlate with BMI and are increased in obesity and T2D. In contrast CCL4 is similarly abundant in the supernatants of all of these monocytes. The degree of adiponectin-mediated induction of the chemokines CCL3, -4, and -5 negatively correlates with their basal levels and upregulation of CCL3 and CCL5 is significantly impaired in OW and T2D cells. Serum concentrations of these chemokines are almost equal in the three groups and do not correlate with the levels in monocyte supernatants. In conclusion these data demonstrate that adiponectin stimulates release of CCL2 to CCL5 in primary human monocytes, and induction in cells of overweight probands is partly impaired. Adiponectin also lowers surface abundance of CCR2 and CCR5 and downregulation of CCR2 seems to depend on autocrine/paracrine effects of CCL2.
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- 2011
10. Adiponectin reduces connective tissue growth factor in human hepatocytes which is already induced in non-fibrotic non-alcoholic steatohepatitis
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Thomas S. Weiss, Roland Walter, Josef Wanninger, Markus Neumeier, T. Amann, Andreas Schäffler, Kristina Eisinger, Sabrina Bauer, Christa Buechler, Claus Hellerbrand, and Jürgen Schölmerich
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Male ,medicine.medical_specialty ,medicine.medical_treatment ,Primary Cell Culture ,Clinical Biochemistry ,Down-Regulation ,Adipokine ,Smad2 Protein ,Pathology and Forensic Medicine ,Fenofibrate ,Downregulation and upregulation ,Non-alcoholic Fatty Liver Disease ,Transforming Growth Factor beta ,Internal medicine ,medicine ,Humans ,PPAR alpha ,Smad3 Protein ,Phosphorylation ,Molecular Biology ,Adiponectin receptor 2 ,integumentary system ,Adiponectin ,Chemistry ,Anticholesteremic Agents ,Growth factor ,Connective Tissue Growth Factor ,medicine.disease ,Fatty Liver ,CTGF ,Pyrimidines ,Endocrinology ,Hepatocytes ,Female ,Steatohepatitis ,Signal Transduction ,Transforming growth factor - Abstract
Connective tissue growth factor (CTGF) is induced in liver fibrosis and enhances the activity of transforming growth factor β (TGFβ). Recently we have shown that the hepatoprotective adipokine adiponectin downregulates CTGF in primary human hepatocytes (PHH). In the current study, the mechanisms mediating suppression of CTGF by adiponectin and the well described downstream effector of adiponectin receptor 2 (AdipoR2), peroxisome proliferator activated receptor α (PPARα), were analyzed in more detail. Adiponectin downregulated CTGF mRNA and protein in primary human hepatocytes (PHH) and suppression was blocked by a PPARα antagonist indicating that AdipoR2 is involved. The PPARα agonists fenofibrate and WY14643 also reduced CTGF protein in these cells. Adiponectin further impaired TGFβ-mediated upregulation of CTGF. Phosphorylation of the TGFβ downstream effectors SMAD2 and –3 was reduced in PHH incubated with adiponectin or PPARα agonists suggesting that early steps in TGFβ signal transduction are impaired. CTGF and TGFβ mRNA levels were increased in human non-fibrotic non-alcoholic steatohepatitis (NASH), and here AdipoR2 expression was significantly reduced. Current data show that CTGF and TGFβ are already induced in non-fibrotic NASH and this may be partly explained by low adiponectin bioactivity which interferes with TGFβ signaling by reducing phosphorylation of SMAD2/3 and by downregulating CTGF.
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- 2011
11. Lipid accumulation impairs adiponectin-mediated induction of activin A by increasing TGFbeta in primary human hepatocytes
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Andreas Schäffler, Markus Neumeier, Claus Hellerbrand, Sabrina Bauer, Charalampos Aslanidis, Doris Schacherer, Christa Buechler, Jürgen Schölmerich, Hanna Huber, Josef Wanninger, and Thomas S. Weiss
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Adult ,Male ,medicine.medical_specialty ,Palmitic Acid ,Adipokine ,Enzyme-Linked Immunosorbent Assay ,Biology ,Cell Line ,Blood serum ,Transforming Growth Factor beta ,Internal medicine ,medicine ,Humans ,Molecular Biology ,Cells, Cultured ,Aged ,Aged, 80 and over ,Liver injury ,Adiponectin ,Reverse Transcriptase Polymerase Chain Reaction ,Fatty liver ,Cell Biology ,Middle Aged ,medicine.disease ,Activins ,Endocrinology ,medicine.anatomical_structure ,Hepatocyte ,embryonic structures ,Hepatocytes ,biology.protein ,Female ,Steatosis ,hormones, hormone substitutes, and hormone antagonists ,Oleic Acid ,Follistatin - Abstract
Fatty liver is commonly detected in obesity and has been identified as a risk factor for the progression of hepatic fibrosis in a wide range of liver diseases. Transforming growth factor beta (TGFβ) and activin A, both members of the TGFβ superfamiliy, are central regulators in liver fibrosis and regeneration, and the effect of hepatocyte lipid accumulation on the release of these proteins was studied. Primary human hepatocytes (PHH) were incubated with palmitic acid or oleic acid to increase lipid storage. Whereas activin A and its natural inhibitor follistatin were not affected, TGFβ was 2-fold increased. The hepatoprotective adipokine adiponectin dose-dependently induced activin A while lowering follistatin but did not alter TGFβ. Activin A was markedly reduced in hepatocyte cell lines compared to PHH and was not induced upon adiponectin incubation demonstrating significant differences of primary and transformed cells. In free fatty acid (FFA)-incubated PHH adiponectin-mediated induction of activin A was impaired. Inhibition of TGFβ receptors ALK4/5 and blockage of SMAD3 phosphorylation rescued activin A synthesis in FFA and in TGFβ incubated cells suggesting that FFA inhibit adiponectin activity by inducing TGFβ. To evaluate whether serum levels of activin A and its antagonist are altered in patients with hepatic steatosis, both proteins were measured in the serum of patients with sonographically diagnosed fatty liver and age- and BMI-matched controls. Systemic adiponectin was significantly reduced in patients with fatty liver but activin A and follistatin were not altered. In summary the current data demonstrate that lipid accumulation in hepatocytes induces TGFβ which impairs adiponectin bioactivity, and thereby may contribute to liver injury.
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- 2011
12. Adiponectin induces the transforming growth factor decoy receptor BAMBI in human hepatocytes
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Andreas Schäffler, Sabrina Bauer, Christa Buechler, Christoph Dorn, Claus Hellerbrand, Josef Wanninger, Thomas S. Weiss, Kristina Eisinger, Roland Walter, and Markus Neumeier
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Male ,medicine.medical_specialty ,medicine.medical_treatment ,Liver fibrosis ,Immunoblotting ,Biophysics ,Smad2 Protein ,Biochemistry ,Cholesterol, Dietary ,Mice ,Fatty liver disease ,Structural Biology ,Fibrosis ,Cell Line, Tumor ,Internal medicine ,Genetics ,medicine ,Animals ,Humans ,Hepatocyte ,Phosphorylation ,Transforming growth factor β ,Molecular Biology ,Cells, Cultured ,Aged ,Liver injury ,Adiponectin ,Reverse Transcriptase Polymerase Chain Reaction ,Chemistry ,Growth factor ,Fatty liver ,Membrane Proteins ,Hep G2 Cells ,Cell Biology ,Middle Aged ,medicine.disease ,Dietary Fats ,Fatty Liver ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Endocrinology ,Hepatocytes ,Female ,BAMBI ,Transforming growth factor - Abstract
Transforming growth factor (TGF) β is the central cytokine in fibrotic liver diseases. We analyzed whether hepatoprotective adiponectin directly interferes with TGFβ1 signaling in primary human hepatocytes (PHH). Adiponectin induces the TGFβ decoy receptor BMP-and activin-membrane-bound inhibitor (BAMBI) in PHH. Overexpression of BAMBI in hepatoma cells impairs TGFβ-mediated phosphorylation of SMAD2 and induction of connective tissue growth factor. BAMBI is lower in human fatty liver with a higher susceptibility to liver fibrosis and negatively correlates with BMI of the donors. Hepatic BAMBI is reduced in rodent models of liver inflammation and fibrosis. In summary, the current data show that hepatoprotective effects of adiponectin include induction of BAMBI which is reduced in human fatty liver and rodent models of metabolic liver injury.
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- 2011
13. Portal levels of latent transforming growth factor-β are related to liver function in patients with liver cirrhosis
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Sabrina Bauer, Christa Buechler, Josef Wanninger, Kristina Eisinger, Andreas Schäffler, Stefan Farkas, Markus Neumeier, Reiner Wiest, and Marcus N. Scherer
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Adult ,Liver Cirrhosis ,Male ,medicine.medical_specialty ,Cirrhosis ,Severity of Illness Index ,Gastroenterology ,Cohort Studies ,Transforming Growth Factor beta1 ,Liver disease ,Immune system ,Fibrosis ,Internal medicine ,medicine ,Humans ,Interleukin 6 ,Aged ,Hepatology ,medicine.diagnostic_test ,biology ,Interleukin-6 ,Portal Vein ,business.industry ,Middle Aged ,medicine.disease ,Liver ,Creatinine ,biology.protein ,Female ,Liver function ,business ,Liver function tests ,Transforming growth factor - Abstract
Transforming growth factor-β1 (TGFβ1) is a short-lived immune suppressive and profibrotic protein. Its latent precursor is relatively stable and may even protect from fibrosis. Latent TGFβ1 is synthesized by various tissues including the liver and portal, hepatic, and systemic concentrations of latent TGFβ1 were determined in patients with liver cirrhosis and patients with normal liver function to find out whether circulating levels are affected by liver disease.Latent TGFβ1 was measured in portal venous serum (PVS), hepatic venous serum (HVS), and systemic venous serum (SVS) of 26 patients with liver cirrhosis and nine patients with normal liver function.Latent TGFβ1 was similarly abundant in HVS, PVS,and SVS of patients with liver cirrhosis and controls. There was a strong positive correlation of HVS, PVS, and SVS TGFβ1 to each other. PVS levels of latent TGFβ1 were significantly lower in patients with CHILD-PUGH stage C compared with CHILD-PUGH stage A, SVS levels were modestly and HVS levels tended to be reduced. PVS and SVS TGFβ1 concentrations were also lower in patients with a higher model for end-stage liver disease score. Only PVS concentrations were reduced in patients with massive ascites compared with the patients without ascites. Creatinine clearance as a marker of renal function and parameters of coagulation did not correlate with this cytokine indicating that latent TGFβ1 levels are not linked to kidney function and coagulation. Interleukin-6, which is elevated in patients with liver cirrhosis negatively correlated with latent TGFβ1 in PVS and SVS.In patients with liver cirrhosis splanchnic organ-derived latent TGFβ1 is negatively associated with the liver function.
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- 2011
14. Elevated free fatty acids and impaired adiponectin bioactivity contribute to reduced SOD2 protein in monocytes of type 2 diabetes patients
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Josef Wanninger, S. Wurm, Charalampos Aslanidis, Margarita Bala, Markus Neumeier, Sabrina Bauer, Andrea Kopp, Christa Buechler, Johanna Weigert, and Andreas Schäffler
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Adult ,Male ,medicine.medical_specialty ,Antioxidant ,medicine.medical_treatment ,Clinical Biochemistry ,SOD2 ,Fatty Acids, Nonesterified ,Biology ,medicine.disease_cause ,Monocytes ,Body Mass Index ,Pathology and Forensic Medicine ,Superoxide dismutase ,Downregulation and upregulation ,Internal medicine ,Adipocytes ,medicine ,Humans ,skin and connective tissue diseases ,Molecular Biology ,Cells, Cultured ,Aged ,chemistry.chemical_classification ,Reactive oxygen species ,Dose-Response Relationship, Drug ,Adiponectin ,Superoxide Dismutase ,Monocyte ,nutritional and metabolic diseases ,Middle Aged ,Recombinant Proteins ,Endocrinology ,medicine.anatomical_structure ,Diabetes Mellitus, Type 2 ,chemistry ,Case-Control Studies ,cardiovascular system ,biology.protein ,Oxidative stress - Abstract
Type 2 diabetes (T2D) is characterized by increased oxidative stress contributing to the development of cardiovascular disease (CVD). Monocytes are critically important in the pathogenesis of CVD and antioxidant enzymes like superoxide dismutase (SOD2) protect these cells from excessive reactive oxygen species (ROS). Adiponectin is an adipocyte-derived protein with atheroprotective function and the effect of adiponectin on monocyte SOD2 was analyzed herein. Adiponectin upregulated SOD2 mRNA and dose- and time-dependently induced SOD2 protein in primary human monocytes. Elevated systemic free fatty acids (FFA) are commonly found in T2D patients and palmitic acid as well as oleic acid reduced monocyte SOD2 protein. Adiponectin mediated upregulation of SOD2, however, was not affected by FFA incubation. SOD2 protein was reduced in T2D monocytes compared to monocytes of age- and body mass index-matched healthy controls. Adiponectin still induced SOD2 in T2D monocytes but efficiency tended to be reduced. In summary this study indicates that elevated systemic free fatty acids and impaired adiponectin activity contribute to reduced SOD2 and most likely increased oxidative stress in T2D monocytes.
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- 2011
15. Sterol Regulatory Element-Binding Protein 2 (SREBP2) Activation after Excess Triglyceride Storage Induces Chemerin in Hypertrophic Adipocytes
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Josef Wanninger, Sandra Schmidhofer, Sabrina Bauer, Nicole Zimara, Charalampos Aslanidis, Christa Buechler, Christoph Dorn, Claus Hellerbrand, Markus Neumeier, Andreas Schäffler, and Johanna Weigert
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medicine.medical_specialty ,Adipose tissue ,Adipokine ,CMKLR1 ,Receptors, G-Protein-Coupled ,Mice ,chemistry.chemical_compound ,Endocrinology ,3T3-L1 Cells ,Adipocyte ,Internal medicine ,Adipocytes ,medicine ,Animals ,Chemerin ,Triglycerides ,Chemotactic Factors ,biology ,Interleukin-6 ,Reverse Transcriptase Polymerase Chain Reaction ,Tumor Necrosis Factor-alpha ,Sterol regulatory element-binding protein ,Mice, Inbred C57BL ,Gene Expression Regulation ,chemistry ,biology.protein ,Intercellular Signaling Peptides and Proteins ,Female ,Receptors, Chemokine ,Sterol regulatory element-binding protein 2 ,Chemokines ,Adipocyte hypertrophy ,Sterol Regulatory Element Binding Protein 2 - Abstract
Chemerin is an adipokine whose systemic concentration and adipose tissue expression is increased in obesity. Chemerin is highly abundant in adipocytes, yet the molecular mechanisms mediating its further induction in obesity have not been clarified. Adipocyte hypertrophy contributes to dysregulated adipokine synthesis, and we hypothesized that excess loading with free fatty acids (FFA) stimulates chemerin synthesis. Chemerin was expressed in mature adipocytes, and differentiation of 3T3-L1 cells in the presence of FFA further increased its level. TNF and IL-6 were induced by FFA, but concentrations were too low to up-regulate chemerin. Sterol regulatory element-binding protein 2 (SREBP2) was activated in these cells, indicative for cholesterol shortage. Suppression of cholesterol synthesis by lovastatin led to activation of SREBP2 and increased chemerin, and supplementation with mevalonate reversed this effect. Knockdown of SREBP2 reduced basal and FFA-induced chemerin. EMSA confirmed binding of 3T3-L1 adipocyte nuclear proteins to a SREBP site in the chemerin promotor. SREBP2 was activated and chemerin was induced in adipose tissue of mice fed a high-fat diet, and higher systemic levels seem to be derived from adipocytes. Lipopolysaccharide-mediated elevation of chemerin was similarly effective as induction by FFA, indicating that both mechanisms are equally important. Chemokine-like receptor 1 was not altered by the incubations mentioned above, and higher expression in fat of mice fed a high-fat diet may reflect increased number of adipose tissue-resident macrophages in obesity. In conclusion, the current data show that adipocyte hypertrophy and chronic inflammation are equally important in inducing chemerin synthesis.
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- 2011
16. Systemic chemerin is related to inflammation rather than obesity in type 2 diabetes
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Reiner Wiest, Christa Buechler, Andreas Schäffler, Josef Wanninger, Marcus N. Scherer, Charalampos Aslanidis, Markus Neumeier, Johanna Weigert, Jürgen Schölmerich, Michael Filarsky, Sabrina Bauer, and Stefan Farkas
- Subjects
Adult ,Male ,medicine.medical_specialty ,endocrine system diseases ,Endocrinology, Diabetes and Metabolism ,Adipokine ,Inflammation ,Type 2 diabetes ,Hepatic Veins ,Systemic inflammation ,CMKLR1 ,Endocrinology ,Internal medicine ,medicine ,Humans ,Chemerin ,Obesity ,Aged ,Aged, 80 and over ,biology ,Portal Vein ,business.industry ,Leptin ,nutritional and metabolic diseases ,Middle Aged ,medicine.disease ,Diabetes Mellitus, Type 2 ,biology.protein ,Intercellular Signaling Peptides and Proteins ,Female ,Resistin ,Chemokines ,medicine.symptom ,business - Abstract
Background The adipokine chemerin modulates the function of innate immune cells and may link obesity and inflammation, and therefore, a possible relation of chemerin to inflammatory proteins in obesity and type 2 diabetes (T2D) was analysed. As visceral fat contributes to systemic inflammation, chemerin was measured in portal venous (PVS), hepatic venous (HVS) and systemic venous (SVS) blood of patients with liver cirrhosis. Patients and methods Systemic chemerin was determined by ELISA in the serum of normal-weight, overweight and T2D males, in the serum of T2D patients of both sexes, and in PVS, HVS and SVS of patients with liver cirrhosis. Results Circulating chemerin was similar in T2D and obese individuals but was significantly elevated in both cohorts compared to normal-weight individuals. Chemerin positively correlated with leptin, resistin and C-reactive protein (CRP). In T2D, chemerin was similar in male and female patients and increased in patients with elevated CRP. Chemerin was similar in PVS and SVS, indicating that visceral fat is not a major site of chemerin synthesis. Higher levels of chemerin in HVS demonstrate that chemerin is also released by the liver. Conclusions Visceral fat is not a major site of chemerin release, and elevated systemic levels of chemerin in obesity and T2D seem to be associated with inflammation rather than body mass index.
- Published
- 2010
17. Serum Galectin-3 Is Elevated in Obesity and Negatively Correlates with Glycosylated Hemoglobin in Type 2 Diabetes
- Author
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Marcus N. Scherer, Josef Wanninger, Stefan Farkas, Johanna Weigert, Markus Neumeier, Jürgen Schölmerich, Andreas Schäffler, Charalampos Aslanidis, Christa Buechler, Andreas A. Schnitzbauer, and Sabrina Bauer
- Subjects
Adult ,Leptin ,Male ,medicine.medical_specialty ,Cirrhosis ,Galectin 3 ,Endocrinology, Diabetes and Metabolism ,Blotting, Western ,Clinical Biochemistry ,Adipokine ,Adipose tissue ,Enzyme-Linked Immunosorbent Assay ,Type 2 diabetes ,Intra-Abdominal Fat ,Systemic inflammation ,Biochemistry ,Statistics, Nonparametric ,Body Mass Index ,Mice ,chemistry.chemical_compound ,Endocrinology ,Diabetes mellitus ,Adipocyte ,Internal medicine ,Adipocytes ,otorhinolaryngologic diseases ,medicine ,Animals ,Humans ,Resistin ,Obesity ,Cells, Cultured ,Aged ,Glycated Hemoglobin ,business.industry ,Biochemistry (medical) ,Middle Aged ,medicine.disease ,Metformin ,stomatognathic diseases ,Diabetes Mellitus, Type 2 ,chemistry ,Female ,medicine.symptom ,business - Abstract
Adipocytes synthesize galectin-3 whose deficiency protects from inflammation associated with metabolic diseases. We aimed to study circulating galectin-3 in obesity and type 2 diabetes (T2D).Galectin-3 was measured by ELISA in the serum of male normal-weight and overweight controls and T2D patients and in T2D patients of both sexes. Because visceral fat contributes to systemic inflammation, galectin-3 was analyzed in paired samples of human and rodent sc and visceral adipose tissue. Visceral adipose tissue adipokines are released to the portal vein, and galectin-3 was analyzed in portal, hepatic, and systemic venous serum (PVS, HVS, and SVS, respectively) of patients with liver cirrhosis and in patients who underwent surgery for nonhepatic diseases. The effect of metformin on adipocyte galectin-3 was analyzed by immunoblot.Circulating galectin-3 was similarly elevated in T2D and obesity compared with normal-weight individuals and revealed a body mass index-dependent positive correlation with leptin, resistin, IL-6, and age. In T2D patients, galectin-3 was increased in serum of patients with elevated C-reactive protein and negatively correlated with glycated hemoglobin. Metformin treatment was associated with lower systemic galectin-3. Reduced galectin-3 in metformin-incubated human adipocytes indicated that low galectin-3 may be a direct effect of this drug. Galectin-3 was higher in PVS compared with HVS and SVS, suggesting that the splanchnic region is a major site of galectin-3 synthesis. Low galectin-3 in HVS compared with PVS demonstrated hepatic removal.Systemic galectin-3 is elevated in obesity and negatively correlates with glycated hemoglobin in T2D patients, pointing to a modifying function of galectin-3 in human metabolic diseases.
- Published
- 2010
18. Adiponectin downregulates galectin-3 whose cellular form is elevated whereas its soluble form is reduced in type 2 diabetic monocytes
- Author
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Margarita Bala, Daniela Sporrer, Josef Wanninger, Andrea Kopp, Markus Neumeier, Markus Weber, Andreas Schäffler, Johanna Weigert, Fabian Stögbauer, Christa Buechler, and S. Wurm
- Subjects
Male ,Time Factors ,Galectin 3 ,Palmitic Acid ,Type 2 diabetes ,Monocyte ,Biochemistry ,Monocytes ,Body Mass Index ,chemistry.chemical_compound ,Structural Biology ,Galectin-3 ,Cells, Cultured ,Aged, 80 and over ,Reverse Transcriptase Polymerase Chain Reaction ,Chemistry ,Middle Aged ,Metformin ,Cholesterol ,medicine.anatomical_structure ,Adiponectin ,medicine.drug ,Adult ,medicine.medical_specialty ,animal structures ,Immunoblotting ,Biophysics ,Enzyme-Linked Immunosorbent Assay ,Internal medicine ,Type 2 diabetes mellitus ,otorhinolaryngologic diseases ,Genetics ,medicine ,Humans ,Obesity ,Molecular Biology ,Aged ,Messenger RNA ,Dose-Response Relationship, Drug ,nutritional and metabolic diseases ,Cell Biology ,Ribonucleotides ,Aminoimidazole Carboxamide ,medicine.disease ,stomatognathic diseases ,Pyrimidines ,Endocrinology ,Diabetes Mellitus, Type 2 ,Solubility ,Pyrazoles ,Oleic Acid - Abstract
Galectin-3 plays a role in atherosclerotic diseases, and the effect of adiponectin that protects from atherosclerotic diseases on monocytic galectin-3 was analysed. Adiponectin reduced galectin-3 mRNA, its cellular and soluble form, and this effect was impaired in T2D cells. Cellular galectin-3 was higher in monocytes of overweight than normal-weight donors and was highest in T2D cells. Cellular galectin-3 positively correlated with the BMI of the donors and negatively with soluble monocyte galectin-3. Circulating levels of total adiponectin did not correlate with cellular or soluble galectin-3 indicating that additional factors contribute to higher cellular monocytic galectin-3 in obesity and T2D.
- Published
- 2009
19. Metformin reduces cellular lysophosphatidylcholine and thereby may lower apolipoprotein B secretion in primary human hepatocytes
- Author
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Christa Buechler, Markus Neumeier, Thomas S. Weiss, Charalampos Aslanidis, Gerd Schmitz, Gerhard Liebisch, Jürgen Schölmerich, Josef Wanninger, Johanna Weigert, and Andreas Schäffler
- Subjects
Apolipoprotein E ,Spectrometry, Mass, Electrospray Ionization ,medicine.medical_specialty ,endocrine system diseases ,Apolipoprotein B ,medicine.drug_class ,chemistry.chemical_compound ,Internal medicine ,medicine ,Humans ,Hypoglycemic Agents ,Secretion ,Molecular Biology ,Apolipoproteins B ,Phosphatidylethanolamine ,biology ,Biguanide ,Lysophosphatidylcholines ,nutritional and metabolic diseases ,Cell Biology ,Phosphatidylserine ,Metformin ,Culture Media ,Lysophosphatidylcholine ,Endocrinology ,chemistry ,Hepatocytes ,biology.protein ,Electrophoresis, Polyacrylamide Gel ,lipids (amino acids, peptides, and proteins) ,medicine.drug - Abstract
The biguanide metformin is an oral antihyperglycemic drug for the treatment of type 2 diabetes mellitus. Further, a moderate improvement of dyslipidemia by metformin was reported, and therefore, the effect of metformin on the release of apolipoprotein B (ApoB) and ApoE in primary human hepatocytes was determined. Metformin at 0.5 and 1 mM reduced hepatic ApoB secretion but ApoE was not altered. Metformin is well known to stimulate the AMP kinase that subsequently reduces hepatic nuclear factor 4-alpha (HNF4-alpha) and HNF4-alpha regulated genes like ApoB. However, HNF4-alpha was only diminished by 1 mM metformin and ApoB mRNA was not suppressed indicating that this pathway may not explain reduced ApoB release. Lower abundance of lysophosphatidylcholine (lysoPC) may also diminish ApoB secretion. Therefore, electrospray ionization tandem mass spectrometry was applied to measure cellular lipids. PC, lysoPC (produced by hydrolysis of PC), phosphatidylserine and sphingomyelin (derived from PC) were lower in metformin-treated hepatocytes whereas phosphatidylethanolamine, an alternative precursor of PC, was not affected. In addition, ABCB4, the canalicular membrane flippase essential for biliary PC secretion, was diminished. Supplementation with lysoPC led to a selective elevation of endogenous lysoPC and rescued ApoB secretion in metformin-treated cells. Therefore, it is concluded that metformin reduces lysoPC in human hepatocytes and this may secondarily lead to a therapeutically beneficial lower release of ApoB.
- Published
- 2008
20. Low molecular weight adiponectin negatively correlates with the waist circumference and monocytic IL-6 release
- Author
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Markus Neumeier, Gerd Schmitz, Charalampos Aslanidis, Gerhard Liebisch, Josef Wanninger, Ashraf Dada, Franziska Schober, Christa Buechler, S. Wurm, Johanna Weigert, and Andreas Schäffler
- Subjects
Adult ,Male ,Gene isoform ,medicine.medical_specialty ,Biophysics ,Overweight ,Biochemistry ,Monocytes ,Body Mass Index ,Internal medicine ,medicine ,Humans ,Protein Isoforms ,Body Weights and Measures ,Secretion ,Obesity ,Interleukin 6 ,Molecular Biology ,Cells, Cultured ,Aged ,biology ,Adiponectin ,Interleukin-6 ,Chemistry ,food and beverages ,nutritional and metabolic diseases ,Type 2 Diabetes Mellitus ,Cell Biology ,Middle Aged ,medicine.disease ,Molecular Weight ,Endocrinology ,Diabetes Mellitus, Type 2 ,biology.protein ,medicine.symptom ,Body mass index ,hormones, hormone substitutes, and hormone antagonists - Abstract
Adiponectin circulates as trimer (LMW), hexamer (MMW) and high molecular weight multimer (HMW) but the distribution and effects of these isoforms have not been studied in detail. Monocytes were isolated from normal weight and overweight controls and patients with type 2 diabetes mellitus (T2D) and monocytic release of IL-6 positively correlated with the body mass index (BMI). HMW-adiponectin further enhanced and LMW-adiponectin reduced IL-6 release in monocytes. Systemic total adiponectin, and the HMW isoform were not different in these groups but MMW-adiponectin was lower in T2D, and LMW-adiponectin was reduced in the obese and T2D. Circulating LMW-adiponectin negatively correlated to monocytic IL-6 release. Systemic IL-6 was higher in the obese control group and T2D, respectively, but did not correlate with monocytic IL-6 secretion. Therefore, the current study indicates that HMW-adiponectin exerts pro- and LMW-adiponectin antiinflammatory effects and reduced LMW-adiponectin in obesity may partly contribute to elevated monocytic IL-6 release.
- Published
- 2007
21. High molecular weight adiponectin reduces apolipoprotein B and E release in human hepatocytes
- Author
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Thomas S. Weiss, Thomas Langmann, Pompiliu Piso, Charalampos Aslanidis, Markus Neumeier, E. Eggenhofer, Hans J. Schlitt, Jürgen Schölmerich, Andreas Schaeffler, Gerd Schmitz, Alexander Sigruener, Christa Buechler, and Johanna Weigert
- Subjects
Apolipoprotein E ,medicine.medical_specialty ,Very low-density lipoprotein ,Apolipoprotein B ,Biophysics ,Biochemistry ,Apolipoproteins E ,Internal medicine ,Gene expression ,polycyclic compounds ,medicine ,Humans ,Secretion ,Molecular Biology ,Cells, Cultured ,Apolipoproteins B ,Messenger RNA ,biology ,Adiponectin ,food and beverages ,nutritional and metabolic diseases ,Cell Biology ,Molecular Weight ,Endocrinology ,ABCA1 ,Hepatocytes ,biology.protein ,lipids (amino acids, peptides, and proteins) - Abstract
Low circulating levels of high molecular weight adiponectin (HMW-Apm) have been linked to dyslipidaemia and systemic HMW-Apm negatively correlates with very low density lipoprotein (VLDL), apolipoprotein B (ApoB), and ApoE and is positively associated with ApoA-I. Therefore, it was investigated whether HMW-Apm alters the hepatic synthesis of ApoB, ApoE, and ApoA-I or the activity of the hepatic ATP-binding cassette transporter A1 (ABCA1), as the main determinant of plasma HDL. HMW-Apm reduces hepatic ApoB and ApoE release whereas ABCA1 protein, activity and ApoA-I were not altered. Global gene expression analysis revealed that hepatic nuclear factor 4-alpha (HNF4-alpha) and HNF4-alpha regulated genes like ApoB are downregulated by HMW-Apm and this was confirmed at the mRNA and protein level. Therefore it is concluded that HMW-adiponectin may ameliorate dyslipidaemia by reducing the hepatic release of ApoB and ApoE, whereas ABCA1 function and ApoA-I secretion are not influenced.
- Published
- 2007
22. Regulation of adiponectin receptor 1 in human hepatocytes by agonists of nuclear receptors
- Author
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Stefan Kirchner, Johanna Weigert, Christa Buechler, Andreas Schäffler, Sabine Laberer, Markus Neumeier, Jürgen Schölmerich, and Thomas S. Weiss
- Subjects
medicine.medical_specialty ,Peroxisome Proliferator-Activated Receptors ,Biophysics ,Receptors, Cytoplasmic and Nuclear ,Receptors, Cell Surface ,Tretinoin ,CHO Cells ,Biochemistry ,Cell Line ,Troglitazone ,Liver X receptor beta ,Fenofibrate ,Cricetinae ,Internal medicine ,medicine ,Animals ,Humans ,PPAR alpha ,Chromans ,Liver X receptor ,Molecular Biology ,Alitretinoin ,Liver X Receptors ,Adiponectin receptor 1 ,Pregnane X receptor ,Pioglitazone ,Retinoid X receptor alpha ,Chemistry ,Liver receptor homolog-1 ,Liver X receptor alpha ,Cell Biology ,Orphan Nuclear Receptors ,Hydroxycholesterols ,Up-Regulation ,DNA-Binding Proteins ,Retinoid X Receptors ,Endocrinology ,Hepatocytes ,Thiazolidinediones ,Estrogen-related receptor gamma ,Adiponectin ,Caco-2 Cells ,Receptors, Adiponectin ,HeLa Cells - Abstract
The adiponectin receptors AdipoR1 and AdipoR2 have been identified to mediate the insulin-sensitizing effects of adiponectin. Although AdipoR2 was suggested to be the main receptor for this adipokine in hepatocytes, AdipoR1 protein is highly abundant in primary human hepatocytes and hepatocytic cell lines. Nuclear receptors are main regulators of lipid metabolism and activation of peroxisome proliferator-activated receptor α and γ, retinoid X receptor (RXR), and liver X receptor (LXR) by specific ligands may influence AdipoR1 abundance. AdipoR1 protein is neither altered by RXR or LXR agonists nor by pioglitazone. In contrast, fenofibric acid reduces AdipoR1 whereas hepatotoxic troglitazone upregulates AdipoR1 protein in HepG2 cells. Taken together this work shows for the first time that AdipoR1 protein is expressed in human hepatocytes but that it is not a direct target gene of nuclear receptors. Elevated AdipoR1 induced by hepatotoxic troglitazone may indicate a role of this receptor in adiponectin-mediated beneficial effects in liver damage.
- Published
- 2005
23. Highly efficient and low-cost method to isolate human blood monocytes with high purity
- Author
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Markus Neumeier, Andreas Schäffler, Gerd Schmitz, Christa Buechler, Jürgen Schölmerich, Josef Wanninger, Karla Lehle, Fabian Stögbauer, Margot Grandl, Johanna Weigert, and Charalampos Aslanidis
- Subjects
Adult ,Male ,Human blood ,Immunomagnetic Separation ,business.industry ,Monocyte ,Immunology ,Lipopolysaccharide Receptors ,Flow Cytometry ,Microspheres ,Monocytes ,Microsphere ,medicine.anatomical_structure ,medicine ,Humans ,Immunology and Allergy ,Female ,business - Abstract
Several techniques are available to purify circulating blood monocytes for research. CD14-containing MicroBeads are suitable and reliable tools to reproducibly isolate human monocytes with a high purity but are quite expensive. This report describes that a comparable number of highly pure monocytes can be isolated from samples using up to tenfold lower amounts of CD14-MicroBeads. MicroBeads are widely used to isolate different cell populations and with this report more researchers may be encouraged to use this highly efficient, low-cost and thus affordable method to pursue their scientific goals.
- Published
- 2008
24. Adipocyte chemerin release is induced by insulin without being translated to higher levels in vivo
- Author
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Sabrina, Bauer, Margarita, Bala, Andrea, Kopp, Kristina, Eisinger, Andreas, Schmid, Sylvia, Schneider, Markus, Neumeier, and Christa, Buechler
- Subjects
Adult ,Male ,Chemotactic Factors ,Glucose Tolerance Test ,Middle Aged ,Overweight ,Body Mass Index ,Cohort Studies ,Mice ,Glucose ,Hyperinsulinism ,Adipocytes ,Animals ,Humans ,Insulin ,Intercellular Signaling Peptides and Proteins ,Female ,Obesity ,Chemokines ,Insulin Resistance ,Cells, Cultured - Abstract
Chemerin is an adipokine that regulates insulin sensitivity and insulin secretion. Prolonged hyperinsulinaemia is associated with higher systemic chemerin, and insulin induces adipose tissue chemerin release. These findings led us to hypothesize that systemic chemerin may be associated with post-prandial glucose metabolism and/or may even be induced after oral glucose load. Therefore, the effect of insulin on adipocyte chemerin levels and systemic chemerin in mice was analysed. Further, systemic levels of chemerin after oral glucose load in nondiabetic individuals were studied.Chemerin levels were determined in adipocytes after short-term and long-term treatment with insulin. Effects of acute hyperinsulinaemia were studied in mice. Chemerin was measured during oral glucose tolerance test in 66 healthy, nondiabetic individuals stratified for established body mass index categories.Insulin induces chemerin release from adipocytes within 24 h, while cellular levels are not affected. Short-term hyperinsulinaemia also upregulates adipocyte chemerin in vitro but has no effect on adipose tissue and chemerin serum levels of mice. Systemic chemerin is higher in overweight/obese than normal-weight controls and positively correlates with total cholesterol. Chemerin is not associated with markers of insulin sensitivity like fasting glucose or insulin. Fasting chemerin levels are similar to concentrations measured 1 and 2 h after oral glucose uptake in overweight and obese donors.Post-prandial hyperinsulinaemia does not contribute to higher chemerin levels in nondiabetic individuals.
- Published
- 2012
25. Systemic resistin is increased in type 2 diabetic patients treated with loop diuretics
- Author
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Sabrina Bauer, Andreas Schäffler, Margarita Bala, Andrea Kopp, Christa Buechler, Josef Wanninger, Roland Walter, and Markus Neumeier
- Subjects
Adult ,Male ,medicine.medical_specialty ,endocrine system diseases ,medicine.drug_class ,Endocrinology, Diabetes and Metabolism ,Adrenergic beta-Antagonists ,Type 2 diabetes ,Monocytes ,Body Mass Index ,Cohort Studies ,Endocrinology ,Insulin resistance ,Sodium Potassium Chloride Symporter Inhibitors ,Furosemide ,Internal medicine ,Diabetes mellitus ,Internal Medicine ,medicine ,Humans ,Diabetic Nephropathies ,Resistin ,Renal Insufficiency ,Cells, Cultured ,Aged ,Uremia ,Aged, 80 and over ,business.industry ,Interleukin-6 ,nutritional and metabolic diseases ,Type 2 Diabetes Mellitus ,respiratory system ,Loop diuretic ,Middle Aged ,Overweight ,medicine.disease ,Diabetes Mellitus, Type 2 ,business ,Body mass index ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug - Abstract
Increased serum resistin was found in rodent models of obesity and insulin resistance, whereas contradictory results have been obtained in human studies. In humans, resistin is primarily released by monocytes/macrophages, suggesting that soluble levels may be associated with macrophage activation. Here, systemic and monocyte-released resistin levels were found to be similar in type 2 diabetic (T2D) patients, overweight controls and normal-weight controls. When adjusted for body mass index and age, serum resistin modestly correlated with gamma-glutamyltransferase levels, fasting glucose and interleukin-6. Systemic resistin was marginally increased in T2D patients treated with beta-blockers or urate-lowering drugs and was considerably higher in patients treated with loop diuretics. Monocyte-released resistin was even reduced by the loop diuretic furosemide, excluding the possibility that this drug may directly stimulate resistin synthesis. In summary, the current data indicate that changes accompanying renal dysfunction but not obesity or type 2 diabetes are associated with increased serum resistin.
- Published
- 2011
26. Systemic and hepatic vein galectin-3 are increased in patients with alcoholic liver cirrhosis and negatively correlate with liver function
- Author
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Claus Hellerbrand, Thomas S. Weiss, Andreas Schäffler, Roland Walter, Reiner Wiest, Markus Neumeier, Josef Wanninger, Johanna Weigert, Marcus N. Scherer, Christa Buechler, Sabrina Bauer, Thomas Karrasch, and Stefan Farkas
- Subjects
Adult ,Liver Cirrhosis ,Male ,medicine.medical_specialty ,animal structures ,Cirrhosis ,Portal venous pressure ,Galectin 3 ,Immunology ,Immunoblotting ,Renal function ,Hepatic Veins ,Kidney ,Biochemistry ,Gastroenterology ,Antithrombins ,Liver Cirrhosis, Alcoholic ,Internal medicine ,Ascites ,otorhinolaryngologic diseases ,medicine ,Immunology and Allergy ,Humans ,Urea ,Molecular Biology ,Aged ,Aged, 80 and over ,Fibrous capsule of Glisson ,medicine.diagnostic_test ,business.industry ,Kidney metabolism ,Hematology ,Middle Aged ,medicine.disease ,stomatognathic diseases ,Creatinine ,Hepatocytes ,Female ,Liver function ,medicine.symptom ,business ,Liver function tests - Abstract
Recently we demonstrated higher galectin-3 in portal venous serum (PVS) compared to hepatic venous serum (HVS) in a small cohort of patients with normal liver function suggesting hepatic removal of galectin-3. Here, galectin-3 was measured by ELISA in PVS, HVS and systemic venous blood (SVS) of 33 patients with alcoholic liver cirrhosis and a larger cohort of 11 patients with normal liver function. Galectin-3 was cleared by the healthy but not the cirrhotic liver, and subsequently HVS and SVS galectin-3 levels were significantly increased in the patients with liver cirrhosis compared to controls. In healthy liver galectin-3 was produced by cholangiocytes and synthesis by hepatocytes was only observed in cirrhotic liver. Hepatic venous pressure gradient did not correlate with galectin-3 levels excluding hepatic shunting as the principal cause of higher SVS galectin-3. Galectin-3 was elevated in all blood compartments of patients with CHILD-PUGH stage C compared to patients with CHILD-PUGH stage A, and was higher in patients with ascites than patients without this complication. Galectin-3 was negatively associated with antithrombin-3 whose synthesis is reduced with worse liver function. Galectin-3 positively correlated with urea and creatinine, and PVS galectin-3 showed a negative association with creatinine clearance as an accepted measure of kidney function. To summarize in the current study systemic, portal and hepatic levels of galectin-3 were found to be negatively associated with liver function in patients with alcoholic liver cirrhosis and this may in part be related to impaired hepatic removal and/or increased synthesis in cirrhotic liver.
- Published
- 2010
27. Adiponectin, a key adipokine in obesity related liver diseases
- Author
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Christa, Buechler, Josef, Wanninger, and Markus, Neumeier
- Subjects
nutritional and metabolic diseases ,Apoptosis ,Review ,digestive system ,Fibrosis ,digestive system diseases ,Diet ,Fatty Liver ,Adipose Tissue ,Non-alcoholic Fatty Liver Disease ,Animals ,Humans ,Adiponectin ,Obesity ,Receptors, Adiponectin ,Exercise - Abstract
Non-alcoholic fatty liver disease (NAFLD) comprising hepatic steatosis, non-alcoholic steatohepatitis (NASH), and progressive liver fibrosis is considered the most common liver disease in western countries. Fatty liver is more prevalent in overweight than normal-weight people and liver fat positively correlates with hepatic insulin resistance. Hepatic steatosis is regarded as a benign stage of NAFLD but may progress to NASH in a subgroup of patients. Besides liver biopsy no diagnostic tools to identify patients with NASH are available, and no effective treatment has been established. Visceral obesity is a main risk factor for NAFLD and inappropriate storage of triglycerides in adipocytes and higher concentrations of free fatty acids may add to increased hepatic lipid storage, insulin resistance, and progressive liver damage. Most of the adipose tissue-derived proteins are elevated in obesity and may contribute to systemic inflammation and liver damage. Adiponectin is highly abundant in human serum but its levels are reduced in obesity and are even lower in patients with hepatic steatosis or NASH. Adiponectin antagonizes excess lipid storage in the liver and protects from inflammation and fibrosis. This review aims to give a short survey on NAFLD and the hepatoprotective effects of adiponectin.
- Published
- 2010
28. Adiponectin receptor binding proteins--recent advances in elucidating adiponectin signalling pathways
- Author
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Josef Wanninger, Christa Buechler, and Markus Neumeier
- Subjects
Adiponectin receptor ,APPL ,Biophysics ,Biochemistry ,Models, Biological ,Structural Biology ,Genetics ,Chemerin ,Animals ,Humans ,Receptor ,Protein kinase A ,Molecular Biology ,Adaptor Proteins, Signal Transducing ,Adiponectin receptor 1 ,Adiponectin ,biology ,Binding protein ,nutritional and metabolic diseases ,Signal transducing adaptor protein ,Cell Biology ,Endocytosis ,biology.protein ,Signal transduction ,Receptors, Adiponectin ,hormones, hormone substitutes, and hormone antagonists ,Protein Binding ,Signal Transduction - Abstract
Adiponectin whose systemic levels are reduced in obesity-related diseases ameliorates insulin sensitivity and regulates biological processes like apoptosis, proliferation, migration and inflammation. Adiponectin binds to adiponectin receptors, AdipoR1 and AdipoR2, which are ubiquitously expressed. Clathrin-dependent endocytosis of AdipoR1 and adiponectin has been demonstrated to modulate adiponectin bioactivity. Recently, APPL1 has been identified as an AdipoR1 and AdipoR2 binding protein. Furthermore, activated protein kinase C1, endoplasmic reticulum protein 46 and protein kinase CK2β subunit form a complex with AdipoR1. This review summarizes recent studies exploiting heterologous expression of adiponectin receptors in yeast, and the type and function of the recently described adiponectin receptor associated proteins.
- Published
- 2010
29. 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
- Author
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Andreas Schäffler, Markus Neumeier, Christa Buechler, J. Schölmerich, Margarita Bala, and Andrea Kopp
- Subjects
MAPK/ERK pathway ,Adult ,Lipopolysaccharides ,Male ,MAP Kinase Signaling System ,MAP Kinase Kinase 2 ,MAP Kinase Kinase 1 ,Adipose tissue ,Biology ,Proinflammatory cytokine ,chemistry.chemical_compound ,Mice ,Endocrinology ,Adipocyte ,3T3-L1 Cells ,Nitriles ,Adipocytes ,Butadienes ,Animals ,Humans ,Insulin ,RNA, Messenger ,Phosphorylation ,Extracellular Signal-Regulated MAP Kinases ,Chemokine CCL2 ,Anthracenes ,Inflammation ,Interleukin-6 ,c-jun ,Toll-Like Receptors ,JNK Mitogen-Activated Protein Kinases ,Molecular biology ,chemistry ,Adipose Tissue ,Mitogen-activated protein kinase ,Myeloid Differentiation Factor 88 ,biology.protein ,Female ,Interferon Regulatory Factor-3 ,Signal transduction - Abstract
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.
- Published
- 2010
30. Adiponectin-stimulated CXCL8 release in primary human hepatocytes is regulated by ERK1/ERK2, p38 MAPK, NF-kappaB, and STAT3 signaling pathways
- Author
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Andreas Schäffler, Thomas S. Weiss, Charalampos Aslanidis, Johanna Weigert, Josef Wanninger, Cornelia Bleyl, Sabrina Bauer, Jürgen Schölmerich, Christa Buechler, Corinna Krempl, and Markus Neumeier
- Subjects
musculoskeletal diseases ,STAT3 Transcription Factor ,Chemokine ,Time Factors ,Physiology ,p38 mitogen-activated protein kinases ,Cell Culture Techniques ,p38 Mitogen-Activated Protein Kinases ,Downregulation and upregulation ,Physiology (medical) ,Cell Line, Tumor ,Humans ,Interleukin 8 ,RNA, Messenger ,Phosphorylation ,STAT3 ,Protein Kinase Inhibitors ,Adiponectin receptor 1 ,Mitogen-Activated Protein Kinase 1 ,Mitogen-Activated Protein Kinase 3 ,Hepatology ,Adiponectin ,biology ,Interleukin-8 ,Gastroenterology ,NF-kappa B ,Recombinant Proteins ,Up-Regulation ,biology.protein ,Cancer research ,Hepatocytes ,RNA Interference ,Signal transduction ,Receptors, Adiponectin ,hormones, hormone substitutes, and hormone antagonists ,Signal Transduction - Abstract
Adiponectin is believed to exert hepatoprotective effects and induces CXCL8, a chemokine that functions as a survival factor, in vascular cells. In the current study, it is demonstrated that adiponectin also induces CXCL8 expression in primary human hepatocytes but not in hepatocellular carcinoma cell lines. Knock down of the adiponectin receptor (AdipoR) 1 or AdipoR2 by small-interfering RNA indicates that AdipoR1 is involved in adiponectin-stimulated CXCL8 release. Adiponectin activates nuclear factor (NF)-κB in primary hepatocytes and pharmacological inhibition of NF-κB, the p38 mitogen-activated protein kinase, and extracellular signal-regulated kinase (ERK) 1/ERK2 reduces adiponectin-mediated CXCL8 secretion. Furthermore, adiponectin also activates STAT3 involved in interleukin (IL)-6 and leptin-mediated CXCL8 induction in primary hepatocytes. Inhibition of JAK2 by AG-490 does not abolish adiponectin-stimulated CXCL8, indicating that this kinase is not involved. Pretreatment of primary cells with “STAT3 Inhibitor VI,” however, elevates hepatocytic CXCL8 secretion, demonstrating that STAT3 is a negative regulator of CXCL8 in these cells. In accordance with this assumption, IL-6, a well-characterized activator of STAT3, reduces hepatocytic CXCL8. Therefore, adiponectin-stimulated induction of CXCL8 seems to be tightly controlled in primary human hepatocytes, whereas neither NF-κB, STAT3, nor CXCL8 are influenced in hepatocytic cell lines. CXCL8 is a survival factor, and its upregulation by adiponectin may contribute to the hepatoprotective effects of this adipokine.
- Published
- 2009
31. Effects of the new adiponectin paralogous protein CTRP-3 and of LPS on cytokine release from monocytes of patients with type 2 diabetes mellitus
- Author
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Jürgen Schölmerich, Andrea Kopp, Charalampos Aslanidis, Johanna Weigert, Andreas Schäffler, Markus Neumeier, Christa Büchler, and Margarita Bala
- Subjects
Adult ,Lipopolysaccharides ,Male ,medicine.medical_specialty ,endocrine system diseases ,medicine.medical_treatment ,Immunology ,Stimulation ,Biology ,Biochemistry ,Monocytes ,Basal (phylogenetics) ,Young Adult ,Internal medicine ,Diabetes mellitus ,medicine ,Immunology and Allergy ,Animals ,Humans ,Molecular Biology ,Cells, Cultured ,Aged ,Adiponectin ,Interleukin-6 ,Tumor Necrosis Factor-alpha ,Monocyte ,nutritional and metabolic diseases ,Type 2 Diabetes Mellitus ,Hematology ,Middle Aged ,medicine.disease ,medicine.anatomical_structure ,Endocrinology ,Cytokine ,Diabetes Mellitus, Type 2 ,Tumor Necrosis Factors ,Cytokines ,Tumor necrosis factor alpha ,Female - Abstract
It was the aim to investigate the hypothesis that the new C1q/TNF-family member CTRP-3 (C1q/TNF-related protein-3) acts anti-inflammatory in human monocytes from healthy controls and patients with type 2 diabetes mellitus (T2D).Monocytes were isolated from 20 healthy controls and 30 patients with T2D. IL-6 and TNF concentrations were measured by ELISA. CTRP-3 was expressed in insect cells and used for stimulation experiments.Basal IL-6 and TNF were not different in control and in T2D monocytes. LPS-stimulation (1 microg/ml) significantly (p0.001) increased IL-6 and TNF in the supernatants of control and in T2D monocytes to a similar extent. CTRP-3 (1 microg/ml) significantly (p=0.03) inhibited LPS-induced IL-6 in control monocytes but not in T2D monocytes. TNF upon co-stimulation with LPS and CTRP-3 was significantly (p=0.012) lower in control than in T2D monocytes. LPS-induced TNF concentration was significantly and positively correlated with serum total cholesterol and LDL cholesterol in T2D patients.CTRP-3 inhibits LPS-induced IL-6 and TNF release. This anti-inflammatory effect is lost in T2D. Serum cholesterol concentration affects the pro-inflammatory potential of LPS to induce TNF release from T2D monocytes in the presence or absence of CTRP-3. CTRP-3 might partly account for the pro-inflammatory state in T2D.
- Published
- 2009
32. Elevated adiponectin serum levels in patients with chronic alcohol abuse rapidly decline during alcohol withdrawal
- Author
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Norbert Wodarz, Philip Köhl, Andreas Schäffler, Monika Johann, P. Kiefer, Christa Buechler, Claus Hellerbrand, Markus Neumeier, and Thomas S. Weiss
- Subjects
Adult ,Liver Cirrhosis ,Male ,medicine.medical_specialty ,Cirrhosis ,Time Factors ,Alcohol Drinking ,Alcohol ,chemistry.chemical_compound ,Mice ,Liver Cirrhosis, Alcoholic ,Internal medicine ,3T3-L1 Cells ,parasitic diseases ,Adipocytes ,Medicine ,Animals ,Humans ,Aspartate Aminotransferases ,RNA, Messenger ,Ethanol ,Hepatology ,biology ,Adiponectin ,Dose-Response Relationship, Drug ,business.industry ,Fatty liver ,Gastroenterology ,Alanine Transaminase ,Hepatitis C ,Hepatitis C, Chronic ,Middle Aged ,medicine.disease ,Substance Withdrawal Syndrome ,Up-Regulation ,Alcoholism ,Endocrinology ,chemistry ,Alanine transaminase ,Liver ,biology.protein ,Hepatocytes ,Female ,business ,Biomarkers ,Alcohol Abstinence - Abstract
Background: Adiponectin is a circulating protein with hepatoprotective effects. Aims: To study the relationship of excessive alcohol consumption and serum adiponectin levels (SAL). Patients and Methods: The SAL were determined in (i) heavy drinkers without advanced liver damage during the course of alcohol withdrawal, (ii) patients with chronic hepatitis C virus (HCV) infection, (iii) patients with alcohol-associated cirrhosis, and (iv) healthy volunteers that consumed excessive amounts of alcohol for only a short period of time. Further, primary human hepatocytes (PHH) and adipocytes were incubated in vitro with alcohol or serum of patients. Results: Patients with chronic alcohol consumption had significantly higher SAL than HCV-patients with comparable degrees of liver damage. In alcoholics, but not in HCV patients, SAL positively correlated with serum levels of aminotransferases. Further, SAL correlated with the amount of alcohol consumption but declined during the course of alcohol abstinence. After short-term excessive alcohol consumption SAL were not elevated in healthy individuals. Adiponectin mRNA was detectable in adipocytes but not in hepatocytes, and alcohol failed to induce adiponectin in both cell types. In contrast, serum of active drinkers induced adiponectin expression in adipocytes while serum from the same individuals collected after alcohol withdrawal had no effect. Conclusions: Alcohol exhibits a specific effect on SAL that is dose and time dependent, and correlates with the degree of hepatic damage. Alcohol does not seem to affect adiponectin expression directly in adipocytes but potentially via mediators systemically released as a result of the chronic alcohol intake.
- Published
- 2008
33. Adiponectin upregulates monocytic activin A but systemic levels are not altered in obesity or type 2 diabetes
- Author
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Andrea Schramm, Charalampos Aslanidis, Christa Buechler, Andreas Schäffler, Fabian Stögbauer, Daniela Sporrer, S. Wurm, Josef Wanninger, Markus Neumeier, Johanna Weigert, Franziska Schober, Michael Filarsky, Markus Weber, and Jürgen Schölmerich
- Subjects
Male ,medicine.medical_specialty ,animal structures ,MAP Kinase Signaling System ,p38 mitogen-activated protein kinases ,Immunology ,Adipokine ,Type 2 diabetes ,Biochemistry ,p38 Mitogen-Activated Protein Kinases ,Monocytes ,Internal medicine ,Diabetes mellitus ,Immunology and Allergy ,Medicine ,Humans ,Hypoglycemic Agents ,Obesity ,Molecular Biology ,Cells, Cultured ,Foam cell ,Aged ,Adiponectin ,business.industry ,nutritional and metabolic diseases ,Hematology ,Middle Aged ,medicine.disease ,Metformin ,Activins ,Endocrinology ,Diabetes Mellitus, Type 2 ,embryonic structures ,business ,Pioglitazone ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug - Abstract
Adiponectin is an adipocyte-derived protein with atheroprotective and immunoregulatory function. Adiponectin and activin A reduce foam cell formation and adiponectin activates the p38 MAPK pathway that is well described to induce activin A. Therefore, it was analyzed whether adiponectin alters activin A in primary human monocytes. Adiponectin dose- and time-dependently induced activin A in the supernatant, and the maximal amount was observed after 12 h of incubation. Adiponectin-stimulated release of activin A was blocked by a p38 MAPK inhibitor. Metformin and pioglitazone are drugs frequently used to treat diabetic patients and metformin slightly reduced monocytic activin A release whereas pioglitazone had no effect. Type 2 diabetes is associated with elevated inflammatory systemic cytokines but activin A serum levels were similar in slim probands, overweight controls and type 2 diabetic patients. Furthermore, activin A did not correlate to systemic adiponectin, body mass index, waist to hip ratio or C-reactive protein. These findings indicate that adiponectin upregulates monocytic activin A release via the p38 MAPK pathway, and this may in part explain the immunoregulatory and antiatherosclerotic effects of this adipokine.
- Published
- 2008
34. Effects of the new C1q/TNF-related protein (CTRP-3) 'cartonectin' on the adipocytic secretion of adipokines
- Author
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Juergen Schoelmerich, Charalampos Aslanidis, Britta Wölfing, Markus Neumeier, Christa Buechler, Johanna Weigert, and Andreas Schäffler
- Subjects
Leptin ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Blotting, Western ,Medicine (miscellaneous) ,Adipokine ,Enzyme-Linked Immunosorbent Assay ,Body Mass Index ,chemistry.chemical_compound ,Mice ,Endocrinology ,Adipokines ,Species Specificity ,Genes, Reporter ,Internal medicine ,Adipocyte ,3T3-L1 Cells ,medicine ,Adipocytes ,Animals ,Humans ,Secretion ,Luciferase ,Resistin ,Receptor ,Promoter Regions, Genetic ,Nutrition and Dietetics ,Adiponectin ,Interleukin-6 ,Recombinant Proteins ,Subcutaneous Fat, Abdominal ,PPAR gamma ,chemistry ,Tumor Necrosis Factors - Abstract
Background: Cartonectin (collagenous repeat-containing sequence of 26-kDa protein; CORS-26) was described as a new adipokine of the C1q/TNF molecular superfamily C1q/TNF-related protein-3 (CTRP-3), secreted by the adipocytes of mice and humans. The receptor and function of cartonectin are unknown and the recombinant protein is not commercially available. Objective: To investigate the effects of recombinant cartonectin on the secretion of adipokines such as adiponectin, leptin, and resistin from adipocytes of human and murine origin. The effect of the BMI of the adipocyte donor was also investigated. Methods and Procedures: Human adipocytes from pooled lean and preobese healthy individuals and murine 3T3-L1 adipocytes were used for stimulation experiments. Recombinant cartonectin was expressed in insect H5 cells. Adipokine secretion was measured using enzyme-linked immunosorbent assay. In addition, western blot analysis and luciferase reporter gene assays were employed. Results: Cartonectin (1, 10, 50, and 250 ng/ml) in higher doses stimulates the secretion of adiponectin and resistin from murine adipocytes. This effect is not caused by an induction of peroxisome proliferator-activated receptor-γ (PPAR-γ) protein expression, as confirmed by western blot analysis. Also, luciferase reporter gene assay revealed that cartonectin failed to induce luciferase activity at the peroxisome proliferator-activated receptor responsive element site containing the adiponectin/luciferase promoter fragment. Human adipocytes from lean individuals secrete higher amounts of adiponectin and leptin when compared with adipocytes of individuals with a preobesity BMI (25–30 kg/m2). Cartonectin failed to stimulate adiponectin or leptin secretion from human adipocytes, irrespective of the BMI value. Discussion: Cartonectin is a new adipokine that differentially regulates the secretion of classical adipokines, with marked differences between the human and the murine systems. These effects are species-dependent, while basal adipokine secretion is influenced by the BMI.
- Published
- 2008
35. Adiponectin effects on human breast cancer cells are dependent on 17-β estradiol
- Author
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Andreas Schäffler, Markus Neumeier, Oliver Treeck, Gerd Schmitz, Christa Buechler, Georg Pfeiler, and Olaf Ortmann
- Subjects
Cancer Research ,medicine.medical_specialty ,Adiponectin ,Oncogene ,medicine.drug_class ,Estrogen receptor ,Cancer ,General Medicine ,Biology ,medicine.disease ,Endocrinology ,Breast cancer ,Oncology ,Estrogen ,Apoptosis ,Internal medicine ,Cancer cell ,medicine ,skin and connective tissue diseases ,hormones, hormone substitutes, and hormone antagonists - Abstract
Adiponectin, an adipocyte-derived serum protein, is known to positively affect the glucose and lipid metabolism and these effects are mediated by its receptors, AdipoR1 and R2. Serum adiponectin levels are inversely associated with breast cancer risk, but the molecular mechanisms underlying this association are not fully elucidated. Thus, the purpose of this study was to investigate the influence of adiponectin on breast cancer cells in vitro. We were able to demonstrate the expression of AdipoR1 and R2 in MCF-7, MDA-MB-231 and SK-BR-3 breast cancer cells on the mRNA level. Furthermore, the AdipoR1 protein could be detected by immunoblot analysis. In MCF-7 breast cancer cells, the expression of AdipoR1 significantly declined after stimulation with 17-beta estradiol, whereas the cyclin A2 expression significantly increased. Both effects were inhibited by the addition of adiponectin. Treatment with different concentrations of adiponectin in steroid-hormone-free medium did not affect cell proliferation or apoptosis. In contrast, after the addition of 17-beta estradiol, adiponectin slightly decreased the growth of the MDA-MB-231 and SK-BR3 cells but increased proliferation of the hormone-dependent MCF-7 breast cancer cells. Adiponectin also triggered cellular apoptosis in MDA-MB-231 breast cancer cells in the presence of 17-beta estradiol. These findings suggest that a cross-talk between adiponectin and estrogen receptor signaling exists in breast cancer cells and that adiponectin effects on the growth and apoptosis of breast cancer cells in vitro are dependent on the presence of 17-beta estradiol.
- Published
- 2008
36. Adiponectin effects on human breast cancer cells are dependent on 17-beta estradiol
- Author
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Georg H, Pfeiler, Christa, Buechler, Markus, Neumeier, Andreas, Schäffler, Gerd, Schmitz, Olaf, Ortmann, and Oliver, Treeck
- Subjects
Estradiol ,Caspases ,Cell Line, Tumor ,Gene Expression ,Humans ,Apoptosis ,Breast Neoplasms ,Drug Interactions ,Female ,Adiponectin ,Receptors, Adiponectin ,Cell Proliferation - Abstract
Adiponectin, an adipocyte-derived serum protein, is known to positively affect the glucose and lipid metabolism and these effects are mediated by its receptors, AdipoR1 and R2. Serum adiponectin levels are inversely associated with breast cancer risk, but the molecular mechanisms underlying this association are not fully elucidated. Thus, the purpose of this study was to investigate the influence of adiponectin on breast cancer cells in vitro. We were able to demonstrate the expression of AdipoR1 and R2 in MCF-7, MDA-MB-231 and SK-BR-3 breast cancer cells on the mRNA level. Furthermore, the AdipoR1 protein could be detected by immunoblot analysis. In MCF-7 breast cancer cells, the expression of AdipoR1 significantly declined after stimulation with 17-beta estradiol, whereas the cyclin A2 expression significantly increased. Both effects were inhibited by the addition of adiponectin. Treatment with different concentrations of adiponectin in steroid-hormone-free medium did not affect cell proliferation or apoptosis. In contrast, after the addition of 17-beta estradiol, adiponectin slightly decreased the growth of the MDA-MB-231 and SK-BR3 cells but increased proliferation of the hormone-dependent MCF-7 breast cancer cells. Adiponectin also triggered cellular apoptosis in MDA-MB-231 breast cancer cells in the presence of 17-beta estradiol. These findings suggest that a cross-talk between adiponectin and estrogen receptor signaling exists in breast cancer cells and that adiponectin effects on the growth and apoptosis of breast cancer cells in vitro are dependent on the presence of 17-beta estradiol.
- Published
- 2008
37. Insulin induces monocytic CXCL8 secretion by the mitogenic signalling pathway
- Author
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Markus Neumeier, Charalampos Aslanidis, Josef Wanninger, Christa Buechler, Melanie Gerl, Jürgen Schölmerich, Andreas Schäffler, S. Wurm, Antonia Gindner, and Johanna Weigert
- Subjects
musculoskeletal diseases ,Blood Glucose ,Male ,Snf3 ,Chemokine ,medicine.medical_specialty ,Glucose uptake ,medicine.medical_treatment ,Immunology ,Biochemistry ,Monocytes ,Body Mass Index ,Wortmannin ,chemistry.chemical_compound ,Phosphatidylinositol 3-Kinases ,Young Adult ,Downregulation and upregulation ,Internal medicine ,medicine ,Leukocytes ,Immunology and Allergy ,Humans ,Insulin ,Secretion ,Phosphatidylinositol ,Molecular Biology ,Cells, Cultured ,Phosphoinositide-3 Kinase Inhibitors ,Flavonoids ,Sirolimus ,biology ,TOR Serine-Threonine Kinases ,Interleukin-8 ,Hematology ,Androstadienes ,Endocrinology ,Glucose ,chemistry ,Calcium-Calmodulin-Dependent Protein Kinases ,biology.protein ,Female ,Protein Kinases ,Signal Transduction - Abstract
Oral glucose uptake alters the function of immune cells and an elevation of systemic CXCL8 was described. Monocytes secrete high amounts of CXCL8 and therefore it was analyzed whether glucose or insulin upregulate monocytic CXCL8 release. Incubation of monocytes with insulin for 2 h induced CXCL8 mRNA and secretion whereas glucose had no effect. Inhibition of the phosphatidylinositol 3-kinase by wortmannin or the mammalian target of rapamycin by rapamycin did not influence insulin-mediated CXCL8 induction. In contrast, blockage of the ERK-specific MAP kinase MEK with PD98059, that prevents phosphorylation of ERK1/ERK2, abrogated insulin-induced CXCL8 release in primary monocytes. To investigate the in vivo effect of oral glucose uptake, monocytes of healthy probands were isolated in the fasted state and 2 h after glucose ingestion and CXCL8 mRNA and protein were increased in the latter. CXCL8 was also higher when determined in the cell lysate of leukocytes 2 h after glucose uptake whereas plasma CXCL8 levels were significantly reduced. In summary, these data indicate that oral glucose uptake in insulin-sensitive adults is associated with elevated monocytic and reduced systemic CXCL8.
- Published
- 2007
38. Adiponectin effects on human breast cancer cells are dependent on 17-ß estradiol
- Author
-
A. Schäffler, Georg Pfeiler, G. Schmitz, O. Ortmann, Markus Neumeier, C. Büchler, and O. Treeck
- Subjects
Oncology ,medicine.medical_specialty ,Adiponectin ,business.industry ,Internal medicine ,Cancer cell ,medicine ,business ,Human breast - Published
- 2007
39. Detection of adiponectin in cerebrospinal fluid in humans
- Author
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J. Schölmerich, Roland Buettner, Sophie Sauerbruch, Stephan Killian, André Michael Müller, Charalampos Aslanidis, Christa Buechler, Markus Neumeier, Andreas Steinbrecher, Josef Wanninger, Felix Schlachetzki, Johanna Weigert, and Andreas Schäffler
- Subjects
Male ,medicine.medical_specialty ,Physiology ,Endocrinology, Diabetes and Metabolism ,Central nervous system ,Adipokine ,Inflammation ,Enzyme-Linked Immunosorbent Assay ,Biology ,Blood–brain barrier ,Diffusion ,Cerebrospinal fluid ,Physiology (medical) ,Internal medicine ,medicine ,Animals ,Humans ,Cells, Cultured ,Aged ,Adiponectin ,nutritional and metabolic diseases ,Endothelial Cells ,Middle Aged ,Rats ,medicine.anatomical_structure ,Endocrinology ,Female ,medicine.symptom ,hormones, hormone substitutes, and hormone antagonists - Abstract
Adiponectin circulates in the body in high concentrations, and 100-fold lower amounts were described in the cerebrospinal fluid (CSF) of mice, whereas in humans, contradictory results have been published. To clarify whether adiponectin is present in human CSF and is derived from the circulation, it was determined in human CSF and plasma of 52 nonselected patients. Adiponectin was detected by immunoblot in CSF and was quantified in CSF and serum by ELISA. CSF adiponectin was positively correlated to systemic levels, and the CSF/serum adiponectin ratio was correlated to the CSF/serum albumin ratio. Furthermore, disturbed function of the blood-brain barrier (BBB) was associated with an elevated CSF/serum adiponectin ratio. Adiponectin mRNA was not found in the brain, indicating that adiponectin crosses the BBB and/or the blood-cerebrospinal fluid barrier (BCB). Rat adiponectin with a COOH-terminal tag was injected into the tail vein of rats and was detected 3 h later in CSF. However, CSF adiponectin in humans and rats was ∼0.1% of the serum concentration and therefore was below the 0.5% expected in the CSF because of the residual leakage of an undisturbed BBB/BCB. Taken together, data from the present study show that adiponectin in human CSF is far below the level expected by the baseline BBB/BCB permeability, indicating that adiponectin enters the brain much less efficiently than albumin, thus supporting recent data that exclude adiponectin transport to the CSF. Additional studies are needed to reveal whether these low levels of adiponectin in CSF have a physiological function.
- Published
- 2007
40. Kombinierte Effekte von Adiponectin und Östradiol auf Mammakarzinomzellen in vitro
- Author
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Georg Pfeiler, O. Treeck, O. Ortmann, A. Schäffler, C. Büchler, Markus Neumeier, C. Singer, and C. Lattrich
- Published
- 2007
41. Der Einfluss von Adiponectin auf humane Brustkrebszellen in vitro
- Author
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A. Schäffler, Georg Pfeiler, Olaf Ortmann, Markus Neumeier, C. Büchler, Claus Lattrich, and Oliver Treeck
- Subjects
Maternity and Midwifery ,Obstetrics and Gynecology - Published
- 2006
42. Adiponectin and its receptors in rodent models of fatty liver disease and liver cirrhosis
- Author
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Erwin Gäbele, Thomas S. Weiss, Claus Hellerbrand, Christa Buechler, Jürgen Schölmerich, Cornelius Bollheimer, Markus Neumeier, Roland Buettner, Andreas Schäffler, M. Lichtenauer, and Johanna Weigert
- Subjects
Liver Cirrhosis ,Male ,medicine.medical_specialty ,Cirrhosis ,Receptors, Cell Surface ,Biology ,Mice ,Clinical Research ,Internal medicine ,medicine ,Animals ,Humans ,RNA, Messenger ,Rats, Wistar ,Receptor ,Cells, Cultured ,Adiponectin receptor 1 ,Regulation of gene expression ,Messenger RNA ,Adiponectin receptor 2 ,Adiponectin ,Fatty liver ,Gastroenterology ,nutritional and metabolic diseases ,General Medicine ,medicine.disease ,Rats ,Fatty Liver ,Mice, Inbred C57BL ,Disease Models, Animal ,Endocrinology ,Gene Expression Regulation ,Hepatocytes ,Receptors, Adiponectin ,hormones, hormone substitutes, and hormone antagonists - Abstract
AIM: To determine circulating and hepatic adiponectin in rodents with fatty liver disease or liver cirrhosis and investigate expression of the adiponectin receptors AdipoR1 on the mRNA and protein level and AdipoR2 on the mRNA level. METHODS: Fat fed rats were used as a model for fatty liver disease and bile duct ligation in mice to investigate cirrhotic liver. Expression of AdipoR1 and AdipoR2 mRNA was determined by real time RT-PCR. AdipoR1 protein was analysed by immunoblot. Adiponectin was measured by ELISA. RESULTS: Systemic adiponectin is reduced in fat-fed rats but is elevated in mice after bile duct ligation (BDL). Hepatic adiponectin protein is lower in steatotic liver but not in the liver of BDL-mice when compared to controls. Adiponectin mRNA was not detected in human liver samples or primary human hepatocytes nor in rat liver but recombinant adiponectin is taken up by isolated hepatocytes in-vitro. AdipoR1 mRNA and AdipoR1 protein levels are similar in the liver tissue of control and fat fed animals whereas AdipoR2 mRNA is induced. AdipoR2 mRNA and AdipoR1 mRNA and protein is suppressed in the liver of BDL-mice. CONCLUSION: Our studies show reduced circulating adiponectin in a rat model of fatty liver disease whereas circulating adiponectin is elevated in a mouse model of cirrhosis and similar findings have been described in humans. Diminished hepatic expression of adiponectin receptors was only found in liver cirrhosis.
- Published
- 2006
43. Profiling adipocytokine secretion from creeping fat in Crohn's disease
- Author
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Andreas Schäffler, Alois Fürst, Gerhard Rogler, Jürgen Schölmerich, Ulf Müller-Ladner, Markus Neumeier, Frauke Bataillle, Christa Buechler, Hans H Herfarth, and G. Paul
- Subjects
Adult ,Fibroblast Growth Factor 9 ,Male ,medicine.medical_specialty ,Peptide Hormones ,Adipokine ,Adipose tissue ,Antigens, Differentiation, Myelomonocytic ,Receptors, Cell Surface ,Biology ,Proinflammatory cytokine ,Crohn Disease ,Antigens, CD ,Internal medicine ,medicine ,Immunology and Allergy ,Humans ,RNA, Messenger ,Aged ,Adiponectin receptor 1 ,Adiponectin ,Reverse Transcriptase Polymerase Chain Reaction ,Leptin ,Gastroenterology ,Middle Aged ,Cathepsins ,Endocrinology ,Adipose Tissue ,Cytokines ,Resistin ,Female ,Chemokines ,Receptors, Adiponectin ,Ex vivo - Abstract
Background Adipose tissue is recognized as a compartment secreting highly active molecules. Creeping fat represents a characteristic feature of Crohn's disease (CD). Proinflammatory or anti-inflammatory adipose-derived secretory products, now generally called adipocytokines, may play a role in the pathogenesis of CD. Materials and methods Adipose tissue specimens were obtained from creeping fat contiguous to the involved intestine of 10 patients with CD. Mesenteric adipose tissue specimens resected from 13 patients with colon cancer (CC) and from 7 patients with diverticulitis served as controls. Three fat tissue specimen per well and 6 to 8 wells per patient were incubated ex vivo for 24 h. The release of adiponectin, resistin, leptin, interleukin-6, macrophage colony-stimulating factor, monocyte chemotactic protein-1, and migration inhibitory factor was measured by ELISA. The expression of AdipoR1 and AdipoR2 receptors was investigated by real-time quantitative polymerase chain reaction in a subset of adipose tissues. Results The secretion of adiponectin and macrophage colony-stimulating factor, as well as leptin and migration inhibitory factor, was significantly upregulated in CD compared with CC and diverticulitis or CC only, respectively. Resistin, interleukin-6, and monocyte chemotactic protein-1 were not specifically induced in CD but were associated with unspecific inflammation. Adiponectin receptor expression was not different in CC, CD, or diverticulitis. Steroid treatment in CD patients had differential effects on the ex vivo secretion of adipocytokines. Conclusions A specific secretion pattern of proinflammatory and anti-inflammatory adipocytokines indicates the significance of adipose tissue in intestinal inflammation in CD. Future investigations of this intestinal compartment may provide novel insights into the pathophysiological role of creeping fat and CD.
- Published
- 2006
44. Lipopolysaccharide regulated protein expression is only partly impaired in monocytes from patients with type I diabetes
- Author
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Andrea Kopp, Gabriele Wehrwein, Sabine Abke, Markus Neumeier, Johanna Weigert, Andreas Schäffler, Christa Buechler, and Jürgen Schölmerich
- Subjects
Adult ,Lipopolysaccharides ,Apolipoprotein E ,lcsh:Diseases of the circulatory (Cardiovascular) system ,medicine.medical_specialty ,endocrine system diseases ,Lipopolysaccharide ,Endocrinology, Diabetes and Metabolism ,CCL2 ,Monocytes ,chemistry.chemical_compound ,Apolipoproteins E ,Internal medicine ,Humans ,Medicine ,Secretion ,Interleukin 8 ,Interleukin 6 ,Cells, Cultured ,Chemokine CCL2 ,Original Investigation ,Innate immune system ,biology ,Interleukin-6 ,Superoxide Dismutase ,business.industry ,Blood Proteins ,Middle Aged ,Diabetes Mellitus, Type 1 ,Endocrinology ,chemistry ,lcsh:RC666-701 ,Case-Control Studies ,Immunology ,biology.protein ,Interleukin 19 ,lipids (amino acids, peptides, and proteins) ,Female ,Cardiology and Cardiovascular Medicine ,business ,Chemokines, CXC - Abstract
BackgroundMonocytes play an important role in innate immunity and atherosclerosis. A disturbed secretion of cytokines in lipopolysaccharide (LPS) activated monocytes from type 1 diabetes (T1D) patients has been described and may contribute to the impaired inflammatory response in these individuals. In the present study the influence of LPS on five different proteins with a function in immunity and atherosclerosis was analyzed in monocytes from controls and T1D patients.MethodsMonocytes were isolated from controls and T1D patients and the LPS-stimulated increase of IL-6, CXCL8, monocyte chemotactic protein 1 (CCL2, MCP-1) and superoxide dismutase (SOD 2), as well as the LPS-mediated decrease of apolipoprotein E (Apo E) in primary human monocytes from controls and T1D patients was determined.ResultsCCL2 and IL-6 secretion in response to LPS was found significantly reduced in monocytes from T1D patients when compared to controls whereas basal CCL2 release was similar in control and T1D cells. In contrast, CXCL8 and apolipoprotein E secretion and SOD 2 expression upon LPS stimulation is similar from T1D and control monocytes.ConclusionThese data indicate that LPS-mediated protein expression is only partly disturbed in monocytes from T1D patients. Reduced secretion of IL-6 and CCL2 in activated monocytes of these patients may contribute to an impaired inflammatory response and vascular disease.
- Published
- 2006
45. Different effects of adiponectin isoforms in human monocytic cells
- Author
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Andreas Schäffler, Jürgen Schölmerich, Johanna Weigert, Christa Buechler, Markus Neumeier, Ulf Müller-Ladner, Gabriele Wehrwein, and Christian E. Wrede
- Subjects
medicine.medical_specialty ,Immunology ,610 Medizin ,Inflammation ,Apoptosis ,AMP-Activated Protein Kinases ,Protein Serine-Threonine Kinases ,Monocytes ,Cell Line ,Mice ,AMP-activated protein kinase ,endotoxin ,inflammation ,adipokine ,diabetes ,Multienzyme Complexes ,Internal medicine ,medicine ,Immunology and Allergy ,Animals ,Humans ,Protein Isoforms ,Secretion ,RNA, Messenger ,Phosphorylation ,Protein kinase A ,Cells, Cultured ,Receptors, Scavenger ,biology ,Kinase ,Interleukin-6 ,Anti-Inflammatory Agents, Non-Steroidal ,AMPK ,food and beverages ,Cell Biology ,Recombinant Proteins ,Cell biology ,Interleukin-10 ,Molecular Weight ,Endocrinology ,Cell culture ,biology.protein ,Adiponectin ,medicine.symptom ,Signal transduction - Abstract
Adiponectin (APM) is an adipocyte-derived adipokine with immunosuppressive, antidiabetic, and antiatherosclerotic properties. Low molecular weight (LMW)- and higher molecular weight (HMW)-APM circulate in the serum and activate different signaling pathways. We were interested to see whether LMW-APM exerts different effects on monocytic cells compared with the HMW isoform. Therefore, the effects of recombinant LMW-APM produced in insect cells and the APM from higher eukaryotic cells containing HMW forms on monocytic cells were investigated with respect to apoptosis and inflammation. LMW- and HMW-APM induce apoptosis in nondifferentiated THP-1 cells, reduce macrophage scavenger receptor (MSR) A mRNA expression, and stimulate phosphorylation of adenosine monophosphate-activated protein kinase (AMPK). However, HMW-APM induces the secretion of interleukin (IL)-6 in human monocytes and THP-1 cells but does not suppress lipopolysaccharide (LPS)-induced IL-6 secretion. In contrast, LMW-APM reduces LPS-mediated IL-6 release and furthermore, stimulates IL-10 secretion, most likely by reducing the abundance of inhibitor of nuclear factor (NF)-κB kinase β, leading to a diminished nuclear translocation of NF-κB p65. Our data indicate that the different APM isoforms do share common effects on monocytic cells but also induce isoform-specific responses. Although apoptosis, the activation of AMPK, and the reduction of MSR are mediated by all APM isoforms, only LMW-APM displays anti-inflammatory properties.
- Published
- 2006
46. Genomic structure of human omentin, a new adipocytokine expressed in omental adipose tissue
- Author
-
Andreas Schäffler, Christa Büchler, Markus Neumeier, J. Schölmerich, Hans H Herfarth, and Alois Fürst
- Subjects
Adult ,Male ,medicine.medical_specialty ,Molecular Sequence Data ,Biophysics ,Context (language use) ,Intelectin ,Biology ,GPI-Linked Proteins ,Biochemistry ,chemistry.chemical_compound ,Structural Biology ,Internal medicine ,Adipocyte ,Lectins ,Genetics ,medicine ,Humans ,Amino Acid Sequence ,RNA, Messenger ,Promoter Regions, Genetic ,Gene ,Peptide sequence ,Crohn's disease ,Binding Sites ,Base Sequence ,Genome, Human ,Promoter ,Exons ,Genomics ,Middle Aged ,medicine.disease ,Endocrinology ,chemistry ,Adipose Tissue ,Cytokines ,Female ,Primer (molecular biology) ,Hydrophobic and Hydrophilic Interactions ,Omentum - Abstract
Genomic structure, promoter region, amino acid sequence and exon-specific primer combinations of the human omentin gene are presented. Omentin mRNA expression differs between omental adipose tissue probes from patients with chronic inflammatory bowel diseases such as Crohn's disease. Sequence comparisons revealed a 100% identity of omentin with human intelectin. Based on this, omentin might be a new adipocytokine playing a role in the defense against intestinal bacterial translocation in the context of Crohn's disease.
- Published
- 2005
47. Corrigendum to 'Adiponectin stimulates release of CCL2, -3, -4 and -5 while the surface abundance of CCR2 and -5 is simultaneously reduced in primary human monocytes' [Cytokine 56 (2011) 573–580]
- Author
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Andreas Schäffler, Markus Neumeier, Sabine Abke, Kristina Eisinger, Hilke Brühl, Roland Walter, Sabrina Bauer, Andrea Kopp, and Christa Buechler
- Subjects
CCR2 ,Primary (chemistry) ,Adiponectin ,Chemistry ,medicine.medical_treatment ,Immunology ,Hematology ,CCL2 ,Biochemistry ,Cell biology ,Cytokine ,Abundance (ecology) ,medicine ,Immunology and Allergy ,Molecular Biology - Published
- 2013
48. Corrigendum to 'Adiponectin downregulates galectin-3 whose cellular form is elevated whereas its soluble form is reduced in type 2 diabetic monocytes' [FEBS Lett. 583 (2009) pp. 3718-3724]
- Author
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Andreas Schäffler, Markus Weber, S. Wurm, Daniela Sporrer, Andrea Kopp, Margarita Bala, Markus Neumeier, Fabian Stögbauer, Christa Buechler, Josef Wanninger, and Johanna Weigert
- Subjects
medicine.medical_specialty ,Endocrinology ,Adiponectin ,Structural Biology ,Chemistry ,Galectin-3 ,Internal medicine ,Genetics ,Biophysics ,medicine ,Cell Biology ,Molecular Biology ,Biochemistry - Published
- 2013
49. C1q/TNF-Related Protein-3 Represents a Novel and Endogenous Lipopolysaccharide Antagonist of the Adipose Tissue
- Author
-
Margarita Bala, Philipp Gross, Andreas Schäffler, Markus Neumeier, Andrea Kopp, Jürgen Schölmerich, Christa Buechler, and Werner Falk
- Subjects
Adult ,Lipopolysaccharides ,Male ,medicine.medical_specialty ,Chemokine ,Endocrinology, Diabetes and Metabolism ,Blotting, Western ,Clinical Biochemistry ,Adipose tissue ,Enzyme-Linked Immunosorbent Assay ,Biology ,Transfection ,Biochemistry ,Monocytes ,Proinflammatory cytokine ,Mice ,Endocrinology ,3T3-L1 Cells ,Internal medicine ,Lipid droplet ,Adipocytes ,medicine ,Animals ,Humans ,RNA, Messenger ,Receptor ,Chemokine CCL2 ,Inflammation ,Adiponectin ,Reverse Transcriptase Polymerase Chain Reaction ,Monocyte ,Toll-Like Receptors ,Biochemistry (medical) ,Middle Aged ,medicine.anatomical_structure ,Adipose Tissue ,Diabetes Mellitus, Type 2 ,Tumor Necrosis Factors ,TLR4 ,biology.protein ,Cytokines ,Female ,Signal Transduction - Abstract
Proteins secreted by adipocytes (adipokines) play an important role in the pathophysiology of type 2 diabetes mellitus and the associated chronic and low-grade state of inflammation. It was the aim to characterize the antiinflammatory potential of the new adipocytokine, C1q/TNF-related protein-3 (CTRP-3), which shows structural homologies to the pleiotropic adipocytokine adiponectin. mRNA and protein expression of CTRP-3 was analyzed by RT-PCR and Western blot. Recombinant CTRP-3 and small interfering RNA-based strategies were used to investigate the effect of CTRP-3 on toll-like receptor (TLR) ligand, lipopolysaccharide (LPS)-, and lauric acid-induced chemokine release of monocytes and adipocytes. Together with complex ELISA-based techniques, a designed TLR4/myeloid differentiation protein-2 fusion molecule shown to bind LPS was used to prove the ability of CTRP-3 to act as endogenous LPS antagonist. CTRP-3 is synthesized in monocytes and adipocytes. The recombinant protein dose-dependently inhibits the release of chemokines in monocytes and adipocytes that were induced by lauric acid, LPS, and other TLR ligands in vitro and ex vivo. CTRP-3 inhibits monocyte chemoattractant protein-1 release in adipocytes, whereas small interfering RNA-mediated knockdown of CTRP-3 up-regulates monocyte chemoattractant protein-1 release, reduces lipid droplet size, and decreases intracellular triglyceride concentration in adipocytes, causing a dedifferentiation into a more proinflammatory and immature phenotype. By using a designed TLR4/MD-2 fusion molecule, it is shown by different techniques that CTRP-3 specifically and effectively inhibits the binding of LPS to its receptor, TLR4/MD-2. CTRP-3 inhibits three basic and common proinflammatory pathways involved in obesity and type 2 diabetes mellitus (adipo-inflammation) by acting as an endogenous LPS antagonist of the adipose tissue.
- Published
- 2010
50. M1835 Wounding Induces Mapkap-2 Dependent Small Heat Shock Protein HSP27 Phosphorylation in Intestinal Epithelial Cell Monolayers
- Author
-
Christa Buechler, Thomas Karrasch, Markus Neumeier, and Tanja Spaeth
- Subjects
medicine.anatomical_structure ,Hepatology ,Chemistry ,Heat shock protein ,Monolayer ,Gastroenterology ,medicine ,Hsp27 phosphorylation ,Epithelium ,Cell biology - Published
- 2010
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