Publications by authors named "Juergen Eckel"

40 Publications

Intestinal microbiota and host metabolism - A complex relationship.

Authors:
Juergen Eckel

Acta Physiol (Oxf) 2021 Feb 26:e13638. Epub 2021 Feb 26.

Institute for Clinical Diabetology, German Diabetes Center, Düsseldorf, Germany.

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http://dx.doi.org/10.1111/apha.13638DOI Listing
February 2021

Cannabinoid Receptors in Metabolic Regulation and Diabetes.

Physiology (Bethesda) 2021 Mar;36(2):102-113

Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

There is an urgent need for developing effective drugs to combat the obesity and Type 2 diabetes mellitus epidemics. The endocannabinoid system plays a major role in energy homeostasis. It comprises the cannabinoid receptors 1 and 2 (CB and CB), endogenous ligands called endocannabinoids and their metabolizing enzymes. Because the CB receptor is overactivated in metabolic alterations, pharmacological blockade of the CB receptor arose as a promising candidate to treat obesity. However, because of the wide distribution of CB receptors in the central nervous system, their negative central effects halted further therapeutic use. Although the CB receptor is mostly peripherally expressed, its role in metabolic homeostasis remains unclear. This review discusses the potential of CB and CB receptors at the peripheral level to be therapeutic targets in metabolic diseases. We focus on the impact of pharmacological intervention and/or silencing on peripheral cannabinoid receptors in organs/tissues relevant for energy homeostasis. Moreover, we provide a perspective on novel therapeutic strategies modulating these receptors. Targeting CB with peripherally restricted antagonists, neutral antagonists, inverse agonists, or monoclonal antibodies could represent successful strategies. CB agonism has shown promising results at preclinical level. Beyond classic antagonism and agonism targeting orthosteric sites, the recently described crystal structures of CB and CB open new possibilities for therapeutic interventions with negative and positive allosteric modulators. The challenge of simultaneously targeting CB and CB might be possible by developing dual-steric ligands. The future will tell whether these promising strategies result in a renaissance of the cannabinoid receptors as therapeutic targets in metabolic diseases.
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http://dx.doi.org/10.1152/physiol.00029.2020DOI Listing
March 2021

Integrins-Mediators of cellular adhesion or more?

Authors:
Juergen Eckel

Acta Physiol (Oxf) 2020 07 29;229(3):e13482. Epub 2020 Apr 29.

Institute for Clinical Diabetology, German Diabetes Center, Düsseldorf, Germany.

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http://dx.doi.org/10.1111/apha.13482DOI Listing
July 2020

Soluble dipeptidyl peptidase-4 induces microvascular endothelial dysfunction through proteinase-activated receptor-2 and thromboxane A2 release.

J Hypertens 2016 May;34(5):869-76

aPaul Langerhans Group for Integrative Physiology, German Diabetes Center, Düsseldorf, Germany bDepartment of Pharmacology, School of Medicine, Universidad Autónoma de Madrid, Madrid, Spain cGerman Center for Diabetes Research (DZD e.V.), Düsseldorf, Germany *Carlos F. Sánchez-Ferrer and Concepción Peiró jointly directed this work.

Background: Dipeptidyl peptidase-4 (DPP4) is a key protein in glucose homeostasis and a pharmacological target in type 2 diabetes mellitus. This study explored whether the novel adipokine soluble DPP4 (sDPP4) can cause endothelial dysfunction, an early marker of impaired vascular reactivity.

Method: Reactivity was studied in mesenteric arteries from 3-month-old female mice, using a small vessel myograph. Thromboxane A2 (TXA2) release was explored in cultured human coronary artery endothelial cells by enzyme immunoassay.

Results: Neither the contractility to noradrenaline nor the endothelium-independent relaxations induced by sodium nitroprusside were modified by sDPP4. However, sDPP4 impaired in a concentration-dependent manner the endothelium-dependent relaxation elicited by acetylcholine. The DPP4 inhibitors K579 and linagliptin prevented the defective relaxation induced by sDPP4, as did the protease-activated receptor 2 (PAR2) inhibitor GB83. Downstream of PAR2, the cyclooxygenase (COX) inhibitor indomethacin, the COX2 inhibitor celecoxib or the thromboxane receptors blocker SQ29548 prevented the deleterious effects of sDPP4. Accordingly, sDPP4 triggered the release of TXA2 by endothelial cells, whereas TXA2 release was prevented by inhibiting DPP4, PAR2 or COX.

Conclusion: In summary, these findings reveal sDPP4 as a direct mediator of endothelial dysfunction, acting through PAR2 activation and the release of vasoconstrictor prostanoids. By interfering with these actions, DPP4 inhibitors might help preserving endothelial function in the context of cardiometabolic diseases.
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http://dx.doi.org/10.1097/HJH.0000000000000886DOI Listing
May 2016

DPP4 in Diabetes.

Front Immunol 2015 27;6:386. Epub 2015 Jul 27.

Paul-Langerhans-Group for Integrative Physiology, German Diabetes Center , Düsseldorf , Germany.

Dipeptidyl-peptidase 4 (DPP4) is a glycoprotein of 110 kDa, which is ubiquitously expressed on the surface of a variety of cells. This exopeptidase selectively cleaves N-terminal dipeptides from a variety of substrates, including cytokines, growth factors, neuropeptides, and the incretin hormones. Expression of DPP4 is substantially dysregulated in a variety of disease states including inflammation, cancer, obesity, and diabetes. Since the incretin hormones, glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide (GIP), are major regulators of post-prandial insulin secretion, inhibition of DPP4 by the gliptin family of drugs has gained considerable interest for the therapy of type 2 diabetic patients. In this review, we summarize the current knowledge on the DPP4-incretin axis and evaluate most recent findings on DPP4 inhibitors. Furthermore, DPP4 as a type II transmembrane protein is also known to be cleaved from the cell membrane involving different metalloproteases in a cell-type-specific manner. Circulating, soluble DPP4 has been identified as a new adipokine, which exerts both para- and endocrine effects. Recently, a novel receptor for soluble DPP4 has been identified, and data are accumulating that the adipokine-related effects of DPP4 may play an important role in the pathogenesis of cardiovascular disease. Importantly, circulating DPP4 is augmented in obese and type 2 diabetic subjects, and it may represent a molecular link between obesity and vascular dysfunction. A critical evaluation of the impact of circulating DPP4 is presented, and the potential role of DPP4 inhibition at this level is also discussed.
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http://dx.doi.org/10.3389/fimmu.2015.00386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4515598PMC
August 2015

Adipose tissue dysfunction and inflammation in cardiovascular disease.

Front Horm Res 2014 10;43:79-92. Epub 2014 Jun 10.

Paul Langerhans Group for Integrative Physiology, German Diabetes Center, Düsseldorf, Germany.

Adipose tissue (AT) was long perceived as a passive lipid storage depot but it is now considered as an endocrine organ that produces a large number of mediators that affect metabolism, inflammation and coagulation. In obesity, the increased size of adipocytes and chronic low-grade inflammation within AT alter its normal physiological function. AT dysfunction results in altered production and secretion of adipokines, which in turn affect several tissues, e.g. the liver, skeletal muscles and vasculature, in a para- or endocrine manner. Numerous circulating proinflammatory mediators involved in the development of cardiovascular disease (CVD) are directly released from adipocytes, thereby linking obesity to an increased cardiovascular risk. In the current chapter, we focus, on the one hand, on a small selection of novel adipokines with a potentially strong link to CVD: soluble dipeptidyl peptidase-4, visfatin and lipocalin-2. On the other hand, we summarize the most recent findings on the novel cardioprotective adipokines omentin and apelin.
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http://dx.doi.org/10.1159/000360560DOI Listing
February 2015

Monocyte chemoattractant protein-induced protein 1 impairs adipogenesis in 3T3-L1 cells.

Biochim Biophys Acta 2014 Apr 10;1843(4):780-8. Epub 2014 Jan 10.

Department of General Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland. Electronic address:

Monocyte chemoattractant protein-induced protein 1 (MCPIP1) encoded by the ZC3H12a gene (also known as Regnase-1) is involved in the regulation of degradation of mRNA of inflammatory modulators and for processing of pre-miRNA. These functions depend on the presence of the PIN domain. Moreover, MCPIP1 was described as a negative regulator of NF-κB and AP-1 signaling pathways although mechanisms underlying such activity remain unknown. We aimed at determining the role of MCPIP1 in adipogenesis. Here, we present evidence that Mcpip1 transcription is transiently activated during 3T3-L1 transition from pre- to adipocytes. However Mcpip1 protein expression is also strongly decreased at day one after induction of adipogenesis. Knockdown of Mcpip1 results in an upregulation of C/EBPβ and PPARγ mRNAs, whereas overexpression of MCPIP1 reduces the level of both transcription factors and impairs adipogenesis. MCPIP1-dependend modulation of C/EBPβ and PPARγ levels results in a modulation of the expression of downstream controlled genes. In addition, decreased C/EBPβ, but not PPARγ, depends on the activity of the MCPIP1 PIN domain, which is responsible for RNase properties of this protein. Together, these data confirm that MCPIP1 is a key regulator of adipogenesis.
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http://dx.doi.org/10.1016/j.bbamcr.2014.01.001DOI Listing
April 2014

Adipocyte-derived factors impair insulin signaling in differentiated human vascular smooth muscle cells via the upregulation of miR-143.

Biochim Biophys Acta 2014 Feb 9;1842(2):275-83. Epub 2013 Dec 9.

Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Duesseldorf, Germany; Department of Endocrinology, Ghent University Hospital, Ghent, Belgium. Electronic address:

Cardiovascular complications are common in patients with type 2 diabetes. Adipokines have been implicated in the induction of proliferative and pro-atherogenic alterations in human vascular smooth muscle cells (hVSMC). Other reports demonstrated the importance of the miRNA cluster miR-143/145 in the regulation of VSMC homeostasis and insulin sensitivity. Here we investigated whether the detrimental effects of adipokines on hVSMC function could be ascribed to alterations in miR-143/145 expression. The exposure of hVSMC to conditioned media (CM) from primary human subcutaneous adipocytes increased the expression of smooth muscle α-actin (SMA), and the miR-143/145 cluster, but markedly impaired the insulin-mediated phosphorylation of Akt and its substrate endothelial nitric oxide synthase (eNOS). Furthermore, CM promoted the phosphorylation of SMAD2 and p38, which have both been linked to miR-143/145 induction. Accordingly, the induction of miR-143/145 as well as the inhibition of insulin-mediated Akt- and eNOS-phosphorylation was prevented when hVSMC were treated with pharmacological inhibitors for Alk-4/5/7 and p38 before the addition of CM. The transfection of hVSMC with precursor miR-143, but not with precursor miR-145, resulted in impaired insulin-mediated phosphorylation of Akt and eNOS. This inhibition of insulin signaling by CM and miR-143 is associated with a reduction in the expression of the oxysterol-binding protein-related protein 8 (ORP8). Finally, the knock-down of ORP8 resulted in impaired insulin-mediated phosphorylation of Akt in hVSMC. Thus, the detrimental effects of adipocyte-derived conditioned media on insulin action in primary hVSMC can be ascribed to the Alk- and p38-dependent induction of miR-143 and subsequent downregulation of ORP8.
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http://dx.doi.org/10.1016/j.bbadis.2013.12.001DOI Listing
February 2014

Evidence against a beneficial effect of irisin in humans.

PLoS One 2013 11;8(9):e73680. Epub 2013 Sep 11.

Paul-Langerhans-Group, Integrative Physiology, German Diabetes Center, Düsseldorf, Germany.

Brown adipose tissue has gained interest as a potential target to treat obesity and metabolic diseases. Irisin is a newly identified hormone secreted from skeletal muscle enhancing browning of white fat cells, which improves systemic metabolism by increasing energy expenditure in mice. The discovery of irisin raised expectations of its therapeutic potential to treat metabolic diseases. However, the effect of irisin in humans is unclear. Analyses of genomic DNA, mRNA and expressed sequence tags revealed that FNDC5, the gene encoding the precursor of irisin, is present in rodents and most primates, but shows in humans a mutation in the conserved start codon ATG to ATA. HEK293 cells transfected with a human FNDC5 construct with ATA as start codon resulted in only 1% full-length protein compared to human FNDC5 with ATG. Additionally, in vitro contraction of primary human myotubes by electrical pulse stimulation induced a significant increase in PGC1α mRNA expression. However, FNDC5 mRNA level was not altered. FNDC5 mRNA expression in muscle biopsies from two different human exercise studies was not changed by endurance or strength training. Preadipocytes isolated from human subcutaneous adipose tissue exhibited differentiation to brite human adipocytes when incubated with bone morphogenetic protein (BMP) 7, but neither recombinant FNDC5 nor irisin were effective. In conclusion, our findings suggest that it is rather unlikely that the beneficial effect of irisin observed in mice can be translated to humans.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0073680PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3770677PMC
July 2014

"Browning" of adipose tissue--regulation and therapeutic perspectives.

Arch Physiol Biochem 2013 Oct 30;119(4):151-60. Epub 2013 May 30.

Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari School of Medicine , Bari , Italy and.

Obesity is considered a worldwide health concern. Most of obesity therapies are aimed at decreasing energy intake. However, recent data suggest that increasing cellular energy expenditure could be a useful approach to reduce adiposity. Adaptive thermogenesis, a biological process within the brown fat by which energy is dissipated in mitochondria, is a great tool to increase energy expenditure. Several studies have confirmed the presence of brown adipose tissue in adult humans, whose activity may make it a target for the treatment of obesity. Differentiation of brown adipocytes could be a potent tool to promote weight loss by increasing energy expenditure. Here we review the mechanisms potentially associated with expansion and activation of brown adipose tissue, and modulation of adaptive thermogenesis. Controlling one or more of these pathways could induce a positive regulation of brown adipogenesis. A better understanding of these molecular pathways could potentially result in novel anti-obesity therapies.
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http://dx.doi.org/10.3109/13813455.2013.796995DOI Listing
October 2013

Cardioprotective properties of omentin-1 in type 2 diabetes: evidence from clinical and in vitro studies.

PLoS One 2013 29;8(3):e59697. Epub 2013 Mar 29.

Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Duesseldorf, Germany.

Context: Adipokines are linked to the development of cardiovascular dysfunction in type 2 diabetes (DM2). In DM2-patients, circulating levels of omentin-1, an adipokine preferentially expressed in epicardial adipose tissue, are decreased. This study investigated whether omentin-1 has a cardioprotective function.

Methods: Omentin-1 levels in plasma and cardiac fat depots were determined in DM2-patients versus controls. Moreover, the relation between omentin-1 levels and cardiac function was examined in men with uncomplicated DM2. Finally, we determined whether omentin-1 could reverse the induction of cardiomyocyte dysfunction by conditioned media derived from epicardial adipose tissue from patients with DM2.

Results: Omentin-1 was highly expressed and secreted by epicardial adipose tissue, and reduced in DM2. Circulating omentin-1 levels were lower in DM2 versus controls, and positively correlated with the diastolic parameters early peak filling rate, early deceleration peak and early deceleration mean (all P<0.05). The improved diastolic function following pioglitazone treatment associated with increases in omentin-1 levels (P<0.05). In vitro, exposure of cardiomyocytes to conditioned media derived from epicardial adipose tissue from patients with DM2 induced contractile dysfunction and insulin resistance, which was prevented by the addition of recombinant omentin.

Conclusion: These data identify omentin-1 as a cardioprotective adipokine, and indicate that decreases in omentin-1 levels could contribute to the induction of cardiovascular dysfunction in DM2.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0059697PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3612072PMC
September 2013

Secretory products from epicardial adipose tissue of patients with type 2 diabetes mellitus induce cardiomyocyte dysfunction.

Circulation 2012 Nov 12;126(19):2324-34. Epub 2012 Oct 12.

Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Auf'm Hennekamp 65, 40225, Düsseldorf, Germany.

Background: Secreted factors from epicardial adipose tissue (EAT) have been implicated in the development of cardiomyocyte dysfunction. This study aimed to assess whether alterations in the secretory profile of EAT in patients with type 2 diabetes mellitus (DM2) affect contractile function and insulin action in cardiomyocytes.

Methods And Results: Contractile function and insulin action were analyzed in primary adult rat cardiomyocytes incubated with conditioned media (CM) generated from explants of EAT biopsies obtained from patients without and with DM2. CM from subcutaneous and pericardial adipose tissue biopsies from the same patients served as the control. Cardiomyocytes treated with CM (EAT) from DM2 patients showed reductions in sarcomere shortening, cytosolic Ca(2+) fluxes, expression of sarcoplasmic endoplasmic reticulum ATPase 2a, and decreased insulin-mediated Akt-Ser473-phosphorylation as compared with CM from the other groups. Profiling of the CM showed that activin A, angiopoietin-2, and CD14 selectively accumulated in CM-EAT-DM2 versus CM-EAT in patients without DM2 and CM from the other fat depots. Accordingly, EAT biopsies from DM2 patients were characterized by clusters of CD14-positive monocytes. Furthermore, SMAD2-phosphorylation, a downstream target of activin A signaling, was elevated in cardiomyocytes treated with CM (EAT) from DM2 patients, and the detrimental effects of CM (EAT) from DM2 patients were partially abolished in cardiomyocytes pretreated with a neutralizing antibody against activin A. Finally, both recombinant activin A and angiopoietin-2 reduced cardiomyocyte contractile function, but only activin A reduced the expression of sarcoplasmic endoplasmic reticulum ATPase 2a.

Conclusions: Collectively, our data implicate DM2-related alterations in the secretory profile of EAT in the pathogenesis of diabetes mellitus-related heart disease.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.111.039586DOI Listing
November 2012

Measurement of insulin sensitivity in skeletal muscle in vitro.

Methods Mol Biol 2012 ;933:255-63

Paul-Langerhans-Group Integrative Physiology, German Diabetes Center, Düsseldorf, Germany.

Glucose disposal in skeletal muscle is a major target for insulin action and assessment of insulin-regulated glucose uptake under in vitro conditions allows the direct determination of insulin sensitivity in this organ. For this purpose, a variety of muscle preparations from different parts of the body can be used. We describe here a detailed protocol for using epitrochlearis muscle strips and additionally for using primary skeletal muscle cells.
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http://dx.doi.org/10.1007/978-1-62703-068-7_16DOI Listing
January 2013

Adaptive immunity in obesity and insulin resistance.

Nat Rev Endocrinol 2012 Dec 31;8(12):709-16. Epub 2012 Jul 31.

Paul-Langerhans Group, German Diabetes Center, Leibniz Center for Diabetes Research at the Heinrich-Heine-University Düsseldorf, Auf'm Hennekamp 65, 40225 Düsseldorf, Germany.

Obesity is the hallmark of the metabolic syndrome and predisposes patients to the development of major chronic metabolic diseases including type 2 diabetes mellitus. Adipose tissue expansion in obesity is characterized by increasing infiltration of proinflammatory immune cells into adipose tissue causing chronic, low-grade inflammation. Phenotypic switching of macrophages is an important mechanism of adipose tissue inflammation, and there is involvement of cells from the adaptive immune system in this process. T-cell phenotype changes and recruitment of B cells and T cells precedes macrophage infiltration. Cytokines and chemokines produced by immune cells influence localized and systemic inflammation, which is a pathogenic link between obesity and insulin resistance. Antigens absorbed from the gut might contribute to T-cell activation and recruitment into visceral adipose tissue in obesity. This Review summarizes, in the context of obesity, the evidence for infiltration of adipose tissue by cells of the adaptive immune system, how adaptive system cells affect innate cell populations and the influence of adaptive immune cells on the development of insulin resistance.
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http://dx.doi.org/10.1038/nrendo.2012.114DOI Listing
December 2012

Differential impact of oleate, palmitate, and adipokines on expression of NF-κB target genes in human vascular smooth muscle cells.

Mol Cell Endocrinol 2012 Oct 28;362(1-2):194-201. Epub 2012 Jun 28.

Paul-Langerhans-Group, Integrative Physiology, German Diabetes Center, Düsseldorf, Germany.

It is widely accepted that obesity is a major risk factor for the development of atherosclerosis. In this context, adipose tissue produces a variety of adipokines and releases free fatty acids, contributing to a chronic-low grade inflammation state implicated in vascular complications. In this study, we investigated the role of adipokines, oleic acid (OA), palmitic acid (PA), and the combinations on activation of NF-κB target genes in human vascular smooth muscle cells (SMC) to assess the hypothesis of synergistic interactions between these molecules. Adipocyte-conditioned medium (CM), generated from human adipocytes, in combination with low concentrations of OA, but not PA, induces SMC proliferation and activation of the transcription factor NF-κB in a synergistic way. Combined treatment of CM and OA further regulates a set of downstream NF-κB target genes including angiopoietin-1, activin A, and MMP-1, all critically involved in SMC dysfunction. This suggests that the lipotoxic potential of fatty acids is substantially enhanced by the presence of adipocyte-derived factors.
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http://dx.doi.org/10.1016/j.mce.2012.06.010DOI Listing
October 2012

Adipokines promote lipotoxicity in human skeletal muscle cells.

Arch Physiol Biochem 2012 Jul 12;118(3):92-101. Epub 2012 Jun 12.

Paul-Langerhans-Group, Integrative Physiology, German Diabetes Center, Duesseldorf, Germany.

Studies have shown the implication of specific adipokines or fatty acids (FA) in the pathogenesis of insulin resistance. However, the interplay of adipokines with FA remains poorly understood. This study aimed to investigate the combined effects of adipokines and low concentrations of palmitic acid (PA, 100 µmol/l) on skeletal muscle metabolism. Human skeletal muscle cells were incubated with adipocyte-conditioned medium (CM), PA or PA+CM, and FA transporter and FA metabolism were analysed. CM-incubation increased CD36 level (1.8 fold) and PA-uptake (1.4 fold). However, only co-application of PA+CM resulted in profound lipid accumulation (5.3 fold), 60% reduction of PA-oxidation and 3.5 fold increased diacylglycerol content. Our results support a novel role for adipokines in the pathogenesis of T2D by increasing the lipotoxic potential of PA, notably of low concentrations. This implies an increased lipotoxic risk already at an early stage of weight gain, when lipolysis has not yet contributed to increased plasma free FA levels.
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http://dx.doi.org/10.3109/13813455.2012.688751DOI Listing
July 2012

COST Action BM0602: a European network to combat obesity and the metabolic syndrome.

Authors:
Juergen Eckel

Arch Physiol Biochem 2012 Jul 7;118(3):83. Epub 2012 Jun 7.

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http://dx.doi.org/10.3109/13813455.2012.699971DOI Listing
July 2012

Functional annotation of the human fat cell secretome.

Arch Physiol Biochem 2012 Jul 23;118(3):84-91. Epub 2012 May 23.

Karolinska Institutet, Department of Medicine, Huddinge, 141 86 Stockholm, Sweden.

Context: Recent secretome analyses suggest that human fat cells secrete hundreds of proteins (adipokines).

Objective: We made an overall analysis of their potential functional importance.

Materials And Methods: A secretome of 347 adipokines was evaluated by in silico analysis of their expression during adipocyte differentiation, regulation by obesity and adipose region. The gene expression in human adipose tissue was investigated in microarray studies using samples from different adipose depots from lean or obese patients.

Results: 60% of the adipokines were regulated by obesity and 50% between visceral and subcutaneous adipose region. Eight adipokines, all novel, scored particularly high in the in silico analysis. Among those, four were both regulated by obesity and adipose region, namely WNT1-inducible-signaling pathway protein 2, transmembrane glycoprotein NMB, inter-alpha-trypsin inhibitor heavy chain H5, and complement C4-A. Furthermore, many adipokines were extracellular matrix proteins.

Conclusion: Several novel adipokines have potential important functional features warranting in depth analysis.
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http://dx.doi.org/10.3109/13813455.2012.685745DOI Listing
July 2012

Sex steroid-induced changes in circulating monocyte chemoattractant protein-1 levels may contribute to metabolic dysfunction in obese men.

J Clin Endocrinol Metab 2012 Jul 20;97(7):E1187-91. Epub 2012 Apr 20.

Department of Endocrinology, Ghent University Hospital, 9000 Ghent, Belgium.

Context: Low testosterone accompanied by elevated estradiol associates with the development of metabolic dysfunction in men.

Objective: The aim of the study was to explore the hypothesis that alterations in sex steroid levels induce metabolic dysfunction through adipokines.

Design: Circulating levels of sex steroids and 28 adipokines were determined in a cross-sectional study of morbidly obese men and aged-matched controls, as well as in a randomized clinical trial with healthy young men in which obesity-related alterations in sex steroid levels were mimicked by treatment with an aromatase inhibitor plus estradiol patches.

Results: Morbidly obese men had lower testosterone levels than normal-weight controls. Estradiol levels were increased in morbidly obese men (without DM2) as compared to normal-weight controls. Circulating levels of multiple proinflammatory cytokines, including IL-1Ra, IL-5, IL-6, IL-10, leptin, monocyte chemoattractant protein 1 (MCP1), and macrophage inflammatory protein 1α, positively associated with estradiol and negatively with testosterone. The associations with estradiol, but not with testosterone, remained significant after adjusting for adipocyte cell size. In a separate clinical trial, the direct adverse effects of lowering testosterone and raising estradiol on MCP1 were substantiated in vivo.

Conclusions: Initial alterations in sex steroid levels may contribute to metabolic dysfunction through adverse effects on adipokine levels in obese men. The direct adverse effects on MCP1, a chemokine highly linked to the development of metabolic dysfunction, were substantiated in a trial mimicking obesity-related alterations of sex steroid levels in healthy young males.
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http://dx.doi.org/10.1210/jc.2011-3069DOI Listing
July 2012

Inflammation and metabolic dysfunction: links to cardiovascular diseases.

Am J Physiol Heart Circ Physiol 2012 Jun 23;302(11):H2148-65. Epub 2012 Mar 23.

Paul Langerhans Group, German Diabetes Center, Duesseldorf, Germany.

Abdominal obesity is a major risk factor for cardiovascular disease, and recent studies highlight a key role of adipose tissue dysfunction, inflammation, and aberrant adipokine release in this process. An increased demand for lipid storage results in both hyperplasia and hypertrophy, finally leading to chronic inflammation, hypoxia, and a phenotypic change of the cellular components of adipose tissue, collectively leading to a substantially altered secretory output of adipose tissue. In this review we have assessed the adipo-vascular axis, and an overview of adipokines associated with cardiovascular disease is provided. This resulted in a first list of more than 30 adipokines. A deeper analysis only considered adipokines that have been reported to impact on inflammation and NF-κB activation in the vasculature. Out of these, the most prominent link to cardiovascular disease was found for leptin, TNF-α, adipocyte fatty acid-binding protein, interleukins, and several novel adipokines such as lipocalin-2 and pigment epithelium-derived factor. Future work will need to address the potential role of these molecules as biomarkers and/or drug targets.
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http://dx.doi.org/10.1152/ajpheart.00907.2011DOI Listing
June 2012

Chemerin as biomarker for insulin sensitivity in males without typical characteristics of metabolic syndrome.

Arch Physiol Biochem 2012 Jul 15;118(3):135-8. Epub 2012 Feb 15.

Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Duesseldorf, Germany.

To allow early detection and prevention of metabolic disorders, circulating levels of adipokines involved in insulin sensitivity were compared with the hyperinsulinemic-euglycemic clamp. Twenty non-obese normo-glycaemic men (age 32.1 ± 6 years) underwent a clamp procedure. Levels of leptin, adiponectin, resistin, visfatin, omentin and chemerin levels were determined in fasting blood samples. Pearson correlation coefficients between the M-value for insulin sensitivity and fasting levels of chemerin (r = -0.63, P = 0.003) and leptin (r = -0.54, P = 0.013) performed better than conventional surrogate measures of insulin sensitivity (HOMA-IR: r = -0.45, P = 0.048; Quicki: r = 0.36, P = 0.12). However, only the relation between M-value(LBM) and chemerin remained significant when adjusting for BMI and fasting insulin levels (r = -0.559, P = 0.016). In conclusion, fasting levels of chemerin might be used as biomarker to identify insulin resistance in healthy men without typical characteristics of metabolic disorders.
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http://dx.doi.org/10.3109/13813455.2012.654800DOI Listing
July 2012

Combined gene and protein expression of hormone-sensitive lipase and adipose triglyceride lipase, mitochondrial content, and adipocyte size in subcutaneous and visceral adipose tissue of morbidly obese men.

Obes Facts 2011 14;4(5):407-16. Epub 2011 Oct 14.

Department of Abdominal Surgery, University Hospital, Ghent, Belgium.

Aims: Lipotoxicity in obesity might be a failure of adipocytes to respond sufficiently adequate to persistent energy surplus. To evaluate the role of lipolytic enzymes or mitochondria in lipotoxicity, we studied expression levels of genes and proteins involved in lipolysis and mitochondrial DNA (mtDNA) content.

Methods: As differences in lipid metabolism between men and women are extremely complex, we recruited only men (lean and morbidly obese) and collected subcutaneous and visceral adipose tissue during abdominal surgery for real-time PCR gene expression, protein expression, and microscopic study.

Results: Although mRNA levels of hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) were increased in visceral adipose tissue of morbidly obese men, this was not paralleled by alterations in protein expression and phosphorylation of HSL and ATGL. mtDNA content of visceral adipose tissue was increased in morbidly obese men as compared to lean controls (p < 0.013). Positive correlations were observed between visceral adipocyte size and serum triacylglycerol (r = 0.6, p < 0.007) as well as between visceral adipocyte size and CRP (r = 0.6, p < 0.009) in analyses performed separately in obese men.

Conclusion: Lipotoxicity of morbidly obese men might be related to the quantitative impact of the visceral fat depot rather than to important dysregulation of involved lipolytic enzymes or adipocyte mitochondria.
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http://dx.doi.org/10.1159/000333445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450043PMC
May 2012

Qualitative characteristics of HDL in young patients of an acute myocardial infarction.

Atherosclerosis 2012 Jan 20;220(1):257-64. Epub 2011 Oct 20.

Pharmacology Unit, Department of Medicine, University of Patras School of Health Sciences, Patras, Greece.

Aim: Recently, the concept that high density lipoprotein (HDL) quality is an important parameter for atheroprotection is gaining ground, though little data exists so far to support it. In an attempt to identify measurable qualitative parameters of HDL associated with increased risk for premature myocardial infarction (MI), we studied the structural characteristics of HDL from patients who survived an MI at a young age (≤35 years).

Methods And Results: We studied 20 MI patients and 20 healthy control subjects. HDL of patients had reduced apolipoprotein A-I (apoA-I), apolipoprotein M, and paraoxonase 1 levels and significantly elevated apolipoprotein C-III (apoCIII) levels (all p<0.05). Specifically, the HDL apoA-I/apoC-III ratio was 0.24±0.01 in patients versus 4.88±0.90 in controls (p<0.001). These structural alterations correlated with increased oxidation potential of HDL of the MI group compared to controls (2.5-fold, p=0.026). Electron microscopy showed no significant difference in average HDL particle diameter between the two groups though a significant difference existed in HDL diameter distribution, suggesting the presence of different HDL subpopulations in MI and control subjects. Indeed, non-denaturing two-dimensional electrophoresis revealed that MI patients had reduced pre-β1(α), pre-β1(b) and α(2), and elevated α(1), α(3), and pre-α(4) HDL.

Conclusions: Reduction in the HDL apoA-I/apoC-III ratio, changes in the HDL subpopulation distribution and an increase in HDL oxidation potential correlated with the development of MI in young patients. The possibility that such changes may serve as markers for the early identification of young individuals at high risk for an acute coronary event should be further explored.
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http://dx.doi.org/10.1016/j.atherosclerosis.2011.10.017DOI Listing
January 2012

Identification and validation of novel adipokines released from primary human adipocytes.

Mol Cell Proteomics 2012 Jan 26;11(1):M111.010504. Epub 2011 Sep 26.

Paul-Langerhans-Group, German Diabetes Center, Duesseldorf, Germany.

Adipose tissue is a major endocrine organ, releasing signaling and mediator proteins, termed adipokines, via which adipose tissue communicates with other organs. Expansion of adipose tissue in obesity alters adipokine secretion, which may contribute to the development of metabolic diseases. Although recent profiling studies have identified numerous adipokines, the amount of overlap from these studies indicates that the adipokinome is still incompletely characterized. Therefore, we conducted a complementary protein profiling on concentrated conditioned medium derived from primary human adipocytes. SDS-PAGE/liquid chromatography-electrospray ionization tandem MS and two-dimensional SDS-PAGE/matrix-assisted laser desorption ionization/time of flight MS identified 347 proteins, 263 of which were predicted to be secreted. Fourty-four proteins were identified as novel adipokines. Furthermore, we validated the regulation and release of selected adipokines in primary human adipocytes and in serum and adipose tissue biopsies from morbidly obese patients and normal-weight controls. Validation experiments conducted for complement factor H, αB-crystallin, cartilage intermediate-layer protein, and heme oxygenase-1 show that the release and expression of these factors in adipocytes is regulated by differentiation and stimuli, which affect insulin sensitivity, as well as by obesity. Heme oxygenase-1 especially reveals to be a novel adipokine of interest. In vivo, circulating levels and adipose tissue expression of heme oxygenase-1 are significantly increased in obese subjects compared with lean controls. Collectively, our profiling study of the human adipokinome expands the list of adipokines and further highlights the pivotal role of adipokines in the regulation of multiple biological processes within adipose tissue and their potential dysregulation in obesity.
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http://dx.doi.org/10.1074/mcp.M111.010504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3270100PMC
January 2012

Dipeptidyl peptidase 4 is a novel adipokine potentially linking obesity to the metabolic syndrome.

Diabetes 2011 Jul 18;60(7):1917-25. Epub 2011 May 18.

Paul-Langerhans-Group, German Diabetes Center, Duesseldorf, Germany.

Objective: Comprehensive proteomic profiling of the human adipocyte secretome identified dipeptidyl peptidase 4 (DPP4) as a novel adipokine. This study assessed the functional implications of the adipokine DPP4 and its association to the metabolic syndrome.

Research Design And Methods: Human adipocytes and skeletal and smooth muscle cells were used to monitor DPP4 release and assess the effects of soluble DPP4 on insulin signaling. In lean and obese subjects, depot-specific expression of DPP4 and its release from adipose tissue explants were determined and correlated to parameters of the metabolic syndrome.

Results: Fully differentiated adipocytes exhibit a substantially higher release of DPP4 compared with preadipocytes or macrophages. Direct addition of DPP4 to fat and skeletal and smooth muscle cells impairs insulin signaling. A fivefold higher level of DPP4 protein expression was seen in visceral compared with subcutaneous fat of obese patients, with no regional difference in lean subjects. DPP4 serum concentrations significantly correlated with adipocyte size. By using adipose tissue explants from lean and obese subjects, we observed a twofold increase in DPP4 release that strongly correlated with adipocyte volume and parameters of the metabolic syndrome and was decreased to the lean level after weight reduction. DPP4 released from adipose tissue correlated positively with an increasing risk score for the metabolic syndrome.

Conclusions: DPP4 is a novel adipokine that may impair insulin sensitivity in an autocrine and paracrine fashion. Furthermore, DPP4 release strongly correlates with adipocyte size, potentially representing an important source of DPP4 in obesity. Therefore, we suggest that DPP4 may be involved in linking adipose tissue and the metabolic syndrome.
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http://dx.doi.org/10.2337/db10-1707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3121429PMC
July 2011

The adipokine zinc-α2-glycoprotein activates AMP kinase in human primary skeletal muscle cells.

Arch Physiol Biochem 2011 May;117(2):88-93

Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Duesseldorf, Germany.

Context: Zinc-α2-glycoprotein (ZAG) induces lipid mobilization in adipose tissue (AT) and stimulates energy utilization in AT and skeletal muscle by up-regulation of UCP isoforms and GLUT4.

Objective: Our study aimed to investigate whether ZAG activates AMPKα, an important regulator of energy metabolism, in human skeletal muscle cells (SkMc).

Materials And Methods: SkMc were treated with recombinant ZAG, and activation of AMPKα and ACC, protein abundance of GLUT4, and UCP2 and UCP3 gene expression were analysed.

Results: Treatment of SkMc with ZAG induced short-time phosphorylation of AMPKα and ACC. Furthermore, AMPKα phosphorylation was elevated after 24 h, while for ACC no activation was observed. GLUT4 level was increased by 1.3-fold. However, UCP2 and UCP3 expression remained unaltered.

Discussion And Conclusion: These results show that ZAG leads to phosphorylation of AMPKα and ACC, thereby activating a pathway central to the regulation of energy metabolism. This mechanism may be involved in mediating the effects of ZAG in relation to increased energy utilization.
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http://dx.doi.org/10.3109/13813455.2011.560950DOI Listing
May 2011

Adipose tissue. Editorial.

Arch Physiol Biochem 2011 May 11;117(2):45-6. Epub 2011 Feb 11.

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http://dx.doi.org/10.3109/13813455.2010.547862DOI Listing
May 2011

Randomized comparison of reduced fat and reduced carbohydrate hypocaloric diets on intrahepatic fat in overweight and obese human subjects.

Hepatology 2011 May 11;53(5):1504-14. Epub 2011 Mar 11.

Max Delbrück Center for Molecular Medicine, Berlin, Germany.

Unlabelled: Obesity-related hepatic steatosis is a major risk factor for metabolic and cardiovascular disease. Fat reduced hypocaloric diets are able to relieve the liver from ectopically stored lipids. We hypothesized that the widely used low carbohydrate hypocaloric diets are similarly effective in this regard. A total of 170 overweight and obese, otherwise healthy subjects were randomized to either reduced carbohydrate (n = 84) or reduced fat (n = 86), total energy restricted diet (-30% of energy intake before diet) for 6 months. Body composition was estimated by bioimpedance analyses and abdominal fat distribution by magnetic resonance tomography. Subjects were also submitted to fat spectroscopy of liver and oral glucose tolerance testing. In all, 102 subjects completed the diet intervention with measurements of intrahepatic lipid content. Both hypocaloric diets decreased body weight, total body fat, visceral fat, and intrahepatic lipid content. Subjects with high baseline intrahepatic lipids (>5.56%) lost ≈7-fold more intrahepatic lipids compared with those with low baseline values (<5.56%) irrespective of diet composition. In contrast, changes in visceral fat mass and insulin sensitivity were similar between subgroups, with low and high baseline intrahepatic lipids.

Conclusion: A prolonged hypocaloric diet low in carbohydrates and high in fat has the same beneficial effects on intrahepatic lipid accumulation as the traditional low-fat hypocaloric diet. The decrease in intrahepatic lipids appears to be independent of visceral fat loss and is not tightly coupled with changes in whole body insulin sensitivity during 6 months of an energy restricted diet.
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http://dx.doi.org/10.1002/hep.24242DOI Listing
May 2011

Obesity-associated insulin resistance in skeletal muscle: role of lipid accumulation and physical inactivity.

Rev Endocr Metab Disord 2011 Sep;12(3):163-72

Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Duesseldorf, Germany.

An alarming increase in the prevalence of obesity, type 2 diabetes mellitus, and associated diseases can be observed world-wide during the past 20 years. In obesity, profound alterations in the secretion profile of adipokines and inflammatory markers as well as increased lipolysis occur, leading besides other events to elevated levels of free fatty acids, which in turn are distributed to nonadipose tissue such as skeletal muscle. While the amount of intramyocellular lipids can be used as a marker of insulin resistance in physical inactive individuals, these neutral triglycerides themselves are not thought to be harmful. However, they provide a source for the generation of harmful lipid metabolites such as diacylglycerol and ceramide, which are implicated in insulin resistance by perturbing insulin signaling pathways. In this review, we will discuss the role of lipid metabolites in insulin resistance and potential mechanism involved in accumulation of intramyocellular lipids. Furthermore, we will highlight the key role of PGC-1α, which is a master regulator of mitochondrial biogenesis and coordinates the activation of genes involved in oxidative energy production as well as genes involved in fiber type transformation. Finally, the role of exercise in stimulating PGC-1α activity and expression as well as the release of contraction-induced myokines is discussed.
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http://dx.doi.org/10.1007/s11154-011-9168-2DOI Listing
September 2011

Secretory products of guinea pig epicardial fat induce insulin resistance and impair primary adult rat cardiomyocyte function.

J Cell Mol Med 2011 Nov;15(11):2399-410

Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Centre, Düsseldorf, Germany.

Epicardial adipose tissue (EAT) has been implicated in the development of heart disease. Nonetheless, the crosstalk between factors secreted from EAT and cardiomyocytes has not been studied. Here, we examined the effect of factors secreted from EAT on contractile function and insulin signalling in primary rat cardiomocytes. EAT and subcutaneous adipose tissue (SAT) were isolated from guinea pigs fed a high-fat (HFD) or standard diet. HFD feeding for 6 months induced glucose intolerance, and decreased fractional shortening and ejection fraction (all P < 0.05). Conditioned media (CM) generated from EAT and SAT explants were subjected to cytokine profiling using antibody arrays, or incubated with cardiomyocytes to assess the effects on insulin action and contractile function. Eleven factors were differentially secreted by EAT when compared to SAT. Furthermore, secretion of 30 factors by EAT was affected by HFD feeding. Most prominently, activin A-immunoreactivity was 6.4-fold higher in CM from HFD versus standard diet-fed animals and, 2-fold higher in EAT versus SAT. In cardiomyocytes, CM from EAT of HFD-fed animals increased SMAD2-phosphorylation, a marker for activin A-signalling, decreased sarcoplasmic-endoplasmic reticulum calcium ATPase 2a expression, and reduced insulin-mediated phosphorylation of Akt-Ser473 versus CM from SAT and standard diet-fed animals. Finally, CM from EAT of HFD-fed animals as compared to CM from the other groups markedly reduced sarcomere shortening and cytosolic Ca(2+) fluxes in cardiomyocytes. These data provide evidence for an interaction between factors secreted from EAT and cardiomyocyte function.
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http://dx.doi.org/10.1111/j.1582-4934.2010.01232.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3822951PMC
November 2011