Paul Langerhans Group

Düsseldorf, Germany

Paul Langerhans Group

Düsseldorf, Germany
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Vallejo S.,Autonomous University of Madrid | Palacios E.,Autonomous University of Madrid | Palacios E.,Universidad de Las Americas Puebla | Romacho T.,Autonomous University of Madrid | And 4 more authors.
Cardiovascular Diabetology | Year: 2014

Background: Endothelial dysfunction is a crucial early phenomenon in vascular diseases linked to diabetes mellitus and associated to enhanced oxidative stress. There is increasing evidence about the role for pro-inflammatory cytokines, like interleukin-1β (IL-1β), in developing diabetic vasculopathy. We aimed to determine the possible involvement of this cytokine in the development of diabetic endothelial dysfunction, analysing whether anakinra, an antagonist of IL-1 receptors, could reduce this endothelial alteration by interfering with pro-oxidant and pro-inflammatory pathways into the vascular wall. Results: In control and two weeks evolution streptozotocin-induced diabetic rats, either untreated or receiving anakinra, vascular reactivity and NADPH oxidase activity were measured, respectively, in isolated rings and homogenates from mesenteric microvessels, while nuclear factor (NF)-κB activation was determined in aortas. Plasma levels of IL-1β and tumor necrosis factor (TNF)-α were measured by ELISA. In isolated mesenteric microvessels from control rats, two hours incubation with IL-1β (1 to 10 ng/mL) produced a concentration-dependent impairment of endothelium-dependent relaxations, which were mediated by enhanced NADPH oxidase activity via IL-1 receptors. In diabetic rats treated with anakinra (100 or 160 mg/Kg/day for 3 or 7 days before sacrifice) a partial improvement of diabetic endothelial dysfunction occurred, together with a reduction of vascular NADPH oxidase and NF-κB activation. Endothelial dysfunction in diabetic animals was also associated to higher activities of the pro-inflammatory enzymes cyclooxygenase (COX) and the inducible isoform of nitric oxide synthase (iNOS), which were markedly reduced after anakinra treatment. Circulating IL-1β and TNF-α levels did not change in diabetic rats, but they were lowered by anakinra treatment. Conclusions: In this short-term model of type 1 diabetes, endothelial dysfunction is associated to an IL-1 receptor-mediated activation of vascular NADPH oxidase and NF-κB, as well as to vascular inflammation. Moreover, endothelial dysfunction, vascular oxidative stress and inflammation were reduced after anakinra treatment. Whether this mechanism can be extrapolated to a chronic situation or whether it may apply to diabetic patients remain to be established. However, it may provide new insights to further investigate the therapeutic use of IL-1 receptor antagonists to obtain vascular benefits in patients with diabetes mellitus and/or atherosclerosis. © 2014 Vallejo et al.


Lamers D.,Paul Langerhans Group | Famulla S.,Paul Langerhans Group | Wronkowitz N.,Paul Langerhans Group | Hartwig S.,Institute of Clinical Biochemistry and Pathobiochemistry | And 11 more authors.
Diabetes | Year: 2011

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. © 2011 by the American Diabetes Association.


Ezenwaka C.,University of the West Indies | Eckel J.,Paul Langerhans Group
Archives of Physiology and Biochemistry | Year: 2011

The IDF report has indicated that about 80% of four million diabetes-related deaths that occur every year comes from the developing world. The IDF report suggests the need to focus more on preventing diabetes complications in poor countries. Thus, considering the economic constraints in combating the explosion of diabetes complications in the developing regions of the world, it appears that exploring culturally adaptable educational intervention programmes for specific regions would be the appropriate strategy. We believe that diabetes-related deaths could be reduced in developing countries through intensified diabetes self-management education. © 2011 Informa UK, Ltd.


Lamers D.,Paul Langerhans Group | Schlich R.,Paul Langerhans Group | Horrighs A.,Paul Langerhans Group | Cramer A.,Paul Langerhans Group | And 2 more authors.
Molecular and Cellular Endocrinology | Year: 2012

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. © 2012 Elsevier Ireland Ltd.


Lambernd S.,Paul Langerhans Group | Taube A.,Paul Langerhans Group | Schober A.,Institute of Clinical Biochemistry and Pathobiochemistry | Platzbecker B.,Institute of Clinical Biochemistry and Pathobiochemistry | And 6 more authors.
Diabetologia | Year: 2012

Aims/hypothesis Obesity is closely associated with muscle insulin resistance and is a major risk factor for the pathogenesis of type 2 diabetes. Regular physical activity not only prevents obesity, but also considerably improves insulin sensitivity and skeletal muscle metabolism. We sought to establish and characterise an in vitro model of human skeletal muscle contraction, with a view to directly studying the signalling pathways and mechanisms that are involved in the beneficial effects of muscle activity. Methods Contracting human skeletal muscle cell cultures were established by applying electrical pulse stimulation. To induce insulin resistance, skeletal muscle cells were incubated with human adipocyte-derived conditioned medium, monocyte chemotactic protein (MCP)-1 and chemerin. Results Similarly to in exercising skeletal muscle in vivo, electrical pulse stimulation induced contractile activity in human skeletal muscle cells, combined with the formation of sarcomeres, activation of AMP-activated protein kinase (AMPK) and increased IL-6 secretion. Insulin-stimulated glucose uptake was substantially elevated in contracting cells compared with control. The incubation of skeletal muscle cells with adipocyte-conditioned media, chemerin and MCP-1 significantly reduced the insulin-stimulated phosphorylation of Akt. This effect was abrogated by concomitant pulse stimulation of the cells. Additionally, proinflammatory signalling by adipocyte-derived factors was completely prevented by electrical pulse stimulation of the myotubes. Conclusions/interpretation We showed that the effects of electrical pulse stimulation on skeletal muscle cells were similar to the effect of exercise on skeletal muscle in vivo in terms of enhanced AMPK activation and IL-6 secretion. In our model, muscle contractile activity eliminates insulin resistance by blocking pro-inflammatory signalling pathways. This novel model therefore provides a unique tool for investigating the molecular mechanisms that mediate the beneficial effects of muscle contraction. © 2012 Springer-Verlag.


Lehr S.,Institute of Clinical Biochemistry and Pathobiochemistry | Hartwig S.,Institute of Clinical Biochemistry and Pathobiochemistry | Sell H.,Paul Langerhans Group
Proteomics - Clinical Applications | Year: 2012

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. Consequently, this correlation has emphasized the importance to further characterize the adipocyte secretion profile, and several attempts have been made to characterize the complex nature of the adipose tissue secretome by utilizing diverse proteomic profiling approaches. Although the entirety of human adipokines is still incompletely characterized, to date more than 600 potentially secretory proteins were identified providing a rich source to identify putative novel biomarkers associated with metabolic diseases. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Taube A.,Paul Langerhans Group | Schlich R.,Paul Langerhans Group | Sell H.,Paul Langerhans Group | Eckardt K.,Paul Langerhans Group | Eckel J.,Paul Langerhans Group
American Journal of Physiology - Heart and Circulatory Physiology | Year: 2012

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. © 2012 the American Physiological Society.


Famulla S.,Paul Langerhans Group | Horrighs A.,Paul Langerhans Group | Cramer A.,Paul Langerhans Group | Sell H.,Paul Langerhans Group | Eckel J.,Paul Langerhans Group
International Journal of Obesity | Year: 2012

Objective: Obesity is associated with adipose tissue hypoxia, and is thought to be linked to the chronic low-grade inflammation of adipose tissue, although the precise mechanism has remained unclear. In this study, we investigated the effect of a prominent hypoxia on human primary adipocyte secretion and tumor necrosis factor alpha (TNFα)-induced nuclear factor-B (NF-B) signaling. Results: Using cytokine array and ELISA analysis, we compared the secretion patterns of normoxic and hypoxic (1% O 2) adipocytes and observed various alterations in adipokine release. We could reproduce known alterations like an induction of interleukin (IL)-6, vascular endothelial growth factor, leptin and a reduction in adiponectin release under hypoxia. Interestingly, we observed a significant reduction in the secretion of macrophage chemotactic protein (MCP)-1 and other NF-B-related genes, such as growth-regulated oncogene-α, eotaxin and soluble TNF-Receptor1 (TNF-R1) under hypoxia. TNFα stimulation of hypoxic adipocytes resulted in a significantly reduced phosphorylation of NF-B and its inhibitor IBα compared with normoxic cells. Furthermore, chronic treatment of hypoxic adipocytes with TNFα resulted in an expected higher secretion of the chemokines MCP-1 and IL-8, but under hypoxia, the secretion level was substantially lower than that under normoxia. This reduction in protein release was accompanied by a reduced mRNA expression of MCP-1, whereas IL-8 mRNA expression was not altered. Additionally, we observed a significantly reduced expression of the TNF-receptor TNF-R1, possibly being one cause for the reduced responsiveness of hypoxic adipocytes towards TNFα stimulation. Conclusion: In conclusion, human primary adipocytes show a basal and TNFα-induced reduction of MCP-1 release under hypoxia. This effect may be due to a reduced expression of TNF-R1 and therefore attenuated TNFα-induced NF-B signaling. These observations demonstrate a reduced responsiveness of hypoxic adipocytes towards inflammatory stimuli like TNFα, which may represent an adaptation process to maintain adipose tissue function under hypoxia and inflammatory conditions. © 2012 Macmillan Publishers Limited All rights reserved.


Peschechera A.,University of Bari | Eckel J.,Paul Langerhans Group
Archives of Physiology and Biochemistry | Year: 2013

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. © 2013 Informa UK Ltd.


Raschke S.,Paul Langerhans Group
PloS one | Year: 2013

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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