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Becker M.,Leibniz Institute for Molecular Pharmacology | Siems W.-E.,Leibniz Institute for Molecular Pharmacology | Kluge R.,Deutsches Institute For Ernahrungsforschung | Gembardt F.,University of Hull | And 5 more authors.
PLoS ONE | Year: 2010

Background: According to the World Health Organization (WHO) there is a pandemic of obesity with approximately 300 million people being obese. Typically, human obesity has a polygenetic causation. Neutral endopeptidase (NEP), also known as neprilysin, is considered to be one of the key enzymes in the metabolism of many active peptide hormones. Methodology/Principal Findings: An incidental observation in NEP-deficient mice was a late-onset excessive gain in body weight exclusively from a ubiquitous accumulation of fat tissue. In accord with polygenetic human obesity, mice were characterized by deregulation of lipid metabolism, higher blood glucose levels, with impaired glucose tolerance. The key role of NEP in determining body mass was confirmed by the use of the NEP inhibitor candoxatril in wild-type mice that increased body weight due to increased food intake. This is a peripheral and not a central NEP action on the switch for appetite control, since candoxatril cannot cross the blood-brain barrier. Furthermore, we demonstrated that inhibition of NEP in mice with cachexia delayed rapid body weight loss. Thus, lack in NEP activity, genetically or pharmacologically, leads to a gain in body fat. Conclusions/Significance: In the present study, we have identified NEP to be a crucial player in the development of obesity. NEP-deficient mice start to become obese under a normocaloric diet in an age of 6-7 months and thus are an ideal model for the typical human late-onset obesity. Therefore, the described obesity model is an ideal tool for research on development, molecular mechanisms, diagnosis, and therapy of the pandemic obesity. © 2010 Becker et al.


Li H.,University of California at Los Angeles | Zemel R.,University of California at Los Angeles | Lopes D.H.J.,University of California at Los Angeles | Monien B.H.,University of California at Los Angeles | And 2 more authors.
ChemMedChem | Year: 2012

Neurotoxic Aβ42 oligomers are believed to be the main cause of Alzheimer's disease. Previously, we found that the C-terminal fragments (CTFs), Aβ(30-42) and Aβ(31-42) were the most potent inhibitors of Aβ42 oligomerization and toxicity in a series of Aβ(x-42) peptides (x=28-39). Therefore, we chose these peptides as leads for further development. These CTFs are short (12-13 amino acids) hydrophobic peptides with limited aqueous solubility. Our first attempt to attach hydrophilic groups to the Nterminus resulted in toxic peptides. Therefore, we next incorporated N-methyl amino acids, which are known to increase the solubility of such peptides by disrupting the β-sheet formation. Focusing on Aβ(31-42), we used a two-step N-methyl amino acid substitution strategy to study the structural factors controlling inhibition of Aβ42-induced toxicity. First, each residue was substituted by N-Me-alanine (N-Me-A). In the next step, in positions where substitution produced a significant effect, we restored the original side chain. This strategy allowed exploring the role of both side chain structure and N-Me substitution in inhibitory activity. We found that the introduction of an N-Me amino acid was an effective way to increase both the aqueous solubility and the inhibitory activity of Aβ(31-42). In particular, N-Me amino acid substitution at position9 or 11 increased the inhibitory activity relative to the parent peptide. The data suggest that inhibition of Aβ42 toxicity by short peptides is highly structure-specific, providing a basis for the design of new peptidomimetic inhibitors with improved activity, physicochemical properties, and metabolic stability. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Schmid H.A.,Novartis | Lambertini C.,Novartis | Van Vugt H.H.,Novartis | Barzaghi-Rinaudo P.,Novartis | And 5 more authors.
Neuroendocrinology | Year: 2012

Background: Activation of somatostatin receptors (sstr1-5) by somatostatin and its analogues exerts an inhibitory effect on hormone secretion and provides the basis for the treatment of a range of endocrine diseases such as acromegaly, Cushing's disease and neuroendocrine tumors (NET). The lack of well-characterized commercially available sstr subtype-specific antibodies prevents routine identification of the sstr expression profile in patients. Methods: We generated and characterized new mouse monoclonal antibodies (mAbs) targeting the five human sstr subtypes using ELISA and immunohistochemistry, and tested their suitability in formalin-fixed and paraffin-embedded (FFPE) human tissues and archival samples of normal pancreatic tissue and NET. Results: All mAbs were highly specific with no cross-reactivity. The sstr1-5 immunoreactivity in gastrointestinal NET (n = 67) was correlated with clinicopathologic data. With the exception of sstr3, NET were highly positive for all receptor subtypes (42, 63, 6, 32 and 65% of tumors were positive for sstr1, sstr2a, sstr3, sstr4 and sstr5, respectively). sstr1, sstr2a and sstr5 were present at the plasma membrane and in the cytoplasm of tumor cells, whereas sstr3 and sstr4 were almost exclusively cytoplasmic. Immunoreactivity of sstr1, sstr2a and sstr4 tended to decrease as tumor aggressiveness increased. sstr5 showed an opposite pattern, with higher staining in well-differentiated carcinomas compared with well-differentiated tumors. sstr5 immunoreactivity was correlated with the presence of metastases and angioinvasion, suggesting a possible association with more aggressive behavior. Conclusion: Determination of the sstr1-5 by immunohistochemistry using subtype-specific mAbs is feasible in FFPE tissue and may provide a tool for routine clinical practice. Copyright © 2011 S. Karger AG, Basel.


Von Ruesten A.,Deutsches Institute For Ernahrungsforschung | Feller S.,Deutsches Institute For Ernahrungsforschung | Boeing H.,Deutsches Institute For Ernahrungsforschung
Ernahrungs Umschau | Year: 2011

Associations between adherence to recommendations of the Food Circle of the German Society of Nutrition (DGE) and the risk of cardiovascular diseases, type 2 diabetes and cancer were evaluated in 23 531 participants of the EPIC-Potsdam study, using Cox proportional hazard regression models. A healthy eating index (HEI-DGE) was calculated for this purpose, by scoring the ratio of actual and recommended consumption of relevant food groups. Higher scores indicated better adherence to the recommendations. The HEI-DGE score was inversely related to cardiovascular diseases (p for trend = 0.002), type 2 diabetes (p for trend = 0.032) and chronic disease risk (p for trend = 0.031) in men but not in women. No association was observed between the HEI scores and cancer. High adherences to German food recommendations probably lower the occurrence of chronic diseases. This association was more pronounced in men than in women in this study.


Muhlenbruch K.,Deutsches Institute For Ernahrungsforschung | Schulze M.B.,Deutsches Institute For Ernahrungsforschung
Diabetes Aktuell | Year: 2015

For the prevention of type 2 diabetes and its complications an early identification of type 2 diabetes or of people at high risk for developing type 2 diabetes is of great interest. The German Diabetes Risk Score enables the precise prediction of the 5-year risk for developing diabetes. The updated version with additional or modified questions and the modified display of the result with the simplified paper questionnaire have a high value for the application in practice.


The biological effect of many polyphenols, such as flavonoids and lignans, is influenced by the way in which they are metabolised in the gut. Compounds that are not resorbed in the small intestine can be metabolised by bacteria in the large intestine. The bacterial transformation of bioactive polyphenols can increase or attenuate their effect. Studies have shown that isoflavonoids and phytolignans develop their full biological activity only once they have been activated by intestinal bacteria. By isolating the gut bacteria involved, researchers have successfully explained the transformation of the lignan secoisolariciresinol diglucoside (SDG) into the notably more bioactive enterolactone. A human study showed that the metabolisation of SDG depends on the individually different composition of the gut microbiota. Gut bacteria therefore influence the bioavailability and chemopreventive effectiveness of polyphenols. © Georg Thieme Verlag KG Stuttgart · New York.


Microbiome analyses have shown that genes of the carbohydrate metabolism are overrepresented in the human gut microbiome. Accordingly, gut bacteria contain a wide spectrum of enzymes that enable the breakdown of dietary fibres. The main substrates for the gut bacteria are resistant starches, followed by non-starch polysaccharides such as cellulose, hemicellulose, and pectin. During fermentation, short-chain fatty acids develop, such as acetate, propionate, and butyrate, among others. According to data from epidemiological studies, a diet rich in fibres lowers the risk of bowel cancer. In vitro studies have shown that bacterially produced butyrate may have a role in this, as it inhibits the proliferation of cancer cells and induces cell differentiation. Furthermore, the effects of short-chain fatty acids are associated with the prevention of the metabolic syndrome. Diets rich in fibre correlate with higher concentrations of the appetite-lowering hormone peptide YY (PYY) and GLP-1 (glucagon-like peptide), which has a positive effect on insulin secretion in the pancreatic cells and insulin sensitivity in the target tissues.©Georg Thieme Verlag KG Stuttgart.


Stjernschantz E.,VU University Amsterdam | Reinen J.,VU University Amsterdam | Meinl W.,Deutsches Institute For Ernahrungsforschung | George B.J.,VU University Amsterdam | And 3 more authors.
Molecular and Cellular Endocrinology | Year: 2010

It is well established that various endocrine disrupting compounds (EDCs) can inhibit human estrogen sulfotransferase (SULT1E1). In this study, we investigate murine SULT1E1 inhibition in vitro and in silico and compare this to data for the human enzyme. 34 potential EDCs were screened for their ability to inhibit both murine and human SULT1E1 and IC 50 values were determined for 14 of the inhibitory EDCs. Only estrone, dienestrol and enterolactone showed significant differences in affinity between the human and murine SULT1E1. Extensive molecular modelling was performed using molecular dynamics (MD) simulations. During the MD simulations the ligands moved away from the catalytically active position, something which was not observed when simulating the unit cell of the crystal structure. This finding suggests that catalytically inactive binding modes, other than the one observed in the crystal structures, are possible in SULT1E1. The ligands stayed longer in the catalytically active position in mSULT1E1, which is likely a result of simultaneous hydrogen bond formation on both sides of the binding pocket, which does not seem to be possible in hSULT1E1. The ligands in the human protein moved to a sub-pocket near the entrance of the active site, which offers hydrogen bond formation possibilities with Asp22 and Lys85 as well as favourable hydrophobic interactions. The ligands moved more randomly in mSULT1E1. These observations offer a possible explanation for the substrate inhibition only observed in hSULT1E1. © 2009 Elsevier Ireland Ltd. All rights reserved.


Schurmann A.,Deutsches Institute For Ernahrungsforschung
Diabetologie und Stoffwechsel | Year: 2016

Prof. Dr. Annette Schürmann received the Werner-Creutzfeld Award from the German Diabetes Assoziation in May 2016 for her outstanding contributions to improve the knowledge on the pathomechansims of type 2 diabetes. Her research focus is on the genetics and pathpyhsiology of obesity and type 2 diabetes. In this field she participated in the clarification of (1) the genetic contribution on the development of obesity and diabetes, the (2) role of ARF-GTPases on lipid storage and (3) the molecular structure and function of glucose transporters. In this article Dr. Schürmann summarizes the most important findings of her research group. Copyright © 2016, Georg Thieme Verlag KG. All rights reserved.


Since dietary fibres influence many diseases, a global view on these associations seem useful. A global view is achieved i. a. through studying mortality which summaries the general disease occurrence. Cancer and cardio-vascular diseases are the most important causes of death in Germany. Thereby, dietary fibres influence the mortality due to chronic diseases in manifold ways: With it, one can count the direct influence on cancer and cardio-vascular diseases and the indirect influence on hypertension, obesity, and type 2 diabetes. According to large studies, mortality risk is reduced with increasing intake of dietary fibre. This association is particularly seen in case of cereal fibres. Intake of dietary fibre is also inversely associated with risk for especially colorectal cancer. Dietary fibres are probably effective through local effects in the intestinal lumen as well as through metabolic effects, among others on the glucose metabolism. Inverse associations in connection with dietary fibre intake have also been observed for cardiovascular diseases such as coronary heart disease and stroke. Dietary fibres influence the occurrence of such disorders presumably by affecting blood pressure and insulin metabolism. © 2014 Georg Thieme Verlag KG Stuttgart New York.

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