Publications by authors named "V Kodelja"

27 Publications

Lemon balm extract causes potent antihyperglycemic and antihyperlipidemic effects in insulin-resistant obese mice.

Mol Nutr Food Res 2014 Apr 24;58(4):903-7. Epub 2013 Nov 24.

Otto Warburg Laboratory, Max Planck Institute for Molecular Genetics, Berlin, Germany; Department of Biology, Chemistry, and Pharmacy, Free University of Berlin, Berlin, Germany.

Over the last decades polyetiological metabolic diseases such as obesity and type 2 diabetes have emerged as a global epidemic. Efficient strategies for prevention and treatment include dietary intervention and the development of validated nutraceuticals. Safe extracts of edible plants provide a resource of structurally diverse molecules that can effectively interfere with multifactorial diseases. In this study, we describe the application of ethanolic lemon balm (Melissa officinalis) leaves extract for the treatment of insulin-resistance and dyslipidemia in mice. We show that lemon balm extract (LBE) activates the peroxisome proliferator-activated receptors (PPARs), which have key roles in the regulation of whole body glucose and lipid metabolism. Application of LBE (0.6 mg/mL) to human primary adipocytes resulted in specific peroxisome proliferator-activated receptor target gene expression. LBE treatment of insulin-resistant high-fat diet-fed C57BL/6 mice (200 mg/kg/day) for 6 weeks considerably reduced hyperglycemia and insulin resistance, plasma triacylglycerol, nonesterified fatty acids and LDL/VLDL cholesterol levels. Taken together, ethanolic lemon balm extract can potentially be used to prevent or concomitantly treat type 2 diabetes and associated disorders such as dyslipidemia and hypercholesterolemia.
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http://dx.doi.org/10.1002/mnfr.201300477DOI Listing
April 2014

Antidiabetic effects of chamomile flowers extract in obese mice through transcriptional stimulation of nutrient sensors of the peroxisome proliferator-activated receptor (PPAR) family.

PLoS One 2013 12;8(11):e80335. Epub 2013 Nov 12.

Otto Warburg Laboratory, Max Planck Institute for Molecular Genetics, Berlin, Germany ; Department of Biology, Chemistry, and Pharmacy, Free University of Berlin, Berlin, Germany.

Given the significant increases in the incidence of metabolic diseases, efficient strategies for preventing and treating of these common disorders are urgently needed. This includes the development of phytopharmaceutical products or functional foods to prevent or cure metabolic diseases. Plant extracts from edible biomaterial provide a potential resource of structurally diverse molecules that can synergistically interfere with complex disorders. In this study we describe the safe application of ethanolic chamomile (Matricaria recutita) flowers extract (CFE) for the treatment and prevention of type 2 diabetes and associated disorders. We show in vitro that this extract activates in particular nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) and its isotypes. In a cellular context, in human primary adipocytes CFE administration (300 µg/ml) led to specific expression of target genes of PPARγ, whereas in human hepatocytes CFE-induced we detected expression changes of genes that were regulated by PPARα. In vivo treatment of insulin-resistant high-fat diet (HFD)-fed C57BL/6 mice with CFE (200 mg/kg/d) for 6 weeks considerably reduced insulin resistance, glucose intolerance, plasma triacylglycerol, non-esterified fatty acids (NEFA) and LDL/VLDL cholesterol. Co-feeding of lean C57BL/6 mice a HFD with 200 mg/kg/d CFE for 20 weeks showed effective prevention of fatty liver formation and hepatic inflammation, indicating additionally hepatoprotective effects of the extract. Moreover, CFE treatment did not reveal side effects, which have otherwise been associated with strong synthetic PPAR-targeting molecules, such as weight gain, liver disorders, hemodilution or bone cell turnover. Taken together, modulation of PPARs and other factors by chamomile flowers extract has the potential to prevent or treat type 2 diabetes and related disorders.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0080335PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3827197PMC
July 2014

Foam cell specific LXRα ligand.

PLoS One 2013 25;8(2):e57311. Epub 2013 Feb 25.

Otto Warburg Laboratory, Max Planck Institute for Molecular Genetics, Berlin, Germany.

Objective: The liver X receptor α (LXRα) is a ligand-dependent nuclear receptor and the major regulator of reverse cholesterol transport in macrophages. This makes it an interesting target for mechanistic study and treatment of atherosclerosis.

Methods And Results: We optimized a promising stilbenoid structure (STX4) in order to reach nanomolar effective concentrations in LXRα reporter-gene assays. STX4 displayed the unique property to activate LXRα effectively but not its subtype LXRβ. The potential of STX4 to increase transcriptional activity as an LXRα ligand was tested with gene expression analyses in THP1-derived human macrophages and oxLDL-loaded human foam cells. Only in foam cells but not in macrophage cells STX4 treatment showed athero-protective effects with similar potency as the synthetic LXR ligand T0901317 (T09). Surprisingly, combinatorial treatment with STX4 and T09 resulted in an additive effect on reporter-gene activation and target gene expression. In physiological tests the cellular content of total and esterified cholesterol was significantly reduced by STX4 without the undesirable increase in triglyceride levels as observed for T09.

Conclusions: STX4 is a new LXRα-ligand to study transcriptional regulation of anti-atherogenic processes in cell or ex vivo models, and provides a promising lead structure for pharmaceutical development.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057311PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3581588PMC
September 2013

Genome-wide analysis of LXRα activation reveals new transcriptional networks in human atherosclerotic foam cells.

Nucleic Acids Res 2013 Apr 7;41(6):3518-31. Epub 2013 Feb 7.

Max Planck Institute for Molecular Genetics, Ihnestraße 63-73, 14195 Berlin, Germany.

Increased physiological levels of oxysterols are major risk factors for developing atherosclerosis and cardiovascular disease. Lipid-loaded macrophages, termed foam cells, are important during the early development of atherosclerotic plaques. To pursue the hypothesis that ligand-based modulation of the nuclear receptor LXRα is crucial for cell homeostasis during atherosclerotic processes, we analysed genome-wide the action of LXRα in foam cells and macrophages. By integrating chromatin immunoprecipitation-sequencing (ChIP-seq) and gene expression profile analyses, we generated a highly stringent set of 186 LXRα target genes. Treatment with the nanomolar-binding ligand T0901317 and subsequent auto-regulatory LXRα activation resulted in sequence-dependent sharpening of the genome-binding patterns of LXRα. LXRα-binding loci that correlated with differential gene expression revealed 32 novel target genes with potential beneficial effects, which in part explained the implications of disease-associated genetic variation data. These observations identified highly integrated LXRα ligand-dependent transcriptional networks, including the APOE/C1/C4/C2-gene cluster, which contribute to the reversal of cholesterol efflux and the dampening of inflammation processes in foam cells to prevent atherogenesis.
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http://dx.doi.org/10.1093/nar/gkt034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3616743PMC
April 2013

Amorfrutins are potent antidiabetic dietary natural products.

Proc Natl Acad Sci U S A 2012 May 16;109(19):7257-62. Epub 2012 Apr 16.

Otto Warburg Laboratory, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, 14195 Berlin, Germany.

Given worldwide increases in the incidence of obesity and type 2 diabetes, new strategies for preventing and treating metabolic diseases are needed. The nuclear receptor PPARγ (peroxisome proliferator-activated receptor gamma) plays a central role in lipid and glucose metabolism; however, current PPARγ-targeting drugs are characterized by undesirable side effects. Natural products from edible biomaterial provide a structurally diverse resource to alleviate complex disorders via tailored nutritional intervention. We identified a family of natural products, the amorfrutins, from edible parts of two legumes, Glycyrrhiza foetida and Amorpha fruticosa, as structurally new and powerful antidiabetics with unprecedented effects for a dietary molecule. Amorfrutins bind to and activate PPARγ, which results in selective gene expression and physiological profiles markedly different from activation by current synthetic PPARγ drugs. In diet-induced obese and db/db mice, amorfrutin treatment strongly improves insulin resistance and other metabolic and inflammatory parameters without concomitant increase of fat storage or other unwanted side effects such as hepatoxicity. These results show that selective PPARγ-activation by diet-derived ligands may constitute a promising approach to combat metabolic disease.
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http://dx.doi.org/10.1073/pnas.1116971109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3358853PMC
May 2012
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