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  Amorfrutin B is an efficient natural peroxisome proliferator-activated receptor gamma (PPARgamma) agonist with potent glucose-lowering properties

Weidner, C., Wowro, S. J., Freiwald, A., Kawamoto, K., Witzke, A., Kliem, M., et al. (2013). Amorfrutin B is an efficient natural peroxisome proliferator-activated receptor gamma (PPARgamma) agonist with potent glucose-lowering properties. Diabetologia, 56(8), 1802-1812. doi:10.1007/s00125-013-2920-2.

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© 2013 Springer, Part of Springer Science+Business Media
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 Creators:
Weidner, C.1, Author              
Wowro, S. J.1, Author              
Freiwald, A.1, Author              
Kawamoto, K., Author
Witzke, A.1, Author              
Kliem, M.1, Author              
Siems, K., Author
Müller-Kuhrt, L., Author
Schroeder, F. C., Author
Sauer, S.1, Author              
Affiliations:
1Nutrigenomics and Gene Regulation (Sascha Sauer), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society, Ihnestr. 73, 14195 Berlin, Germany, ou_1479662              

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Free keywords: Animals Cells, Cultured Diabetes Mellitus, Type 2/drug therapy Humans Hypoglycemic Agents/*therapeutic use Insulin Resistance/physiology Male Mice Mice, Inbred C57BL PPAR gamma/*agonists Salicylates/*therapeutic use
 Abstract: AIMS/HYPOTHESIS: The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is an important gene regulator in glucose and lipid metabolism. Unfortunately, PPARgamma-activating drugs of the thiazolidinedione class provoke adverse side effects. As recently shown, amorfrutin A1 is a natural glucose-lowering compound that selectively modulates PPARgamma. In this study we aimed to characterise, in vitro, a large spectrum of the amorfrutins and similar molecules, which we isolated from various plants. We further studied in vivo the glucose-lowering effects of the so far undescribed amorfrutin B, which featured the most striking PPARgamma-binding and pharmacological properties of this family of plant metabolites. METHODS: Amorfrutins were investigated in vitro by binding and cofactor recruitment assays and by transcriptional activation assays in primary human adipocytes and murine preosteoblasts, as well as in vivo using insulin-resistant high-fat-diet-fed C57BL/6 mice treated for 27 days with 100 mg kg(-1) day(-1) amorfrutin B. RESULTS: Amorfrutin B showed low nanomolar binding affinity to PPARgamma, and micromolar binding to the isotypes PPARalpha and PPARbeta/delta. Amorfrutin B selectively modulated PPARgamma activity at low nanomolar concentrations. In insulin-resistant mice, amorfrutin B considerably improved insulin sensitivity, glucose tolerance and blood lipid variables after several days of treatment. Amorfrutin B treatment did not induce weight gain and furthermore showed liver-protecting properties. Additionally, amorfrutins had no adverse effects on osteoblastogenesis and fluid retention. CONCLUSIONS/INTERPRETATION: The application of plant-derived amorfrutins or synthetic analogues thereof constitutes a promising approach to prevent or treat complex metabolic diseases such as insulin resistance or type 2 diabetes.

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Language(s): eng - English
 Dates: 2013-05-182013-08
 Publication Status: Published in print
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 Rev. Type: Peer
 Identifiers: DOI: 10.1007/s00125-013-2920-2
ISSN: 1432-0428 (Electronic)0012-186X (Print)
URI: http://www.ncbi.nlm.nih.gov/pubmed/23680913
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Title: Diabetologia
Source Genre: Journal
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Publ. Info: Heidelberg : Springer-Verlag Heidelberg
Pages: - Volume / Issue: 56 (8) Sequence Number: - Start / End Page: 1802 - 1812 Identifier: ISSN: 0012-186X
CoNE: https://pure.mpg.de/cone/journals/resource/954925394387