Unknown,Transcriptomics,Genomics,Proteomics

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Amorfrutins are selective PPARM-NM-3 agonists with potent antidiabetic properties

ABSTRACT: Faced by an alarming incidence of metabolic diseases including obesity and type 2 diabetes worldwide, there is an urgent need for effective strategies for preventing and treating these common diseases. The nuclear receptor PPARM-NM-3 (peroxisome proliferator-activated receptor gamma) plays a crucial role in metabolism. We isolated the amorfrutins from edible parts of the plants Glychyrrhiza foetida and Amorpha fruticosa, and identified these natural products as a new chemical class to treat insulin resistance and diabetes by selectively activating PPARM-NM-3. In contrast to existing synthetic PPARM-NM-3 drugs, the amorfrutins display unique properties by separating insulin sensitization from unwanted side effects. In obese mouse models, amorfrutin treatment significantly improved important metabolic and inflammatory parameters. In summary, PPARM-NM-3 activation by selective amorfrutins derived from edible biomaterial is a promising approach to combat metabolic diseases and other diseases in which PPARM-NM-3 is involved in. GSM701612-GSM701623: Male DIO C57BL/6 mice (age 18 wks), 3 groups (n=4 each after pooling of 8 samples per group). Mice were fed over 3 wks with high fat diet (HFD) without compound (vehicle), HFD with 4 mg/kg/d rosiglitazone or with 100 mg/kg/d amorfrutin 1. Liver RNA extracted. --> 4 biological replicates, vehicle vs. rosiglitazone or amorfrutin 1 GSM702299-GSM702344: Biological replicates (n = 3-4 each) of human primary adipocytes were treated with the following compounds for 24 hours. 10M-BM-5M rosiglitazone, 10M-BM-5M pioglitazone, 30M-BM-5M telmisartan, 10M-BM-5M nTZDpa, 30M-BM-5M amorfrutin 1, 30M-BM-5M amorfrutin 2, 30M-BM-5M amorfrutin 3 or 30M-BM-5M amorfrutin 4 vs. 0.1% DMSO (vehicle)

ORGANISM(S): Homo sapiens

SUBMITTER: Christopher Weidner

PROVIDER: E-GEOD-28384 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Amorfrutins are potent antidiabetic dietary natural products.

Weidner Christopher C de Groot Jens C JC Prasad Aman A Freiwald Anja A Quedenau Claudia C Kliem Magdalena M Witzke Annabell A Kodelja Vitam V Han Chung-Ting CT Giegold Sascha S Baumann Matthias M Klebl Bert B Siems Karsten K Müller-Kuhrt Lutz L Schürmann Annette A Schüler Rita R Pfeiffer Andreas F H AF Schroeder Frank C FC Büssow Konrad K Sauer Sascha S

Proceedings of the National Academy of Sciences of the United States of America 20120416 19

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 nutritio ...[more]

PMID: 22509006

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Project description:The transcription factor Peroxisome Proliferator-Activated Receptor M-NM-1 (PPARM-NM-1) is an important regulator of hepatic lipid metabolism. While PPARM-NM-1 is known to activate transcription of numerous genes, no comprehensive picture of PPARM-NM-1 binding to endogenous genes has yet been reported. To fill this gap, we performed ChIP-chip in combination with transcriptional profiling on HepG2 human hepatoma cells treated with the PPARM-NM-1 agonist GW7647. We found that GW7647 increased PPARM-NM-1 binding to 4220 binding regions. GW7647-induced binding regions showed a bias around the transcription start site and most contained a predicted PPAR binding motif. Several genes known to be regulated by PPARM-NM-1, such as ACOX1, SULT2A1, ACADL, CD36, IGFBP1 and G0S2, showed GW7647-induced PPARM-NM-1 binding to their promoter. A GW7647-induced PPARM-NM-1-binding region was also assigned to SREBP-targets HMGCS1, HMGCR, FDFT1, SC4MOL, and LPIN1, expression of which was induced by GW7647, suggesting cross-talk between PPARM-NM-1 and SREBP signaling. Our data furthermore demonstrate interaction between PPARM-NM-1 and STAT transcription factors in PPARM-NM-1-mediated transcriptional repression, and suggest interaction between PPARM-NM-1 and TBP and C/EBPM-NM-1 in PPARM-NM-1-mediated transcriptional activation. Overall, our analysis leads to important new insights into the mechanisms and impact of transcriptional regulation by PPARM-NM-1 in human liver and highlight the importance of cross-talk with other transcription factors. HepG2 cells were grown in phenol red-free DulbeccoM-bM-^@M-^Ys modified medium (DMEM) supplemented with 10% fetal bovine serum (FBS), 2 mM L-glutamine, 0.1 mg/ml streptomycin and 100 U/ml penicillin. Cells were split the day before experiments. Cells were kept at 37 M-BM-0C and 5% CO2. The following day, cells were treated with either 100 nM of the PPARM-NM-1 agonist GW7647 or control vehicle (DMSO). Cells used for gene expression analysis were harvested after 6 h or 24 h of GW7647 treatment. This submission represents the gene expression component of the study.

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Dataset Information

Amorfrutins are selective PPARM-NM-3 agonists with potent antidiabetic properties

Publications

Amorfrutins are potent antidiabetic dietary natural products.

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