- 作者：Atanas G. Atanasov ; Jian N. Wang ; Shi P. Gu ; Jing Bu ; Matthias P. Kramer ; Lisa Baumgartner ; Nanang Fakhrudin ; Angela Ladurner ; Clemens Malainer ; Anna Vuorinen ; Stefan M. Noha ; Stefan Schwaiger ; Judith M. Rollinger ; Daniela Schuster ; Hermann Stuppner ; Verena M. Dirsch ; Elke H. Heiss
- 关键词：AMPK ; AMP-activated kinase ; ANOVA ; analysis of variance ; ATCC ; American type culture collection ; BADGE ; bisphenol A diglycidyl ether ; BMP ; bone morphogenic protein 4 ; BSA ; bovine serum albumin ; CMCNa ; sodium carboxymethyl cellulose ; DMEM ; Dulbecco's modif
- 刊名：Biochimica et Biophysica Acta (BBA)/General Subjects
- 出版年：2013
- 出版时间：October, 2013
- 年：2013
- 卷：1830
- 期：10
- 页码：4813-4819
- 全文大小：713 K
Background
Peroxisome proliferator-activated receptor gamma (PPAR¦Ã) agonists are clinically used to counteract hyperglycemia. However, so far experienced unwanted side effects, such as weight gain, promote the search for new PPAR¦Ã activators.Methods
We used a combination of in silico, in vitro, cell-based and in vivo models to identify and validate natural products as promising leads for partial novel PPAR¦Ã agonists.
Results
The natural product honokiol from the traditional Chinese herbal drug Magnolia bark was in silico predicted to bind into the PPAR¦Ã ligand binding pocket as dimer. Honokiol indeed directly bound to purified PPAR¦Ã ligand-binding domain (LBD) and acted as partial agonist in a PPAR¦Ã-mediated luciferase reporter assay. Honokiol was then directly compared to the clinically used full agonist pioglitazone with regard to stimulation of glucose uptake in adipocytes as well as adipogenic differentiation in 3T3-L1 pre-adipocytes and mouse embryonic fibroblasts. While honokiol stimulated basal glucose uptake to a similar extent as pioglitazone, it did not induce adipogenesis in contrast to pioglitazone. In diabetic KKAy mice oral application of honokiol prevented hyperglycemia and suppressed weight gain.
Conclusion
We identified honokiol as a partial non-adipogenic PPAR¦Ã agonist in vitro which prevented hyperglycemia and weight gain in vivo.
General significance
This observed activity profile suggests honokiol as promising new pharmaceutical lead or dietary supplement to combat metabolic disease, and provides a molecular explanation for the use of Magnolia in traditional medicine.