和厚朴酚
吡格列酮
罗格列酮
兴奋剂
脂肪生成
药理学
体内
过氧化物酶体增殖物激活受体
部分激动剂
化学
生物信息学
受体
内科学
内分泌学
体外
生物
生物化学
医学
糖尿病
2型糖尿病
生物技术
基因
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-Leena Vuorinen,Stefan M. Noha,Stefan Schwaiger,Judith M. Rollinger,Daniela Schuster,Hermann Stuppner,Verena M. Dirsch,Elke H. Heiss
标识
DOI:10.1016/j.bbagen.2013.06.021
摘要
Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are clinically used to counteract hyperglycemia. However, so far experienced unwanted side effects, such as weight gain, promote the search for new PPARγ activators.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 PPARγ agonists.The natural product honokiol from the traditional Chinese herbal drug Magnolia bark was in silico predicted to bind into the PPARγ ligand binding pocket as dimer. Honokiol indeed directly bound to purified PPARγ ligand-binding domain (LBD) and acted as partial agonist in a PPARγ-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.We identified honokiol as a partial non-adipogenic PPARγ agonist in vitro which prevented hyperglycemia and weight gain in vivo.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.
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